Effects of environmental enrichment on behavioral and spatial cognitive deficits in morphine-dependent and -withdrawn rats.

PubMed

Hammami-Abrand Abadi, Arezoo; Miladi-Gorji, Hossein

2017-02-01

This study was designed to examine the effect of environmental enrichment during morphine dependence and withdrawal on morphine-induced behavioral and spatial cognitive disorders in morphine-withdrawn rats. Adult male Wistar rats (190 ± 20 g) were injected with bi-daily doses (10 mg/kg, 12 h intervals) of morphine for 14 days. Rats were reared in SE or EE during the development of dependence on morphine and withdrawal. Then, rats were tested for spatial learning and memory (the water maze), spontaneous withdrawal signs, and grooming behavior. We found that the EE blocked chronic morphine-induced partial impairments of spatial memory retention. Moreover, the EE diminished the occurrence of spontaneous morphine withdrawal signs as mild and the self-grooming behavior. Our findings showed that EE ameliorates chronic morphine-induced partial deficits of spatial cognition, obsessive-like behavior, and the overall severity of the morphine withdrawal. Thus, environmental enrichment may be a potential therapeutic strategy for spatial memory and behavioral deficits in morphine-dependent individuals.

Rational use and effectiveness of morphine in the palliative care of cancer patients at the Ocean Road Cancer Institute in Dar es Salaam, Tanzania.

PubMed

Kamuhabwa, A; Ezekiel, D

2009-10-01

Morphine and other opioids is the mainstay of cancer pain management. However, considerable fears surrounding their use present barriers to pain control. The aim of this study was to assess the rational use and effectiveness of morphine for management of pain in the palliative care of cancer patients at Ocean Road Cancer Institute (ORCI) in Tanzania. A total of 100 cancer patients who were receiving morphine therapy at the ORCI were interviewed to get information on morphine use. In addition, information on the prescribed doses of morphine was obtained from medical records of 200 patients who have used morphine from September 2005 to April 2006. Both outpatients and inpatients with advanced cancer who were receiving morphine for palliative care were involved. Seven (7) palliative caregivers, including two doctors, two nurses, a pharmacist, a pharmaceutical technician and a social worker were also interviewed. Of the 100 interviewees, 37% were aware of morphine. The level of education and duration of therapy had an impact on the awareness. The results also showed that oral morphine solution was the most common route (96%) of administration. Fifty-seven percent of the patients described the doses of morphine given to be effective in relieving their pain. Although most patients (79%) experienced morphine-induced side effects, the majority (93%) were continuing with the therapy. There were no indication of irrational use of morphine and morphine-induced side effects were well managed. The majority of patients and caregivers had positive attitude towards the use of morphine. In conclusion, the study revealed that the use of morphine is acceptable among a large proportion of patients receiving palliative care and that the majority of them find the doses given effective to relieve their pain.

Effects of Repeated Morphine on Intracranial Self-Stimulation in Male Rats In the Absence or Presence of a Noxious Pain Stimulus

PubMed Central

Miller, Laurence L.; Altarifi, Ahmad A.; Negus, S. Stevens

2015-01-01

Research on opioid analgesics such as morphine suggests that expression of abuse-related effects increases with repeated exposure. Repeated exposure to opioids often occurs clinically in the context of pain management, and a major concern for clinicians is the risk of iatrogenic addiction and dependence in patients receiving opioids for treatment of pain. This study compared abuse-related morphine effects in male rats in an intracranial self-stimulation (ICSS) procedure after repeated treatment either with morphine alone or with morphine in combination with a repeated noxious stimulus (intraperitoneal administration of dilute acid). The study also permitted comparison of morphine potency and effectiveness to block acid-induced depression of ICSS (antinociception) and to produce enhanced facilitation of ICSS (abuse-related effect). There were three main findings. First, initial morphine exposure to drug naïve rats did not produce abuse-related ICSS facilitation. Second, repeated daily treatment with 3.2 mg/kg/day morphine for six days increased expression of ICSS facilitation. This occurred whether morphine was administered in the absence or presence of the noxious stimulus. Finally, a lower dose of 1.0 mg/kg/day morphine was sufficient to produce antinociception during repeated acid treatment, but this lower dose did not reliably increase abuse-related morphine effects. Taken together, these results suggest that prior morphine exposure can increase abuse liability of subsequent morphine treatments even when that morphine exposure occurs in the context of a pain state. However, it may be possible to relieve pain with relatively low morphine doses that do not produce increases in abuse-related morphine effects. PMID:26375515

Effects of repeated morphine on intracranial self-stimulation in male rats in the absence or presence of a noxious pain stimulus.

PubMed

Miller, Laurence L; Altarifi, Ahmad A; Negus, S Stevens

2015-10-01

Research on opioid analgesics such as morphine suggests that expression of abuse-related effects increases with repeated exposure. Repeated exposure to opioids often occurs clinically in the context of pain management, and a major concern for clinicians is the risk of iatrogenic addiction and dependence in patients receiving opioids for treatment of pain. This study compared abuse-related morphine effects in male rats in an intracranial self-stimulation (ICSS) procedure after repeated treatment either with morphine alone or with morphine in combination with a repeated noxious stimulus (intraperitoneal administration of dilute acid). The study also permitted comparison of morphine potency and effectiveness to block acid-induced depression of ICSS (antinociception) and to produce enhanced facilitation of ICSS (abuse-related effect). There were 3 main findings. First, initial morphine exposure to drug naïve rats did not produce abuse-related ICSS facilitation. Second, repeated daily treatment with 3.2 mg/kg/day morphine for 6 days increased expression of ICSS facilitation. This occurred whether morphine was administered in the absence or presence of the noxious stimulus. Finally, a lower dose of 1.0 mg/kg/day morphine was sufficient to produce antinociception during repeated acid treatment, but this lower dose did not reliably increase abuse-related morphine effects. Taken together, these results suggest that prior morphine exposure can increase abuse liability of subsequent morphine treatments even when that morphine exposure occurs in the context of a pain state. However, it may be possible to relieve pain with relatively low morphine doses that do not produce increases in abuse-related morphine effects. (c) 2015 APA, all rights reserved).

Social influences on morphine conditioned place preference in adolescent mice.

PubMed

Cole, Shannon L; Hofford, Rebecca S; Evert, Daniel J; Wellman, Paul J; Eitan, Shoshana

2013-03-01

Social/peer influences are among the strongest predictors of adolescent drug use. However, this important subject does not get much attention in pre-clinical studies. We recently observed that exposure to different social partners modulates morphine locomotor sensitization. Sensitivity to the hyper-locomotor response of drugs of abuse is a predictor of sensitivity to other drug-induced behaviors. Thus, this study examined how exposure to different social partners affected the rewarding properties of morphine. All animals were group-housed four per cage in one of two conditions referred to as 'only' and 'cage-mates'. In the mixed treatment condition, morphine- and saline-treated mice were housed together. These groups are referred to as 'morphine cage-mates' and 'saline cage-mates', respectively. In the separated treatment conditions, all mice in the cage received morphine (i.e. 'morphine only') or saline (i.e. 'saline only'), and cages were visually separated from each other. All animals were subsequently individually tested for the acquisition of morphine conditioned place preference (CPP) following one conditioning session with 10, 20 or 40 mg/kg morphine or saline. As expected, one conditioning session established morphine CPP in the morphine only animals, but not in the saline only animals. Notably, morphine CPP was not acquired by the morphine cage-mate animals. Additionally, 40 mg/kg morphine was sufficient to establish morphine CPP in the saline cage-mate animals. These results indicate that social environment has an effect on the rewarding properties of morphine. It suggests that exposure to different peers can alter the abuse potential of opioids and potentially other illicit drugs. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

Midazolam Exacerbates Morphine Tolerance and Morphine-induced Hyperactive Behaviors in Young Rats with Burn Injury

PubMed Central

Song, Li; Wang, Shuxing; Zuo, Yunxia; Chen, Lucy; Martyn, Jeevendra A.; Mao, Jianren

2014-01-01

Midazolam and morphine are often used in pediatric intensive care unit (ICU) for analgesia and sedation. However, how these two drugs interact behaviorally remains unclear. Here, we examined whether 1) co-administration of midazolam with morphine would exacerbate morphine tolerance and morphine-induced hyperactive behaviors, and 2) protein kinase C (PKC) would contribute to these behavioral changes. Male rats of 3 to 4 weeks old were exposed to a hindpaw burn injury. In Experiment 1, burn-injured young rats received once daily saline or morphine (10 mg/kg, subcutaneous, s.c.), followed 30 min later by either saline or midazolam (2 mg/kg, intraperitoneal, i.p.), for 14 days beginning 3 days after burn injury. In Experiment 2, young rats with burn injury were administered with morphine (10 mg/kg, s.c.), midazolam (2 mg/kg, i.p.), and chelerythrine chloride (a non-specific PKC inhibitor 10 nmol, intrathecal) for 14 days. For both experiments, cumulative morphine anti-nociceptive dose-response (ED50) was tested and hyperactive behaviors such as jumping and scratching were recorded. Following 2 weeks of each treatment, ED50 dose was significantly increased in rats receiving morphine alone as compared with rats receiving saline or midazolam alone. The ED50 dose was further increased in rats receiving both morphine and midazolam. Co-administration of morphine and midazolam also exacerbated morphine-induced hyperactive behaviors. Expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and PKCγ in the spinal cord dorsal horn (immunohistochemistry; Western blot) was upregulated in burn-injured young rats receiving morphine alone or in combination with midazolam, and chelerythrine prevented the development of morphine tolerance. These results indicate that midazolam exacerbated morphine tolerance through a spinal NMDA/PKC-mediated mechanism. PMID:24713351

The γ-aminobutyric acid type B (GABAB) receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens.

PubMed

Fu, Zhenyu; Yang, Hongfa; Xiao, Yuqiang; Zhao, Gang; Huang, Haiyan

2012-07-10

Repeated morphine exposure can induce behavioral sensitization. There are evidences have shown that central gamma-aminobutyric acid (GABA) system is involved in morphine dependence. However, the effect of a GABAB receptor agonist baclofen on morphine-induced behavioral sensitization in rats is unclear. We used morphine-induced behavioral sensitization model in rat to investigate the effects of baclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleus accumbens was evaluated using microdialysis assay in vivo. The present study demonstrated that morphine challenge (3 mg/kg, s.c.) obviously enhanced the locomotor activity following 4-day consecutive morphine administration and 3-day withdrawal period, which indicated the expression of morphine sensitization. In addition, chronic treatment with baclofen (2.5, 5 mg/kg) significantly inhibited the development of morphine sensitization. It was also found that morphine challenge 3 days after repeated morphine administration produced a significant increase of extracellular dopamine release in nucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopamine release induced by morphine challenge. Our results indicated that gamma-aminobutyric acid system plays an important role in the morphine sensitization in rat and suggested that behavioral sensitization is a promising model to study the mechanism underlying drug abuse.

Treadmill exercise attenuates the severity of physical dependence, anxiety, depressive-like behavior and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment.

PubMed

Alizadeh, Maryam; Zahedi-Khorasani, Mahdi; Miladi-Gorji, Hossein

2018-05-30

This study was designed to examine whether treadmill exercise would attenuate the severity of physical dependence, methadone-induced anxiety, depression and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment (MMT). The rats were chronically treated with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 14 days. The exercising rats receiving MMT were forced to run on a motorized treadmill for 30 days during morphine withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that naloxone- precipitated opioid withdrawal signs were decreased in exercising morphine-dependent rats receiving MMT than sedentary rats. Also, the exercising morphine-dependent rats receiving MMT exhibited an increased time on open arms, preference for sucrose and a lower morphine preference ratio than sedentary rats. We conclude that treadmill exercise decreased the severity of physical dependence, anxiety/depressive-like behaviors and also the voluntary morphine consumption in morphine withdrawn rats receiving MMT. Thus, exercise may benefit in the treatment of addicts during MMT. Copyright © 2018. Published by Elsevier B.V.

Systemic morphine blocks the seizures induced by intracerebroventricular (i.c.v.) injections of opiates and opioid peptides.

PubMed

Urca, G; Frenk, H

1982-08-19

Intracerebroventricular (i.c.v.) injections of the endorphins and of morphine in rats produce highly characteristic, naloxone sensitive, electrographic seizures. In contrast, systemic injections of morphine have been shown to exert a marked anticonvulsant effect. The present study demonstrates that systemic morphine pretreatment can prevent the occurrence of electrographic seizures injected by i.c.v. morphine, Leu-enkephalin and beta-endorphin and that the anti-epileptic effect of morphine can be reversed by naloxone. Male albino rats, previously prepared for chronic i.c.v. injections and EEG recordings, were pretreated with 0--100 mg/kg of intraperitoneal (i.p.) morphine. Thirty five minutes later morphine (520 nmol), Leu-enkephalin (80 nmol) or beta-endorphin (5 nmol) were injected i.c.v. Pretreatment with i.p. morphine blocked the occurrence of seizures induced by morphine and both endogenous opioids. Lower doses of systemic morphine (50 mg/kg) were necessary to block i.c.v. morphine seizures than the dose (100 mg/kg) necessary to block seizures induced by i.c.v. Leu-enkephalin and beta-endorphin. Naloxone (1 mg/kg) administered 25 min following 50 mg/kg of i.p. morphine and preceding the injections of i.c.v. morphine reversed the antiepileptic effect of systemic morphine. These results demonstrate the possible existence of two opiate sensitive systems, one with excitatory-epileptogenic effects and the other possessing inhibitory-antiepileptic properties. The possible relationship between these findings and the known heterogeneity of opiate receptors and opiate actions is discussed.

Lubiprostone Reverses the Inhibitory Action of Morphine on Intestinal Secretion in Guinea Pig and Mouse

PubMed Central

Fei, Guijun; Raehal, Kirsten; Liu, Sumei; Qu, Mei-Hua; Sun, Xiaohong; Wang, Guo-Du; Wang, Xi-Yu; Xia, Yun; Schmid, Cullen L.; Bohn, Laura M.

2010-01-01

Lubiprostone activates ClC-2 chloride channels in epithelia. It is approved for treatment of chronic idiopathic constipation in adults and constipation-predominate irritable bowel syndrome in women. We tested a hypothesis that lubiprostone can reverse the constipating action of morphine and investigated the mechanism of action. Short-circuit current (Isc) was recorded in Ussing chambers as a marker for chloride secretion during pharmacological interactions between morphine and lubiprostone. Measurements of fecal wet weight were used to obtain information on morphine-lubiprostone interactions in conscious mice. Morphine decreased basal Isc, with an IC50 of 96.1 nM. The action of dimethylphenylpiperazinium (DMPP), a nicotinic receptor agonist that stimulates neurogenic Isc, was suppressed by morphine. Lubiprostone applied after pretreatment with morphine reversed morphine suppression of both basal Isc and DMPP-evoked chloride secretion. Electrical field stimulation (EFS) of submucosal neurons evoked biphasic increases in Isc. Morphine abolished the first phase and marginally suppressed the second phase. Lubiprostone reversed, in concentration-dependent manner, the action of morphine on the first and second phases of the EFS-evoked responses. Subcutaneous lubiprostone increased fecal wet weight and numbers of pellets expelled. Morphine significantly reduced fecal wet weight and number of pellets. Injection of lubiprostone, 30-min after morphine, reversed morphine-induced suppression of fecal wet weight. We conclude that inhibitory action of morphine on chloride secretion reflects suppression of excitability of cholinergic secretomotor neurons in the enteric nervous system. Lubiprostone, which does not directly affect enteric neurons, bypasses the neurogenic constipating effects of morphine by directly opening chloride channels in the mucosal epithelium. PMID:20406855

Lubiprostone reverses the inhibitory action of morphine on intestinal secretion in guinea pig and mouse.

PubMed

Fei, Guijun; Raehal, Kirsten; Liu, Sumei; Qu, Mei-Hua; Sun, Xiaohong; Wang, Guo-Du; Wang, Xi-Yu; Xia, Yun; Schmid, Cullen L; Bohn, Laura M; Wood, Jackie D

2010-07-01

Lubiprostone activates ClC-2 chloride channels in epithelia. It is approved for treatment of chronic idiopathic constipation in adults and constipation-predominate irritable bowel syndrome in women. We tested a hypothesis that lubiprostone can reverse the constipating action of morphine and investigated the mechanism of action. Short-circuit current (Isc) was recorded in Ussing chambers as a marker for chloride secretion during pharmacological interactions between morphine and lubiprostone. Measurements of fecal wet weight were used to obtain information on morphine-lubiprostone interactions in conscious mice. Morphine decreased basal Isc, with an IC(50) of 96.1 nM. The action of dimethylphenylpiperazinium (DMPP), a nicotinic receptor agonist that stimulates neurogenic Isc, was suppressed by morphine. Lubiprostone applied after pretreatment with morphine reversed morphine suppression of both basal Isc and DMPP-evoked chloride secretion. Electrical field stimulation (EFS) of submucosal neurons evoked biphasic increases in Isc. Morphine abolished the first phase and marginally suppressed the second phase. Lubiprostone reversed, in concentration-dependent manner, the action of morphine on the first and second phases of the EFS-evoked responses. Subcutaneous lubiprostone increased fecal wet weight and numbers of pellets expelled. Morphine significantly reduced fecal wet weight and number of pellets. Injection of lubiprostone, 30-min after morphine, reversed morphine-induced suppression of fecal wet weight. We conclude that inhibitory action of morphine on chloride secretion reflects suppression of excitability of cholinergic secretomotor neurons in the enteric nervous system. Lubiprostone, which does not directly affect enteric neurons, bypasses the neurogenic constipating effects of morphine by directly opening chloride channels in the mucosal epithelium.

Detection and identification of 2-nitro-morphine and 2-nitro-morphine-6-glucuronide in nitrite adulterated urine specimens containing morphine and its glucuronides.

PubMed

Luong, Susan; Fu, Shanlin

2014-03-01

In vitro urine adulteration is a well-documented practice adopted by individuals aiming to evade detection of drug use, when required to undergo mandatory sports and workplace drug testing. Potassium nitrite is an effective urine adulterant due to its oxidizing potential, and has been shown to mask the presence of many drugs of abuse. However, limited research has been conducted to understand its mechanism of action, and to explore the possibility of the drugs undergoing direct oxidation to form stable reaction products. In this study, opiates including morphine, codeine, morphine-3-glucuronide and morphine-6-glucuronide were exposed to potassium nitrite in water and urine to mimic the process of nitrite adulteration. It was found that two stable reaction products were detected by liquid chromatography-mass spectrometry (LC-MS) when morphine and morphine-6-glucuronide were exposed to nitrite. Isolation and elucidation using spectrometric and spectroscopic techniques revealed that they were 2-nitro-morphine and 2-nitro-morphine-6-glucuronide, respectively. These reaction products were also formed when an authentic morphine-positive urine specimen was fortified with nitrite. 2-Nitro-morphine was found to be stable enough to undergo the enzymatic hydrolysis procedure and also detectable by gas chromatography-mass spectrometry (GC-MS) after forming a trimethylsilyl derivative. On the contrary, morphine-3-glucuronide did not appear to be chemically manipulated when exposed to potassium nitrite in urine. These reaction products are not endogenously produced, are relatively stable and can be monitored with both LC-MS and GC-MS confirmatory techniques. As a result, these findings have revealed the possibility for the use of 2-nitro-morphine and 2-nitro-morphine-6-glucuronide as markers for the indirect monitoring of morphine and morphine-6-glucuronide in urine specimens adulterated with nitrite. Copyright © 2013 John Wiley & Sons, Ltd.

Phosphoproteomics and Bioinformatics Analyses of Spinal Cord Proteins in Rats with Morphine Tolerance

PubMed Central

Liaw, Wen-Jinn; Tsao, Cheng-Ming; Huang, Go-Shine; Wu, Chin-Chen; Ho, Shung-Tai; Wang, Jhi-Joung; Tao, Yuan-Xiang; Shui, Hao-Ai

2014-01-01

Introduction Morphine is the most effective pain-relieving drug, but it can cause unwanted side effects. Direct neuraxial administration of morphine to spinal cord not only can provide effective, reliable pain relief but also can prevent the development of supraspinal side effects. However, repeated neuraxial administration of morphine may still lead to morphine tolerance. Methods To better understand the mechanism that causes morphine tolerance, we induced tolerance in rats at the spinal cord level by giving them twice-daily injections of morphine (20 µg/10 µL) for 4 days. We confirmed tolerance by measuring paw withdrawal latencies and maximal possible analgesic effect of morphine on day 5. We then carried out phosphoproteomic analysis to investigate the global phosphorylation of spinal proteins associated with morphine tolerance. Finally, pull-down assays were used to identify phosphorylated types and sites of 14-3-3 proteins, and bioinformatics was applied to predict biological networks impacted by the morphine-regulated proteins. Results Our proteomics data showed that repeated morphine treatment altered phosphorylation of 10 proteins in the spinal cord. Pull-down assays identified 2 serine/threonine phosphorylated sites in 14-3-3 proteins. Bioinformatics further revealed that morphine impacted on cytoskeletal reorganization, neuroplasticity, protein folding and modulation, signal transduction and biomolecular metabolism. Conclusions Repeated morphine administration may affect multiple biological networks by altering protein phosphorylation. These data may provide insight into the mechanism that underlies the development of morphine tolerance. PMID:24392096

Extending Time Profile of Morphine-Induced Analgesia Using a Chitosan-Based Molecular Imprinted Polymer Nanogel.

PubMed

Hassanzadeh, Marjan; Ghaemy, Mousa; Ahmadi, Shamseddin

2016-10-01

Chitosan-based molecular imprinted polymer (CS-MIP) nanogel is prepared in the presence of morphine template, fully characterized and used as a new vehicle to extend duration of morphine analgesic effect in Naval Medical Research Institute mice. The CS-MIP nanogel with ≈25 nm size range exhibits 98% loading efficiency, and in vitro release studies show an initial burst followed by an extended slow release of morphine. In order to study the feasibility of CS-MIP nanogel as morphine carrier, 20 mice are divided into two groups randomly and received subcutaneous injection of morphine-loaded CS-MIP and morphine (10 mg kg -1 ) dissolved in physiologic saline. Those received injection of morphine-loaded CS-MIP show slower and long lasting release of morphine with 193 min effective time of 50% (ET50) analgesia compared to 120 min ET50 in mice received morphine dissolved in physiologic saline. These results suggest that CS-MIP nanogel can be a possible strategy as morphine carrier for controlled release and extension of its analgesic efficacy. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The gamma-aminobutyric acid type B (GABAB) receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens

PubMed Central

2012-01-01

Background Repeated morphine exposure can induce behavioral sensitization. There are evidences have shown that central gamma-aminobutyric acid (GABA) system is involved in morphine dependence. However, the effect of a GABAB receptor agonist baclofen on morphine-induced behavioral sensitization in rats is unclear. Methods We used morphine-induced behavioral sensitization model in rat to investigate the effects of baclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleus accumbens was evaluated using microdialysis assay in vivo. Results The present study demonstrated that morphine challenge (3 mg/kg, s.c.) obviously enhanced the locomotor activity following 4-day consecutive morphine administration and 3-day withdrawal period, which indicated the expression of morphine sensitization. In addition, chronic treatment with baclofen (2.5, 5 mg/kg) significantly inhibited the development of morphine sensitization. It was also found that morphine challenge 3 days after repeated morphine administration produced a significant increase of extracellular dopamine release in nucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopamine release induced by morphine challenge. Conclusions Our results indicated that gamma-aminobutyric acid system plays an important role in the morphine sensitization in rat and suggested that behavioral sensitization is a promising model to study the mechanism underlying drug abuse. PMID:22559224

Amnesia induced by morphine in spatial memory retrieval inhibited in morphine-sensitized rats.

PubMed

Farahmandfar, Maryam; Naghdi, Nasser; Karimian, Seyed Morteza; Kadivar, Mehdi; Zarrindast, Mohammad-Reza

2012-05-15

The present study investigated the effect of morphine sensitization on the impairment of spatial memory retrieval induced by acute morphine in adult male rats. Spatial memory was assessed by 2-day Morris water maze task which included training and test day. On the training day, rats were trained by a single training session of 8 trials. On the test day, a probe trial consisting of 60s free swim period without a platform and the visible test were administered. Morphine sensitization was induced by subcutaneous (s.c.) injection of morphine, once daily for 3 days followed by 5 days without drug treatment before training. The results indicated that acute administration of morphine (7.5mg/kg, s.c.) before testing impaired spatial memory on the test day. Pre-test morphine-induced amnesia decreased in morphine-sensitized (15 and 20mg/kg, s.c.) rats. Improvement in spatial memory retrieval in morphine-sensitized rats was inhibited by once daily administration of naloxone (1 and 2mg/kg, s.c.) 30 min prior to the injection of morphine for three days. The results suggest that morphine sensitization reverses the impairment of spatial memory retrieval induced by acute morphine and it is implied that mu-opioid receptors may play an important role in this effect. Copyright © 2012 Elsevier B.V. All rights reserved.

Abuse-deterrent features of an extended-release morphine drug product developed using a novel injection-molding technology for oral drug delivery.

PubMed

Skak, Nikolaj; Elhauge, Torben; Dayno, Jeffrey M; Lindhardt, Karsten

A novel technology platform (Guardian™ Technology, Egalet Corporation, Wayne, PA) was used to manufacture morphine abuse-deterrent (AD), extended-release (ER), injection-molded tablets (morphine-ADER-IMT; ARYMO® ER [morphine sulfate] ER tablets; Egalet Corporation), a recently approved morphine product with AD labeling. The aim of this article is to highlight how the features of Guardian™ Technology are linked to the ER profile and AD characteristics of morphine-ADER-IMT. The ER profile of morphine-ADER-IMT is attributed to the precise release of morphine from the polymer matrix. The approved dosage strengths of morphine-ADER-IMT are bioequivalent to corresponding dosage strengths of morphine ER (MS Contin®; Purdue Pharma LP, Stamford, CT). Morphine-ADER-IMT was very resistant to physical manipulations intended to reduce particle size, with <10 percent of particles being reduced to <500µm, regarded by the US Food and Drug Administration as a relevant cutoff for potential insufflation in their generic solid oral AD opioid guidance. Furthermore, morphine was not readily extracted from the polymer matrix of morphine-ADER-IMT in small- or large-volume solvent extraction studies that evaluated the potential for intravenous and oral abuse. The ER profile and AD characteristics of morphine-ADER-IMT are a result of Guardian™ Technology. The combination of the polyethylene oxide matrix and the use of injection molding differentiate morphine-ADER-IMT from other approved AD opioids that deter abuse using physical and chemical barriers. The high degree of flexibility of the Guardian™ Technology enables the development of products that can be tailored to almost any desired release profile; as such, it is a technology platform that may be useful for the development of a wide range of pharmaceutical products.

Role of dorsal hippocampal orexin-1 receptors in memory restoration induced by morphine sensitization phenomenon.

PubMed

Alijanpour, S; Tirgar, F; Zarrindast, M-R

2016-01-15

The present study was examined the blockade of CA1 orexin-1 receptors (OX1Rs) of the dorsal hippocampus in the induction or expression phase on morphine sensitization-induced memory restoration using the Morris water maze (MWM) apparatus. Results showed that pre-training administration of morphine (5mg/kg, s.c.) increases escape latency and traveled distance, while does not alter swimming speed. This supports the impairing effect of morphine on the spatial memory acquisition in male adult rats. Also, in the retrieval session (probe trial) this treatment decreased the time spent in the target quadrant. Moreover, morphine-induced sensitization (15 or 20mg/kg, s.c.; once daily for 3days and followed by 5days no drug treatment) restored the memory acquisition/retrieval deficit which had been induced by pre-training administration of morphine (5mg/kg, s.c.). Intra-CA1 microinjection of subthreshold doses of SB-334867 (OX1Rs antagonist; 10, 20 and 40nmol/rat), 5min before morphine (20mg/kg/day×3days, s.c.; induction phase for morphine sensitization) did not alter restoration of memory acquisition/retrieval produced by the morphine sensitization phenomenon. In contrast, microinjection of subthreshold doses of SB-334867 (10, 20 and 40nmol/rat) into the CA1 region in the training session, 5min prior to morphine (5mg/kg, s.c.; expression phase for morphine sensitization) blocked the spatial memory acquisition/retrieval in morphine-sensitized rats. In conclusion, these findings show that morphine sensitization reverses morphine-induced amnesia. Furthermore, the blockade of CA1 OX1Rs in the expression phase, but not in the induction phase, disrupts memory restoration induced by morphine sensitization. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Persistent Pain Maintains Morphine-Seeking Behavior after Morphine Withdrawal through Reduced MeCP2 Repression of Glua1 in Rat Central Amygdala

PubMed Central

Hou, Yuan-Yuan; Cai, You-Qing

2015-01-01

As long-term opioids are increasingly used for control of chronic pain, how pain affects the rewarding effect of opioids and hence risk of prescription opioid misuse and abuse remains a healthcare concern and a challenging issue in current pain management. In this study, using a rat model of morphine self-administration, we investigated the molecular mechanisms underlying the impact of pain on operant behavior of morphine intake and morphine seeking before and after morphine withdrawal. We found that rats with persistent pain consumed a similar amount of daily morphine to that in control rats without pain, but maintained their level-pressing behavior of morphine seeking after abstinence of morphine at 0.2 mg/kg, whereas this behavior was gradually diminished in control rats. In the central nucleus of amygdala (CeA), a limbic structure critically involved in the affective dimension of pain, proteins of GluA1 subunits of glutamate AMPA receptors were upregulated during morphine withdrawal, and viral knockdown of CeA GluA1 eliminated the morphine-seeking behavior in withdrawn rats of the pain group. Chromatin immunoprecipitation analysis revealed that the methyl CpG-binding protein 2 (MeCP2) was enriched in the promoter region of Gria1 encoding GluA1 and this enrichment was significantly attenuated in withdrawn rats of the pain group. Furthermore, viral overexpression of CeA MeCP2 repressed the GluA1 level and eliminated the maintenance of morphine-seeking behavior after morphine withdrawal. These results suggest direct MeCp2 repression of GluA1 function as a likely mechanism for morphine-seeking behavior maintained by long-lasting affective pain after morphine withdrawal. PMID:25716866

Involvement of peripheral mechanism in the verapamil-induced potentiation of morphine analgesia in mice.

PubMed

Shimizu, Norifumi; Kishioka, Shiroh; Maeda, Takehiko; Fukazawa, Yohji; Dake, Yoshihiro; Yamamoto, Chizuko; Ozaki, Masanobu; Yamamoto, Hiroyuki

2004-08-01

Morphine's analgesic actions are thought to be mediated through both the central and peripheral nervous systems. L-type calcium channel blockers have been reported to potentiate the analgesic effects of morphine, but the locus of this interaction is not known. In this experiment, we examined the site of verapamil-induced potentiation of morphine analgesia in mice using the quaternary opioid receptor antagonist naloxone-methiodide (NLX-M). Subcutaneous injections of morphine increased locomotor activity and serum corticosterone level, which are mediated by the central nervous system. These central effects were not antagonized by 0.1 mg/kg of NLX-M, whereas this dose of NLX-M partially antagonized the analgesic effect of morphine. Treatment with verapamil potentiated morphine analgesia in a dose-dependent manner. The verapamil-induced potentiation of morphine analgesia was abolished by pretreatment with NLX-M (0.1 and 1 mg/kg). These findings suggest that peripheral mechanisms partially contribute to morphine analgesia and mediate the potentiation of morphine analgesia by verapamil.

Supraspinally administered agmatine prevents the development of supraspinal morphine analgesic tolerance.

PubMed

Kitto, Kelley F; Fairbanks, Carolyn A

2006-04-24

We have determined the effect of intracerebroventricularly (i.c.v.) administered decarboxylated arginine (agmatine) on supraspinally induced chronic morphine analgesic tolerance. Mice pre-treated with a schedule of chronic i.c.v administration of morphine (10 nmol, b.i.d. 3 days) show a 12-fold reduction in the potency of acutely administered i.c.v morphine compared to saline injected controls. Co-administration of agmatine (10 nmol) with one of the two daily morphine injections completely prevents the reduction in i.c.v morphine analgesia. Mice injected with agmatine once daily (but no morphine) do not show a increase in morphine analgesic potency relative to saline controls, indicating that a mere potentiation of acute morphine analgesia cannot account for the agmatine-mediated anti-tolerance effect in those mice subjected to the morphine tolerance induction schedule. These observations agree with previous reports that systemically and intrathecally administered agmatine prevent opioid tolerance, and extend these results to include a supraspinal site of action.

Mitochondrial events responsible for morphine's cardioprotection against ischemia/reperfusion injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

He, Haiyan; Department of Pharmacology, Tianjin Medical University, Tianjin 300070; Huh, Jin

Morphine may induce cardioprotection by targeting mitochondria, but little is known about the exact mitochondrial events that mediate morphine's protection. We aimed to address the role of the mitochondrial Src tyrosine kinase in morphine's protection. Isolated rat hearts were subjected to 30 min ischemia and 2 h of reperfusion. Morphine was given before the onset of ischemia. Infarct size and troponin I release were measured to evaluate cardiac injury. Oxidative stress was evaluated by measuring mitochondrial protein carbonylation and mitochondrial ROS generation. HL-1 cells were subjected to simulated ischemia/reperfusion and LDH release and mitochondrial membrane potential (ΔΨm) were measured. Morphinemore » reduced infarct size as well as cardiac troponin I release which were aborted by the selective Src tyrosine kinase inhibitors PP2 and Src-I1. Morphine also attenuated LDH release and prevented a loss of ΔΨm at reperfusion in a Src tyrosine kinase dependent manner in HL-1 cells. However, morphine failed to reduce LDH release in HL-1 cells transfected with Src siRNA. Morphine increased mitochondrial Src phosphorylation at reperfusion and this was abrogated by PP2. Morphine attenuated mitochondrial protein carbonylation and mitochondrial superoxide generation at reperfusion through Src tyrosine kinase. The inhibitory effect of morphine on the mitochondrial complex I activity was reversed by PP2. These data suggest that morphine induces cardioprotection by preventing mitochondrial oxidative stress through mitochondrial Src tyrosine kinase. Inhibition of mitochondrial complex I at reperfusion by Src tyrosine kinase may account for the prevention of mitochondrial oxidative stress by morphine. - Highlights: • Morphine induced mito-Src phosphorylation and reduced infarct size in rat hearts. • Morphine failed to reduce I/R-induced LDH release in Src-silencing HL-1 cells. • Morphine prevented mitochondria damage caused by I/R through Src. • Morphine reduced mitochondrial ROS generation by inhibiting complex I via Src.« less

Interaction of prenatal stress and morphine alters prolactin and seizure in rat pups.

PubMed

Saboory, Ehsan; Ebrahimi, Loghman; Roshan-Milani, Shiva; Hashemi, Paria

2015-10-01

Prenatal exposure to stress and morphine has complicated effects on epileptic seizure. In the present study, effect of prenatal forced-swim stress and morphine co-administration on pentylenetetrazol (PTZ) induced epileptic behaviors and prolactin blood level (PBL) was investigated in rat offspring. Pregnant Wistar rats were divided to four groups of control-saline, control-morphine, stressed-saline and stressed-morphine. In the stressed group, pregnant rats were placed in 25°C water on gestation days 17, 18 and 19 (GD17, GD18 and GD19) for 30 min. In the morphine/saline group, pregnant rats received morphine (10, 12 and 15 mg/kg, IP, on GD17, GD18 and GD19, respectively) or saline (1 ml, IP). In the morphine/saline-stressed group, the rats received morphine or saline and then exposed to stress. On postnatal days 6 and 15 (P6 and P15), blood samples were obtained and PBL was determined. At P15 and P25, the rest of the pups was injected with PTZ to induce seizure. Then, epileptic behaviors of each rat were observed individually. Latency of first convulsion decreased in control-morphine and stressed-saline groups while increased in stressed-morphine rats compared to control-saline group on P15 (P=0.04). Number of tonic-clonic seizures significantly increased in control-morphine and stressed-saline rats compared to control-saline group at P15 (P=0.02). PBL increased in stressed-saline, control-morphine and stress-morphine groups compared to control-saline rats. It can be concluded that prenatal exposure of rats to forced-swim stress and morphine changed their susceptibility to PTZ-induced seizure and PBL during infancy and prepubertal period. Co-administration of morphine attenuated effect of stress on epileptic behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

Examination of Acute Sensitivity to Morphine and Morphine Self-Administration Following Physical and Environmental Stressors in Fischer-344 and Lewis Female Rats

DTIC Science & Technology

1997-01-16

Administration Following Physical and Environmental Stressors in Fischer-344 and Lewis Female Rats" Name of Candidate: Kelly Brown Doctor...Title ofDissertation: Examination ofAcute Sensitivity to Morphine and Morphine Self- Administration Following Physical and Environmental Stressors in...to tolerance, toxicity, or addiction liability. IV Examination ofAcute Sensitivity to Morphine and Morphine Self-Administration Following Physical and

[The use of the deuterated internal standard for morphine quantitation for the purpose of doping control by gas chromatography with mass-selective detection].

PubMed

Savel'eva, N B; Bykovskaia, N Iu; Dikunets, M A; Bolotov, S L; Rodchenkov, G M

2010-01-01

The objective of this study was to demonstrate the possibility to use deuterated compounds as internal standards for the quantitative analysis of morphine by gas chromatography with mass-selective detection for the purpose of doping control. The paper is focused on the problems associated with the use of deuterated morphine-D3 as the internal standard. Quantitative characteristics of the calibration dependence thus documented are presented along with uncertainty values obtained in the measurements with the use of deuterated morphine-D6. An approach to the assessment of method bias associated with the application of morphine-D6 as the deuterated internal standard is described.

Subcutaneous morphine infusion by syringe driver for terminally ill patients.

PubMed

Cools, H J; Berkhout, A M; De Bock, G H

1996-05-01

The study aimed to find whether subcutaneous morphine administration by syringe driver for terminally ill patients in a Dutch nursing home led to higher morphine doses and earlier death than routine morphine administration. The data comprised the files of all patients dying over a 2 year period in a 355-bed nursing home in Delft in the Netherlands. Thirty-eight per cent of the patients had been given morphine, 29% by continuous subcutaneous syringe driver. In comparing the patients given morphine with and without a syringe driver no differences emerged in mean age, sex, length of admission, type of ward, diagnosis, duration of morphine administration and mean dose. The data indicate that subcutaneous morphine administration by syringe driver decreases dose frequency problems and improves the control of pain and other symptoms in the last week before death. There was no evidence that administration of morphine in this way shortens survival.

Melatonin reverses morphine tolerance by inhibiting microglia activation and HSP27 expression.

PubMed

Lin, Sheng-Hsiung; Huang, Ya-Ni; Kao, Jen-Hsin; Tien, Lu-Tai; Tsai, Ru-Yin; Wong, Chih-Shung

2016-05-01

Melatonin has been reported to attenuate opioid tolerance. In this study, we explored the possible mechanism of melatonin in diminishing morphine tolerance. Two intrathecal (i.t.) catheters were implanted in male Wistar rats for drug delivery. One was linked to a mini-osmotic pump for morphine or saline infusion. On the seventh day, 50μg of melatonin or vehicle was injected through the other catheter instantly after discontinuation of morphine or saline infusion; 3h later, 15μg of morphine or saline was injected. The antinociceptive response was then measured using the tail-flick test every 30min for 120min. The results showed that chronic morphine infusion elicited antinociceptive tolerance and upregulated heat shock protein 27 (HSP27) expression in the dorsal horn of the rat spinal cord. Melatonin pretreatment partially restored morphine's antinociceptive effect in morphine-tolerant rats and reversed morphine-induced HSP27 upregulation. In addition, chronic morphine infusion induced microglial cell activation and was reversed by melatonin treatment. The present study provides evidence that melatonin, acting via inhibiting morphine-induced neuroinflammation, can be useful as a therapeutic adjuvant for patients under long-term opioid treatment for pain relief. Copyright © 2016 Elsevier Inc. All rights reserved.

Pregabalin role in inhibition of morphine analgesic tolerance and physical dependency in rats.

PubMed

Hasanein, Parisa; Shakeri, Saeed

2014-11-05

Pregabalin is recently proposed as analgesic or adjuvant in pain management. While previous preclinical investigations have evaluated pregabalin-opioid interactions, the effect of pregabalin on opioid tolerance and dependency has not yet been studied. Here we evaluated the effects of different doses of pregabalin (50, 100 and 200mg/kg, s.c.) on morphine-induced tolerance and dependency in rats. Adult male Wistar rats were rendered tolerant to analgesic effect of morphine by injection of morphine (10mg/kg, s.c.) twice daily for 7 days. To develop morphine dependence, rats were given escalating doses of morphine. To determine the effect of pregabalin on the development of morphine tolerance and dependence, different doses of pregabalin were administrated before morphine. The tail-flick and naloxone precipitation withdrawal tests were used to evaluate the degree of tolerance and dependence, respectively. Chronic morphine-injected rats showed significant decrements in the percentage maximum possible effect (%MPE) of morphine on the days 5 and 7 (32.5%±3.5, 21.5%±4, respectively) compared to the first day (100%) which showed morphine tolerance. Pregabalin 200mg/kg completely prevented the development of morphine tolerance. In addition, concomitant treatment of morphine with pregabalin attenuated almost all of the naloxone-induced withdrawal signs which include weight loss, jumping, penis licking, teeth chattering, wet dog shakes, rearing, standing, sniffing, face grooming and paw tremor. These data show that pregabaline has a potential anti-tolerant/anti-dependence property against chronic usage of morphine. Therefore, pregabalin appears to be a promising candidate for the treatment of opioid addiction after confirming by future clinical studies. Copyright © 2014 Elsevier B.V. All rights reserved.

The role of orexin type-1 receptors in the development of morphine tolerance in locus coeruleus neurons: An electrophysiological perspective.

PubMed

Abdollahi, Hakime; Ghaemi-Jandabi, Masoumeh; Azizi, Hossein; Semnanian, Saeed

2016-09-01

Long-term exposure to opioid agonists results in tolerance to their analgesic effects, so the effectiveness of opioid agonists in the management of pain becomes limited. The locus coeruleus (LC) nucleus has been involved in the development of tolerance to opiates. Orexin type-1 receptors (OX1Rs) are highly expressed in LC nucleus. Orexin plays a noteworthy role in the occurrence of morphine tolerance. The purpose of the present study is to investigate the role of orexin type-1 receptors in the development of morphine tolerance in LC neurons. In this study, adult male Wistar rats weighing 250-300g were utilized. Induction of morphine tolerance was obtained by single injection of morphine per day for 6 successive days. An orexin type-1 receptor antagonist (SB-334867) was injected into the lateral ventricle instantly prior to morphine injection. On day 7, the effect of morphine on the electrical activity of LC neurons was studied using in vivo extracellular single unit recording. The results demonstrate that morphine injection for 6 consecutive days led to the development of morphine-induced tolerance in LC neurons. In other words, there was a significant decrease in LC neuronal responsiveness to morphine injection. Inhibitory responses of LC neurons to intraperitoneally applied morphine can be observed with the treatment of the SB-334867 prior to morphine injection. This study showed that OX1R blockade by SB-334867 prevents the development of morphine tolerance in LC neurons. We hope that further studies will lead to considerable progress in understanding the molecular adaptations that contribute to morphine tolerance. Copyright © 2016 Elsevier B.V. All rights reserved.

The effect of forced swim stress on morphine sensitization: Involvement of D1/D2-like dopamine receptors within the nucleus accumbens.

PubMed

Charmchi, Elham; Zendehdel, Morteza; Haghparast, Abbas

2016-10-03

Nucleus accumbens (NAc) plays an essential role in morphine sensitization and suppression of pain. Repeated exposure to stress and morphine increases dopamine release in the NAc and may lead to morphine sensitization. This study was carried out in order to investigate the effect of forced swim stress (FSS), as a predominantly physical stressor and morphine on the development of morphine sensitization; focusing on the function of D1/D2-like dopamine receptors in the NAc in morphine sensitization. Eighty-five adult male Wistar rats were bilaterally implanted with cannulae in the NAc and various doses of SCH-23390 (0.125, 0.25, 1 and 4μg/0.5μl/NAc) as a D1 receptor antagonist and sulpiride (0.25, 1 and 4μg/0.5μl/NAc) as a D2 receptor antagonist were microinjected into the NAc, during a sensitization period of 3days, 5min before the induction of FSS. After 10min, animals received subcutaneous morphine injection (1mg/kg). The procedure was followed by 5days free of antagonist, morphine and stress; thereafter on the 9th day, the nociceptive response was evaluated by tail-flick test. The results revealed that the microinjection of sulpiride (at 1 and 4μg/0.5μl/NAc) or SCH-23390 (at 0.25, 1 and 4μg/0.5μl/NAc) prior to FSS and morphine disrupts the antinociceptive effects of morphine and morphine sensitization. Our findings suggest that FSS can potentiate the effect of morphine and causes morphine sensitization which induces antinociception. Copyright © 2016 Elsevier Inc. All rights reserved.

Glutamate transporter type 3 participates in maintaining morphine-induced conditioned place preference.

PubMed

Wan, Li; Bi, Jiangjiang; Li, Jun; Zuo, Zhiyi

2017-03-06

Glutamate transporters (EAAT) have been implicated in the drug addiction behavior. We determined whether EAAT type 3 (EAAT3) played a role in morphine addiction. Six- to eight-week-old EAAT3 knockout (EAAT3 -/- ) mice and their wild-type littermates received 3 intraperitoneal injections of 10mg/kg morphine, each on an alternative day, to induce conditioned place preference (CPP). Two days after the place preference returned to baseline, mice received 2.5mg/kg morphine to induce reinstatement. Some mice received intraperitoneal injection of 4mg/kg riluzole, an EAAT activator, 30min before morphine or saline injection. Hippocampus, medial prefrontal cortex, nucleus accumbens and ventral tegmental area were harvested for Western analysis 24h after the last dose of morphine was injected. Morphine induced CPP in wild-type and EAAT3 -/- mice. Gender is not a statistically significant factor to influence this behavior. This conditioned behavior extinguished after morphine administration was stopped for 8-9days in wild-type mice, while this extinction occurred 6days after discontinuation of morphine injection in EAAT3 -/- mice. A small dose of morphine similarly reinstated the conditioned behavior in the wild-type and EAAT3 -/- mice. Riluzole abolished morphine-induced CPP during the initial place preference. Morphine increased EAAT3 expression in the plasma membrane of medial prefrontal cortex, nucleus accumbens and ventral tegmental area but did not affect EAAT3 expression in the hippocampus. These results suggest that EAAT3 delays the extinction of morphine-induced CPP. EAAT activation may prevent the formation of morphine-induced CPP. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Glutamate transporter type 3 participates in maintaining morphine-induced conditioned place preference

PubMed Central

Wan, Li; Bi, Jiangjiang; Li, Jun; Zuo, Zhiyi

2017-01-01

Glutamate transporters (EAAT) have been implicated in the drug addiction behavior. We determined whether EAAT type 3 (EAAT3) played a role in morphine addiction. Six- to eight-week old EAAT3 knockout (EAAT3−/−) mice and their wild-type littermates received 3 intraperitoneal injections of 10 mg/kg morphine, each on an alternative day, to induce conditioned place preference (CPP). Two days after the place preference returned to baseline, mice received 2.5 mg/kg morphine to induce reinstatement. Some mice received intraperitoneal injection of 4 mg/kg riluzole, an EAAT activator, 30 min before morphine or saline injection. Hippocampus, medial prefrontal cortex, nucleus accumbens and ventral tegmental area were harvested for Western analysis 24 h after the last dose of morphine was injected. Morphine induced CPP in wild-type and EAAT3−/− mice. Gender is not a statistically significant factor to influence this behavior. This conditioned behavior extinguished after morphine administration was stopped for 8 to 9 days in wild-type mice, while this extinction occurred 6 days after discontinuation of morphine injection in EAAT3−/− mice. A small dose of morphine similarly reinstated the conditioned behavior in the wild-type and EAAT3−/− mice. Riluzole abolished morphine-induced CPP during the initial place preference. Morphine increased EAAT3 expression in the plasma membrane of medial prefrontal cortex, nucleus accumbens and ventral tegmental area but did not affect EAAT3 expression in the hippocampus. These results suggest that EAAT3 delays the extinction of morphine-induced CPP. EAAT activation may prevent the formation of morphine-induced CPP. PMID:28049029

PERIAQUEDUCTAL GRAY NEUROPLASTICITY FOLLOWING CHRONIC MORPHINE VARIES WITH AGE: ROLE OF OXIDATIVE STRESS

PubMed Central

Bajic, Dusica; Berde, Charles B.; Commons, Kathryn G.

2012-01-01

The development of tolerance to the antinociceptive effects of morphine has been associated with networks within ventrolateral periaqueductal gray (vlPAG) and separately, nitric oxide signaling. Furthermore, it is known that the mechanisms that underlie tolerance differ with age. In this study, we used a rat model of antinociceptive tolerance to morphine at two ages, postnatal day (PD) 7 and adult, to determine if changes in the vlPAG related to nitric oxide signaling produced by chronic morphine exposure were age-dependent. Three pharmacological groups were analyzed: control, acute morphine, and chronic morphine group. Either morphine (10 mg/kg) or equal volume of normal saline was given subcutaneously twice daily for 6 ½ days. Animals were analyzed for morphine dose-response using Hot Plate test, and for the expression of several genes associated with nitric oxide metabolism was evaluated using rtPCR. In addition, the effect of morphine exposure on immunohistochemistry for Fos, and nNOS as well as nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) reaction at the vlPAG were measured. In both age groups acute morphine activated Fos in the vlPAG, and this effect was attenuated by chronic morphine, specifically in the vlPAG at the level of the laterodorsal tegmental nucleus (LDTg). In adults, but not PD7 rats, chronic morphine administration was associated with activation of nitric oxide function. In contrast, changes in the gene expression of PD7 rats suggested superoxide and peroxide metabolisms may be engaged. These data indicate that there is supraspinal neuroplasticity following morphine administration as early as PD7. Furthermore, oxidative stress pathways associated with chronic morphine exposure appear age-specific. PMID:22999971

Morphine induces albuminuria by compromising podocyte integrity.

PubMed

Lan, Xiqian; Rai, Partab; Chandel, Nirupama; Cheng, Kang; Lederman, Rivka; Saleem, Moin A; Mathieson, Peter W; Husain, Mohammad; Crosson, John T; Gupta, Kalpna; Malhotra, Ashwani; Singhal, Pravin C

2013-01-01

Morphine has been reported to accelerate the progression of chronic kidney disease. However, whether morphine affects slit diaphragm (SD), the major constituent of glomerular filtration barrier, is still unclear. In the present study, we examined the effect of morphine on glomerular filtration barrier in general and podocyte integrity in particular. Mice were administered either normal saline or morphine for 72 h, then urine samples were collected and kidneys were subsequently isolated for immunohistochemical studies and Western blot. For in vitro studies, human podocytes were treated with morphine and then probed for the molecular markers of slit diaphragm. Morphine-receiving mice displayed a significant increase in albuminuria and showed effacement of podocyte foot processes. In both in vivo and in vitro studies, the expression of synaptopodin, a molecular marker for podocyte integrity, and the slit diaphragm constituting molecules (SDCM), such as nephrin, podocin, and CD2-associated protein (CD2AP), were decreased in morphine-treated podocytes. In vitro studies indicated that morphine modulated podocyte expression of SDCM through opiate mu (MOR) and kappa (KOR) receptors. Since morphine also enhanced podocyte oxidative stress, the latter seems to contribute to decreased SDCM expression. In addition, AKT, p38, and JNK pathways were involved in morphine-induced down regulation of SDCM in human podocytes. These findings demonstrate that morphine has the potential to alter the glomerular filtration barrier by compromising the integrity of podocytes.

Cannabinoid 1 receptor blockade in the dorsal hippocampus prevents the reinstatement but not acquisition of morphine-induced conditioned place preference in rats.

PubMed

Zhao, Xin; Yao, Li; Wang, Fang; Zhang, Han; Wu, Li

2017-07-05

The cannabinoid 1 receptors (CB1Rs) signaling is strongly linked to conditioned rewarding effects of opiates. Learned associations between environmental contexts and discrete cues and drug use play an important role in the maintenance and/or relapse of morphine addiction. Although previous studies suggest that context-dependent morphine treatment alters endocannabinoid signaling and synaptic plasticity in the hippocampus, the role of endocannabinoid in morphine conditioned place preference (CPP) and reinstatement remains unknown. In the present study, we found daily escalating doses of morphine induce significant CPP in rats. After the extinction of CPP, a priming dose of morphine was sufficient to reinstate morphine CPP and was associated with the elevated CB1R levels compared with saline control groups, suggesting upregulation of CB1R pathway in the hippocampus contribute to the reinstatement of morphine CPP. By using a pharmacological inhibitor of CB1R administered into the dorsal hippocampus, we showed that blockade of CB1R signaling did not alter the morphine CPP acquisition but inhibited the reinstatement of morphine CPP. In addition, no effects were induced upon CB1R blockade in the prefrontal cortex on reinstatement of morphine CPP. These studies reveal region-specific effects of hippocampal blockade of CB1R signaling pathway on the reinstatement of morphine CPP.

Role of protein kinase C and μ-opioid receptor (MOPr) desensitization in tolerance to morphine in rat locus coeruleus neurons

PubMed Central

Bailey, C P; Llorente, J; Gabra, B H; Smith, F L; Dewey, W L; Kelly, E; Henderson, G

2009-01-01

In morphine tolerance a key question that remains to be answered is whether μ-opioid receptor (MOPr) desensitization contributes to morphine tolerance, and if so by what cellular mechanisms. Here we demonstrate that MOPr desensitization can be observed in single rat brainstem locus coeruleus (LC) neurons following either prolonged (> 4 h) exposure to morphine in vitro or following treatment of animals with morphine in vivo for 3 days. Analysis of receptor function by an operational model indicated that with either treatment morphine could induce a profound degree (70–80%) of loss of receptor function. Ongoing PKC activity in the MOPr-expressing neurons themselves, primarily by PKCα, was required to maintain morphine-induced MOPr desensitization, because exposure to PKC inhibitors for only the last 30–50 min of exposure to morphine reduced the MOPr desensitization that was induced both in vitro and in vivo. The presence of morphine was also required for maintenance of desensitization, as washout of morphine for > 2 h reversed MOPr desensitization. MOPr desensitization was homologous, as there was no change in α2-adrenoceptor or ORL1 receptor function. These results demonstrate that prolonged morphine treatment induces extensive homologous desensitization of MOPrs in mature neurons, that this desensitization has a significant PKC-dependent component and that this desensitization underlies the maintenance of morphine tolerance. PMID:19200236

Maternal swimming exercise during pregnancy attenuates anxiety/depressive-like behaviors and voluntary morphine consumption in the pubertal male and female rat offspring born from morphine dependent mothers.

PubMed

Torabi, Masoumeh; Pooriamehr, Alireza; Bigdeli, Imanollah; Miladi-Gorji, Hossein

2017-10-17

This study was designed to examine whether maternal swimming exercise during pregnancy would attenuate prenatally morphine-induced anxiety, depression and voluntary consumption of morphine in the pubertal male and female rat offspring. Pregnant rats during the development of morphine dependence were allowed to swim (30-45min/d, 3days per a week) on gestational days 11-18. Then, the pubertal male and female rat offspring were tested for the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that male and female rat offspring born of the swimmer morphine-dependent mothers exhibited an increase in EPM open arm time and entries, higher levels of sucrose preference than their sedentary control mothers. Voluntary consumption of morphine was less in the male and female rat offspring born of the swimmer morphine-dependent mothers as compared with their sedentary control mothers during three periods of the intake of drug. Thus, swimming exercise in pregnant morphine dependent mothers decreased anxiety, depressive-like behavior and also the voluntary morphine consumption in the pubertal male and female offspring, which may prevent prenatally morphine-induced behavioral sensitization in offspring. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of agmatine on long-term potentiation in morphine-treated rats.

PubMed

Lu, Wei; Dong, Hua-Jin; Bi, Guo-Hua; Zhao, Yong-Qi; Yang, Zheng; Su, Rui-Bin; Li, Jin

2010-08-01

Agmatine is an endogenous amine derived from l-arginine that potentiates morphine analgesia and inhibits naloxone precipitated abstinent symptoms in morphine dependent rats. In this study, the effects of agmatine on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of the rat dentate gyrus (DG) on saline or morphine-treated rats were investigated. Population spikes (PS), evoked by stimulation of the LPP, was recorded from DG region. Acute agmatine (2.5-10mg/kg, s.c.) treatment facilitated hippocampal LTP. Acute morphine (30mg/kg, s.c.) treatment significantly attenuated hippocampal LTP and agmatine (10mg/kg, s.c.) restored the amplitude of PS that was attenuated by morphine. Chronic morphine treatment resulted in the enhancement of hippocampal LTP, agmatine co-administered with morphine significantly attenuated the enhancement of morphine on hippocampal LTP. Imidazoline receptor antagonist idazoxan (5mg/kg, i.p.) reversed the effect of agmatine. These results suggest that agmatine attenuated the effect of morphine on hippocampal LTP, possibly through activation of imidazoline receptor. Crown Copyright 2010. Published by Elsevier Inc. All rights reserved.

[Effects of odor cue on morphine-induced dependence and craving in mice].

PubMed

Liu, Xiao-Fen; Yang, Guang; Yang, Rui; Jia, Qiang; Guan, Su-Dong

2012-04-01

The olfactory system may play a pivotal role in drug addiction. To clarify the issues, we investigated the morphine dependence and psychological craving in morphine addicted mice using the conditioned place preference (CPP) paradigm by taking an only odor cue as the conditioned stimulus (CS). The results showed that by pairing morphine with odor, the CPP could be induced in mice. When the morphine addicted mice were exposed to a novel environment during morphine withdrawal, they spent significantly longer time in the chamber with morphine-paired odor than in the control chamber. The effects of odor cue on the morphine CPP were blocked by the administration of dopamine D1 or D2 antagonists. The studies indicated that olfactory system plays an important role in drug addiction.

Food deprivation facilitates reinstatement of morphine-induced conditioned place preference: Role of intra-accumbal dopamine D2-like receptors in associating reinstatement of morphine CPP with stress.

PubMed

Sadeghzadeh, Fatemeh; Babapour, Vahab; Haghparast, Abbas

2017-04-01

The high rate of relapse to drug use is one of the main problems in the treatment of addiction. Stress plays the essential role in drug abuse and relapse; nevertheless, little is known about the mechanisms underlying stress and relapse. Accordingly, the effects of intra-accumbal administration of Sulpiride, as a dopamine D2-like receptor antagonist, on an ineffective morphine dose + food deprivation(FD)- and morphine priming-induced reinstatement of conditioned place preference (CPP). About 104 adult male albino Wistar rats weighing 200-280 g were bilaterally implanted by cannula into the nucleus accumbens (NAc). Subcutaneous (sc) injection of morphine (5 mg kg -1 ) was used daily during a 3-day conditioning phase. After a 24-hr "off" period following achievement of extinction criterion, rats were tested for FD- and priming-induced reinstatement of morphine CPP by an ineffective (0.5 mg kg -1 , sc) and priming (1 mg kg -1 , sc) dose of morphine, respectively. In the next experiments, animals received different doses of intra-accumbal Sulpiride (0.25, 1, and 4 µg/0.5 µL saline) bilaterally and were subsequently tested for morphine reinstatement. Our findings indicated that the 24-hr FD facilitated reinstatement of morphine CPP. Furthermore, the D2-like receptor antagonist attenuated the ineffective morphine dose+ FD- and priming-induced reinstatement of morphine CPP dose-dependently. Also, contribution of D2-like receptors in mediation of the ineffective morphine dose+ FD-induced reinstatement of CPP was greater than morphine priming-induced reinstatement of CPP. The role of dopaminergic system in morphine reinstatement through a neural pathway in the NAc provides the evidence that D2-like receptor antagonist can be useful therapeutic targets for reinstatement of morphine CPP. © 2016 Wiley Periodicals, Inc.

Huperzine A inhibits immediate addictive behavior but not behavioral sensitization following repeated morphine administration in rats.

PubMed

Sun, Jinling; Tian, Lin; Cui, Ruisi; Li, Xinwang

2017-04-01

Acetylcholinesterase inhibitors are regarded as promising therapeutic agents to treat addiction. The current study aimed to examine the effects of huperzine A, a cholinesterase inhibitor, on behavioral sensitization induced by repeated morphine administration and relapse induced by contextual conditioning. The present study also assessed whether the state-dependency hypothesis may explain the results. Adult rats were divided into four groups (n=8) and intraperitoneally injected with 0.2, 0.3 or 0.4 mg/kg huperzine A or saline (1 ml/kg, control), for 5 days. The effect of repeated huperzine A administration alone on locomotor activity was assessed. For the experiments that analyzed the development of morphine-induced sensitization, 40 rats were divided into five groups (n=8): Saline+Saline, Saline+Morphine, 0.2, 0.3 and 0.4 mg/kg huperzine A+Morphine. Following a withdrawal period of 7 days, all animals were administered saline or morphine, as appropriate. To test the state-dependency hypothesis, the rats in the Saline+Morphine group were injected with saline and morphine, while the other three groups were administered different doses of huperzine A and morphine. To examine the effect of huperzine A on the expression of morphine-induced sensitization, the rats in huperzine A+Morphine groups were injected with appropriate concentrations of huperzine A, and morphine. The current results indicated that the administration of huperzine A alone did not affect locomotor activity, while higher doses of huperzine A inhibited the addictive behavior induced by morphine at the development phase. Additionally, huperzine A administration during the expression phase of morphine sensitization did not inhibit the relapse induced by administration of saline. Furthermore, 0.4 mg/kg huperzine A inhibited the expression of morphine-induced behavioral sensitization. Therefore, the results of the current study do not support the state-dependency hypothesis.

Huperzine A inhibits immediate addictive behavior but not behavioral sensitization following repeated morphine administration in rats

PubMed Central

Sun, Jinling; Tian, Lin; Cui, Ruisi; Li, Xinwang

2017-01-01

Acetylcholinesterase inhibitors are regarded as promising therapeutic agents to treat addiction. The current study aimed to examine the effects of huperzine A, a cholinesterase inhibitor, on behavioral sensitization induced by repeated morphine administration and relapse induced by contextual conditioning. The present study also assessed whether the state-dependency hypothesis may explain the results. Adult rats were divided into four groups (n=8) and intraperitoneally injected with 0.2, 0.3 or 0.4 mg/kg huperzine A or saline (1 ml/kg, control), for 5 days. The effect of repeated huperzine A administration alone on locomotor activity was assessed. For the experiments that analyzed the development of morphine-induced sensitization, 40 rats were divided into five groups (n=8): Saline+Saline, Saline+Morphine, 0.2, 0.3 and 0.4 mg/kg huperzine A+Morphine. Following a withdrawal period of 7 days, all animals were administered saline or morphine, as appropriate. To test the state-dependency hypothesis, the rats in the Saline+Morphine group were injected with saline and morphine, while the other three groups were administered different doses of huperzine A and morphine. To examine the effect of huperzine A on the expression of morphine-induced sensitization, the rats in huperzine A+Morphine groups were injected with appropriate concentrations of huperzine A, and morphine. The current results indicated that the administration of huperzine A alone did not affect locomotor activity, while higher doses of huperzine A inhibited the addictive behavior induced by morphine at the development phase. Additionally, huperzine A administration during the expression phase of morphine sensitization did not inhibit the relapse induced by administration of saline. Furthermore, 0.4 mg/kg huperzine A inhibited the expression of morphine-induced behavioral sensitization. Therefore, the results of the current study do not support the state-dependency hypothesis. PMID:28413513

Effect of rat parental morphine exposure on passive avoidance memory and morphine conditioned place preference in male offspring.

PubMed

Akbarabadi, Ardeshir; Niknamfar, Saba; Vousooghi, Nasim; Sadat-Shirazi, Mitra-Sadat; Toolee, Heidar; Zarrindast, Mohammad-Reza

2018-02-01

Drug addiction is a chronic disorder resulted from complex interaction of genetic, environmental, and developmental factors. Epigenetic mechanisms play an important role in the development and maintenance of addiction and also memory formation in the brain. We have examined passive avoidance memory and morphine conditioned place preference (CPP) in the offspring of male and/or female rats with a history of adulthood morphine consumption. Adult male and female animals received chronic oral morphine for 21days and then were maintained drug free for 10days. After that, they were let to mate with either an abstinent or control rat. Male offspring's memory was evaluated by step through test. Besides, rewarding effects of morphine were checked with CCP paradigm. Offspring of abstinent animals showed significant memory impairment compared to the control group which was more prominent in the offspring of abstinent females. Conditioning results showed that administration of a high dose of morphine (10mg/kg) that could significantly induce CPP in control rats, was not able to induce similar results in the offspring of morphine abstinent parents; and CPP was much more prominent when it was induced in the offspring of morphine exposed females compared to the progeny of morphine exposed males. It is concluded that parental morphine consumption in adulthood even before mating has destructive effects on memory state of the male offspring and also leads to tolerance to the rewarding effects of morphine. These effects are greater when the morphine consumer parent is the female one. Copyright © 2017 Elsevier Inc. All rights reserved.

Social environment alters opioid-induced hyperalgesia and antinociceptive tolerance in adolescent mice.

PubMed

Bates, M L S; Emery, M A; Wellman, P J; Eitan, S

2016-07-01

Chronic opioid treatment is complicated by the development of tolerance and hyperalgesia. Social environment alters both opioid-induced behaviours and nociceptive mechanisms. Our previous studies demonstrated that, in adolescent rodents, the susceptibility to acquire opioid dependence and reward is dependent on the nature of social housing conditions. Specifically, our previous studies demonstrate that housing morphine-treated mice with drug-naïve animals mitigates the abuse liability of opioids. Thus, this study tested the effect of social housing conditions on the development of adaptive processes to morphine antinociception. Adolescent males were group-housed in different conditions. In the mixed treatment condition, mice treated with 20 mg/kg morphine (i.e. 'morphine cage-mates') and saline (i.e. 'saline cage-mates') were housed together. In the separated treatment conditions, all mice in the cage received morphine (i.e. 'morphine only') or saline (i.e. 'saline only'). All animals were tested for baseline pain sensitivity and for the response to morphine in the tail withdrawal, hot plate, acetone and von Frey filament tests, during and after discontinuation of opioid treatment. Both morphine cage-mate and morphine only animals developed antinociceptive tolerance. However, this effect was more robust and persistent in the morphine only group. Notably, morphine only animals, but not morphine cage-mates, developed opioid-induced hyperalgesia. This study demonstrates that housing morphine-treated mice with drug-naïve animals mitigates the development of opioid-induced hyperalgesia and antinociceptive tolerance. Thus, this study indicates that social environment influences the effectiveness of opioid pain management. © 2016 European Pain Federation - EFIC®

Cancer inpatients morphine usage: a new England area survey.

PubMed

Trollor, John

2003-08-01

This is a one year study of the use of morphine in cancer patients in 10 inpatient facilities in the New England Area Health Service in the north-west of New South Wales. The study explored 170 admissions relating to 122 patients, most of whom were cared for by their general practitioners. The use of morphine in these cancer patients was compared with the recommendations made by the expert working group of the European Association of Palliative Care.1 Those items which matched the recommendations included the initial doses for new users of morphine and the subcutaneous route being the preferred parenteral route. The data in this study differed from the recommendations in that only half of the patients received the immediate release morphine when first given oral morphine, only 43% had orders for immediate release oral morphine for breakthrough pain (with a variable frequency) and a significant number of orders for parenteral and immediate release oral morphine for breakthrough pain were outside the recommended doses (100% and 86.2%, respectively). Written orders for immediate release oral and parenteral morphine involved a dose range in significant numbers while only 30% of patients had orders for parenteral morphine for breakthrough pain. There was a low use of fixed interval variable dose (FIVD) morphine charts despite these being available in most facilities.

Inhibiting social support from massage-like stroking increases morphine dependence.

PubMed

Bates, M L Shawn; Emery, Michael A; Wellman, Paul J; Eitan, Shoshana

2017-12-01

Our previous studies showed that altering solely the drug experience of the cage mates with which rodents are housed affects the development of morphine dependence. In this study, we used designer receptors exclusively activated by designer drugs to artificially increase or decrease the activity of peripheral dorsal root ganglia sensory neurons expressing the G-protein-coupled receptor MRGPRB4. This is because sensory MRGPRB4-expressing neurons were shown to specifically detect the sensation of massage-like stroking resulting from social grooming, which is an important affiliative social behavior in the rodent. Blocking the sensation of social grooming in morphine-treated mice housed with drug-naive mice (i.e. morphine cage mates) significantly increased the display of jumping behavior in morphine-withdrawn animals. Activating the sensation of social grooming in morphine-treated animals housed solely with other morphine-treated animals (i.e. morphine only) did not significantly alter the display of jumping behavior in morphine-withdrawn animals. Repetitive jumping behaviors have been shown to correlate with morphine dependence. Thus, this study showed a role of social grooming in the protective effect of being housed with drug-naive mice on the development of morphine dependence. It further confirms a role of social support in the development of substance use problems.

A test of the opponent-process theory of motivation using lesions that selectively block morphine reward.

PubMed

Vargas-Perez, Hector; Ting-A-Kee, Ryan A; Heinmiller, Andrew; Sturgess, Jessica E; van der Kooy, Derek

2007-06-01

The opponent-process theory of motivation postulates that motivational stimuli activate a rewarding process that is followed by an opposed aversive process in a homeostatic control mechanism. Thus, an acute injection of morphine in nondependent animals should evoke an acute rewarding response, followed by a later aversive response. Indeed, the tegmental pedunculopontine nucleus (TPP) mediates the rewarding effects of opiates in previously morphine-naive animals, but not other unconditioned effects of opiates, or learning ability. The aversive opponent process for acute morphine reward was revealed using a place-conditioning paradigm. The conditioned place aversion induced by 16-h spontaneous morphine withdrawal from an acute morphine injection in nondependent rats was abolished by TPP lesions performed prior to drug experience. However, TPP-lesioned rats did show conditioned aversions for an environment paired with the acute administration of the opioid antagonist naloxone, which blocks endogenous opioids. The results show that blocking the rewarding effects of morphine with TPP lesions also blocked the opponent aversive effects of acute morphine withdrawal in nondependent animals. Thus, this spontaneous withdrawal aversion (the opponent process) is induced by the acute rewarding effects of morphine and not by other unconditioned effects of morphine, the pharmacological effects of morphine or endogenous opioids being displaced from opiate receptors.

Acupuncture at SI5 attenuates morphine seeking behavior after extinction.

PubMed

Lee, Bong Hyo; Ma, Jeong Hun; In, Sunghyun; Kim, Hee Young; Yoon, Seong Shoon; Jang, Eun Young; Yang, Chae Ha

2012-10-31

Our previous studies have shown that acupuncture attenuates morphine self-administration and sensitization behavior as well as withdrawal signs. The present study was designed to investigate the role of acupuncture in the reinstatement of morphine seeking. Male Sprague-Dawley rats weighing 270-300 g were subjected to intravenous catheterization after food training. The animals were trained to self-administer morphine (1.0mg/kg, 3 weeks), followed by extinction (1 week). Extinction conditions were introduced by substituting saline for morphine. The rats were then tested for reinstatement of morphine self-administration by a priming injection of morphine (0.25mg/kg). To see whether acupuncture can reduce morphine reinstatement, acupuncture was performed at SI5 or LI5 for 1 min immediately before a morphine injection. To further test the involvement of gamma aminobutyric acid (GABA) receptors in acupuncture effects, GABA receptor antagonists were injected before acupuncture. In the present results, acupuncture at SI5, but not at control acupoint LI5 attenuated the reinstatement of morphine seeking behavior, which was blocked by the GABA receptor antagonists. It suggests that acupuncture can reduce the reinstatement of morphine seeking, possibly due to the mediation of GABA receptor system. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

The role of injection cues in the production of the morphine preexposure effect in taste aversion learning.

PubMed

Davis, Catherine M; de Brugada, Isabel; Riley, Anthony L

2010-05-01

The attenuation of an LiCl-induced conditioned taste aversion (CTA) by LiCl preexposure is mediated primarily by associative blocking via injection-related cues. Given that preexposure to morphine attenuates morphine-induced CTAs, it was of interest to determine whether injection cues also mediate this effect. Certain morphine-induced behaviors such as analgesic tolerance are controlled associatively, via injection-related cues. Accordingly, animals in the present experiments were preexposed to morphine (or vehicle) every other day for five total exposures, followed by an extinction phase, in which the subjects were given saline injections (or no treatment) for 8 (Experiment 1) or 16 (Experiment 2) consecutive days. All of the animals then received five CTA trials with morphine (or vehicle). The morphine-preexposed animals in Experiment 1 displayed an attenuation of the morphine CTA that was unaffected by extinction saline injections, suggesting that blocking by injection cues during morphine preexposure does not mediate this effect. All of the morphine-preexposed subjects in Experiment 2 displayed a weakened preexposure effect, an effect inconsistent with a selective extinction of drug-associated stimuli. The attenuating effects of morphine preexposure in aversion learning are most likely controlled by nonassociative mechanisms, like drug tolerance.

[Perioperative managements of the patients with cancer-pain receiving morphine].

PubMed

Matsuda, M; Murakawa, K; Noma, K; Uemura, Y; Maeda, S; Tashiro, C

1998-09-01

In the patients receiving morphine preoperatively, it is preoperatively important to avoid withdrawal symptoms postoperatively and to suppress postoperative pain and to maintain an appropriate anesthetic depth during the operation. We experienced six patients who had been under preoperative pain control with oral and/or epidural morphine and undergone palliative operation for their cancer pain. Four of the patients were preoperatively administered with oral morphine ranging from 30 to 270 mg.day-1. One patient was given epidural morphine 10 mg.day-1. Another was with morphine 1800 mg.day-1 orally and 50 mg.day-1 epiduraly. In all cases, general anesthesia was maintained with inhalation anesthetics. Anesthetic supplementation and postoperative pain management were performed with continuous i.v. infusion of morphine (half dosage of daily oral dosage), or subcutaneous injection (one sixth dosage of daily oral morphine) while preoperative epidural morphine was continued throughout the perioperative period. We were able to manage these patients well and none of them developed withdrawal symptom or increased postoperative pain.

Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation.

PubMed

Chen, Ming; Zhao, Yanfang; Yang, Hualan; Luan, Wenjie; Song, Jiaojiao; Cui, Dongyang; Dong, Yi; Lai, Bin; Ma, Lan; Zheng, Ping

2015-07-24

One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.

Ajoene restored behavioral patterns and liver glutathione level in morphine treated C57BL6 mice.

PubMed

Yun, Jaesuk; Oliynyk, Sergiy; Lee, Yeonju; Kim, Jieun; Yun, Kyunghwa; Jeon, Raok; Ryu, Jae-Ha; Oh, Seikwan

2017-01-01

Oxidative stress exacerbates drug dependence induced by administration of opiate analgesics such as morphine-induced tolerance and physical dependence associated with the reduction in hepatic glutathione (GSH) level. Ajoene obtained from garlic (Allium sativum L.) has been reported for anti-tumorigenic, anti-oxidative and neuroprotective properties, however, little is known about its effect on morphine-induced dependence. Therefore, this study aimed at the effect of ajoene on physical and/or psychological dependence and liver GSH content in morphine-treated mice. Conditioned place preference (CPP) test and measurement of morphine withdrawal syndrome were performed in C57BL6 mice for behavioral experiments. Thereafter, mice were sacrificed for measurement of serum and liver GSH levels. Ajoene restored CPP and naloxone-precipitated jumping behavior in mice exposed to morphine. Moreover, the reduced level of liver GSH content in morphine treated mice was back to normal after ajoene administration. Taken together, ajoene improved behavioral patterns in mice exposed to morphine suggesting its potential therapeutic benefit against morphine-induced dependence.

The effect of caudal vs intravenous morphine on early extubation and postoperative analgesic requirements for stage 2 and 3 single-ventricle palliation: a double blind randomized trial.

PubMed

Stuth, Eckehard A E; Berens, Richard J; Staudt, Susan R; Robertson, Frederick A; Scott, John P; Stucke, Astrid G; Hoffman, George M; Troshynski, Todd J; Tweddell, James S T; Zuperku, Edward J

2011-04-01

High-dose single-shot caudal morphine has been postulated to facilitate early extubation and to lower initial analgesic requirements after staged single-ventricle (SV) palliation. With Institutional Review Board approval and written informed parental consent, 64 SV children aged 75-1667 days were randomized to pre-incisional caudal morphine-bupivacaine (100 μg·kg(-1) morphine (concentration 0.1%), mixed with 0.25% bupivacaine with 1 : 200,000 epinephrine, total 1 ml·kg(-1)) and postcardiopulmonary bypass (CPB) intravenous (IV) droperidol (75 μg·kg(-1)) ('active caudal group') or pre-incisional caudal saline (1 ml·kg(-1)) and post-CPB IV morphine (150 μg·kg(-1)) with droperidol (75 μg·kg(-1)) ('active IV group'). Assignment remained concealed from families and the care teams throughout the trial. Early extubation failure rates (primary or reintubation within 24 h), time to first postoperative rescue morphine analgesia, and 12-h postoperative morphine requirements were assessed for extubated patients. Thirty-one (12 stage 2) SV patients received caudal morphine and 32 (15 stage 2) received IV morphine. Extubation failure rates were 6/31 (19%) for caudal and 5/32 (16%) for IV morphine. For successfully extubated patients (n = 54), active caudal treatment significantly delayed the need for postoperative rescue morphine in stage 3 patients (P = 0.02) but not in stage 2 patients (P = 0.189) (Kaplan-Meier survival analysis with LogRank test). The reduction in 12-h postoperative morphine requirements with active caudal treatment did not reach significance (P = 0.085) but morphine requirements were significantly higher for stage 2 compared with stage 3 patients (P < 0.001) (two-way anova in n = 50 extubated patients). High-dose caudal morphine with bupivacaine delayed the need for rescue morphine analgesia in stage 3 patients. All stage 2 patients required early rescue morphine and had significantly higher postoperative 12-h morphine requirements than stage 3 patients. Early extubation is feasible for the majority of stage 2 and 3 SV patients regardless of analgesic regimen. The study was underpowered to assess differences in extubation failure rates. © 2011 Blackwell Publishing Ltd.

Morphine clearance in children: does race or genetics matter?

PubMed

Sadhasivam, Senthilkumar; Krekels, Elke H J; Chidambaran, Vidya; Esslinger, Hope R; Ngamprasertwong, Pornswan; Zhang, Kejian; Fukuda, Tsuyoshi; Vinks, Alexander A

2012-01-01

Interindividual variability in analgesic response and adverse effects of opioids because of narrow therapeutic indices are major clinical problems. Morphine is an opioid commonly used in children to manage perioperative pain. Al-though size and age often are considered primary covariates for morphine pharmacokinetic models, the impact of other factors important in personalizing care such as race and genetic variations on morphine disposition is not well documented. Genotype blinded clinical observational pharmacokinetic study. One hundred forty-six African American and Caucasian children scheduled for elective outpatient adenotonsillectomy were enrolled in our prospective genotype blinded observational study with standard perioperative clinical care. Tertiary care pediatric institution. Morphine bolus for intraoperative analgesia in children and pharmacokinetic analyses in different races. Pharmacokinetics and pharmacogenetics of intravenous morphine in a homogeneous pediatric outpatient surgical pain population were evaluated. The authors observed that African American children have higher morphine clearance than Caucasian children. The increased clearance is directed toward the formation of morphine-3-glucuronide formation, rather than the formation of morphine-6-glucuronide. Common uridine diphosphate glucuronosyl transferase (UGT) 2B7 genetic variations (2161C>T and 802C>T) were not associated with observed racial differences in morphine's clearance although the wild type of the UGT2B7 isozyme is more prevalent in the African Americans. Race of the child is an important factor in perioperative intravenous morphine's clearance and its potential role in personalizing analgesia with morphine needs further investigation.

Down-regulation of MAO-B activity and imidazoline receptors in rat brain following chronic treatment of morphine.

PubMed

Su, R B; Li, J; Li, X; Qin, B Y

2001-07-01

To study the regulation of monoamine oxidase-B (MAO-B) activity and imidazoline receptors (I-R) during long term treatment of morphine. MAO-B activity was detected by high performance liquid chromatography; I-R was detected by [3H]idazoxan binding test. Idazoxan and morphine inhibited whole brain homogenate MAO-B activity in a dose-dependent manner, while agmatine, an endogenous imidazoline ligand, didn't affect the activity of MAO-B, and it had no effect on the inhibition of MAO-B activity by idazoxan or morphine. MAO-B activity of rats decreased markedly in all five brain regions detected (cerebral cortex, hippocampus, thalamus, cerebellum, and striatum) after chronic administration of morphine for 16 d (P < 0.01). Acute challenge with naloxone or idazoxan did not influence MAO-B activity in morphine chronically treated rats. Although agmatine itself did not affect MAO-B activity, co-administration of agmatine with morphine could reverse the effect of morphine on MAO-B activity. Chronic administration of morphine significantly decreased the density of [3H]idazoxan binding sites and increased the binding affinity in cerebral cortex and cerebellum (P < 0.05 or P < 0.01). MAO-B activity was relevant to the abstinent syndrome of morphine dependent rats, but not related to the effect of agmatine on morphine analgesia; influence of agmatine on the pharmacological effects of morphine was based on its activation of imidazoline receptors.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Navarro-Zaragoza, J.; Martínez-Laorden, E.; Mora, L.

Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic–pituitary–adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-inducedmore » increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts. - Highlights: • Morphine withdrawal caused an increase in myocardial sympathetic activity. • ERK regulates TH phosphorylation after naloxone-induced morphine withdrawal. • CRF1R is involved in cardiac adaptive changes during morphine dependence.« less

Analgesic plasma concentrations of morphine in children with terminal malignancy receiving a continuous subcutaneous infusion of morphine sulfate to control severe pain.

PubMed

Nahata, M C; Miser, A W; Miser, J S; Reuning, R H

1984-02-01

Three children with terminal malignancy received a continuous subcutaneous infusion of morphine sulfate for the control of severe pain, the morphine dose being adjusted until the patient and/or parent reported complete freedom from pain. Analgesic plasma morphine concentrations at the steady state in these patients ranged from 12.9 to 57 ng/ml (median 19.6 ng/ml) while receiving morphine doses of 0.45-2.0 mg/h (0.034-0.06 mg/kg/h). One patient, who received 2 mg morphine per hour for 12 days demonstrated a 2-fold variation in steady-state plasma concentration during this period.

Effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds.

PubMed

Kukanich, Butch; Borum, Stacy L

2008-05-01

To assess pharmacokinetics and pharmacodynamics of morphine and the effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds. 6 healthy Greyhounds, 3 male and 3 female. Morphine sulfate (0.5 mg/kg. IV) was administered to Greyhounds prior to and after 5 days of ketoconazole (12.7 +/- 0.6 mg/kg, PO) treatment. Plasma samples were obtained from blood samples that were collected at predetermined time points for measurement of morphine and ketoconazole concentrations by mass spectrometry. Pharmacokinetics of morphine were estimated by use of computer software. Pharmacodynamic effects of morphine in Greyhounds were similar to those of other studies in dogs and were similar between treatment groups. Morphine was rapidly eliminated with a half-life of 1.28 hours and a plasma clearance of 32.55 mL/min/kg. The volume of distribution was 3.6 L/kg. No significant differences in the pharmacokinetics of morphine were found after treatment with ketoconazole. Plasma concentrations of ketoconazole were high and persisted longer than expected in Greyhounds. Ketoconazole had no significant effect on morphine pharmacokinetics, and the pharmacodynamics were similar between treatment groups. Plasma concentrations of ketoconazole were higher than expected and persisted longer than expected in Greyhounds.

Effects of scopolamine on morphine-induced conditioned place preference in mice.

PubMed

Tan, Hua; Liu, Ning; Wilson, Fraser A W; Ma, Yuanye

2007-09-01

It is well known that the cholinergic system plays a crucial role in learning and memory. Psychopharmacological studies in humans and animals have shown that a systemic cholinergic blockade may induce deficits in learning and memory. Accumulated studies have indicated that learning and memory play an important role in drug addition. In the present study, in order to get a further understanding about the functions of the cholinergic system in drug-related learning and memory, we examined the effects of scopolamine (0.5, 1.0 and 2.0 mg/kg) on morphine-induced conditioned place preference (CPP). Two kinds of morphine exposure durations (4 days and 12 days) were used. The main finding was that all doses of scopolamine enhanced the extinction of morphine-induced CPP in mice treated with morphine for 12 days. However, in mice treated with morphine for 4 days, all doses of scopolamine did not inhibit morphine-induced CPP. The highest dose (2.0 mg/kg) of scopolamine even significantly delayed the extinction of morphine-induced CPP. Our results suggest that the effects of a systemic cholinergic blockade on morphine-induced CPP depend on the morphine exposure time.

The effect of various morphine weaning regimens on the sequelae of opioid tolerance involving physical dependency, anxiety and hippocampus cell neurodegeneration in rats.

PubMed

Motaghinejad, Majid; Karimian, Seyed Morteza; Motaghinejad, Ozra; Shabab, Behnaz; Asadighaleni, Majid; Fatima, Sulail

2015-06-01

Chronic consumption of morphine induces physical dependency, anxiety, and neurodegeneration. In this study, morphine on its own has been used for the management of morphine-induced dependency, oxidative stress, and apoptosis. Forty-eight male rats were randomly divided into six groups. Rats in groups 1-5 were made morphine dependent by an increasing manner of morphine for 7 days (15-45 mg/kg). For the next 14 days, morphine was administered using the following regimen: (i) once daily 45 mg/kg (positive controls), (ii) the same dose at additional intervals (6 h longer than the previous intervals each time), (iii) 45 mg/kg of morphine at irregular intervals like of 12, 24, 36 h, (iv) decreasing dose once daily (every time 2.5 mg/kg less than the former dosage). Group 5 received 45 mg/kg of morphine and 10 mg/kg of SOD mimetic agent (M40401) injection per day. Group 6 (negative control) received saline solution only. On day 22, all animals received naloxone (3 mg/kg) and their Total Withdrawal Index (TWI) and blood cortisol levels were measured. After drug treatment, hippocampus cells were isolated, and oxidative, antioxidative, and apoptotic factors were evaluated. Various regimens of morphine reduced TWI, cortisol levels, Bax activity, caspase-3, caspase-9, TNF-α, and IL-1β and lipid peroxidation. In all treatment groups, GSH level, superoxide dismutase, glutathione peroxidase, and Bcl-2 activity were significantly increased. Furthermore, SOD mimetic agent c diminished morphine effect on SOD activity. Thus, varying the dosage regimen of morphine can reduce the severity of morphine-induced dependency and neurodegeneration. © 2015 Société Française de Pharmacologie et de Thérapeutique.

Influence of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference in rats.

PubMed

Gawel, Kinga; Labuz, Krzysztof; Jenda, Malgorzata; Silberring, Jerzy; Kotlinska, Jolanta H

2014-07-15

The influence of systemic administration of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference (CPP) was examined in rats. Additionally, this study aimed to compare the effects of donepezil, which selectively inhibits acetylcholinesterase, and rivastigmine, which inhibits both acetylcholinesterase and butyrylcholinesterase on morphine reward. Morphine-induced CPP (unbiased method) was induced by four injections of morphine (5 mg/kg, i.p.). Donepezil (0.5, 1, and 3 mg/kg, i.p.) or rivastigmine (0.03, 0.5, and 1 mg/kg, i.p.) were given 20 min before morphine during conditioning phase and 20 min before the expression or reinstatement of morphine-induced CPP. Our results indicated that both inhibitors of cholinesterase attenuated the acquisition and expression of morphine CPP. The results were more significant after rivastigmine due to a broader inhibitory spectrum of this drug. Moreover, donepezil (1 mg/kg) and rivastigmine (0.5 mg/kg) attenuated the morphine CPP reinstated by priming injection of 5mg/kg morphine. These properties of both cholinesterase inhibitors were reversed by mecamylamine (3 mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist but not scopolamine (0.5 mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. All effects of cholinesterase inhibitors were observed at the doses that had no effects on locomotor activity of animals. Our results suggest beneficial role of cholinesterase inhibitors in reduction of morphine reward and morphine-induced seeking behavior. Finally, we found that the efficacy of cholinesterase inhibitors in attenuating reinstatement of morphine CPP provoked by priming injection may be due to stimulation of nicotinic acetylcholine receptors. Copyright © 2014 Elsevier B.V. All rights reserved.

Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression.

PubMed

Schwarz, Jaclyn M; Hutchinson, Mark R; Bilbo, Staci D

2011-12-07

A critical component of drug addiction research involves identifying novel biological mechanisms and environmental predictors of risk or resilience to drug addiction and associated relapse. Increasing evidence suggests microglia and astrocytes can profoundly affect the physiological and addictive properties of drugs of abuse, including morphine. We report that glia within the rat nucleus accumbens (NAcc) respond to morphine with an increase in cytokine/chemokine expression, which predicts future reinstatement of morphine conditioned place preference (CPP) following a priming dose of morphine. This glial response to morphine is influenced by early-life experience. A neonatal handling paradigm that increases the quantity and quality of maternal care significantly increases baseline expression of the anti-inflammatory cytokine IL-10 within the NAcc, attenuates morphine-induced glial activation, and prevents the subsequent reinstatement of morphine CPP in adulthood. IL-10 expression within the NAcc and reinstatement of CPP are negatively correlated, suggesting a protective role for this specific cytokine against morphine-induced glial reactivity and drug-induced reinstatement of morphine CPP. Neonatal handling programs the expression of IL-10 within the NAcc early in development, and this is maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. The effect of neonatal handling is mimicked by pharmacological modulation of glia in adulthood with ibudilast, which increases IL-10 expression, inhibits morphine-induced glial activation within the NAcc, and prevents reinstatement of morphine CPP. Taken together, we have identified a novel gene × early-life environment interaction on morphine-induced glial activation and a specific role for glial activation in drug-induced reinstatement of drug-seeking behavior.

Early-Life Experience Decreases Drug-Induced Reinstatement of Morphine CPP in Adulthood via Microglial-Specific Epigenetic Programming of Anti-Inflammatory IL-10 Expression

PubMed Central

Schwarz, Jaclyn M.; Hutchinson, Mark R.; Bilbo, Staci D.

2012-01-01

A critical component of drug addiction research involves identifying novel biological mechanisms and environmental predictors of risk or resilience to drug addiction and associated relapse. Increasing evidence suggests microglia and astrocytes can profoundly affect the physiological and addictive properties of drugs of abuse, including morphine. We report that glia within the rat Nucleus Accumbens (NAcc) respond to morphine with an increase in cytokine/chemokine expression, which predicts future reinstatement of morphine conditioned place preference (CPP) following a priming dose of morphine. This glial response to morphine is influenced by early-life experience. A neonatal handling paradigm that increases the quantity and quality of maternal care significantly increases baseline expression of the anti-inflammatory cytokine IL-10 within the NAcc, attenuates morphine-induced glial activation, and prevents the subsequent reinstatement of morphine CPP in adulthood. IL-10 expression within the NAcc and reinstatement of CPP are negatively correlated, suggesting a protective role for this specific cytokine against morphine-induced glial reactivity and drug-induced reinstatement of morphine CPP. Neonatal handling programs the expression of IL-10 within the NAcc early in development, and this is maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. The effect of neonatal handling is mimicked by pharmacological modulation of glia in adulthood with Ibudilast, which increases IL-10 expression, inhibits morphine-induced glial activation within the NAcc, and prevents reinstatement of morphine CPP. Taken together, we have identified a novel gene X early-life environment interaction on morphine-induced glial activation, and a specific role for glial activation in drug-induced reinstatement of drug-seeking behavior. PMID:22159099

Ultra-low dose (+)-naloxone restores the thermal threshold of morphine tolerant rats.

PubMed

Chou, Kuang-Yi; Tsai, Ru-Yin; Tsai, Wei-Yuan; Wu, Ching-Tang; Yeh, Chun-Chang; Cherng, Chen-Hwan; Wong, Chih-Shung

2013-12-01

As known, long-term morphine infusion leads to tolerance. We previously demonstrated that both co-infusion and post-administration of ultra-low dose (±)-naloxone restores the antinociceptive effect of morphine in morphine-tolerant rats. However, whether the mechanism of the action of ultra-low dose (±)-naloxone is through opioid receptors or not. Therefore, in the present study, we further investigated the effect of ultra-low dose (+)-naloxone, it does not bind to opioid receptors, on the antinociceptive effect of morphine. Male Wistar rats were implanted with one or two intrathecal (i.t.) catheters; one catheter was connected to a mini-osmotic pump, used for morphine (15 μg/h), ultra-low dose (+)-naloxone (15 pg/h), morphine plus ultra-low dose (+)-naloxone (15 pg/h) or saline (1 μl/h) infusion for 5 days. On day 5, either ultra-low dose (+)-naloxone (15 pg) or saline (5 μl) was injected via the other catheter immediately after discontinued morphine or saline infusion. Three hours later, morphine (15 μg in 5 μl saline) or saline were given intrathecally. All rats received nociceptive tail-flick test every 30 minutes for 120 minutes after morphine challenge at different temperature (45-52°C, respective). Our results showed that, both co-infusion and post-treatment of ultra-low dose (+)-naloxone with morphine preserves the antinociceptive effect of morphine. Moreover, in the post administration rats, ultra-low dose (+)-naloxone further enhances the antinociceptive effect of morphine. This study provides an evidence for ultra-low dose (+)-naloxone as a therapeutic adjuvant for patients who need long-term opioid administration for pain management. Copyright © 2013. Published by Elsevier B.V.

Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation.

PubMed

Pan, Yinbing; Sun, Xiaodi; Jiang, Lai; Hu, Liang; Kong, Hong; Han, Yuan; Qian, Cheng; Song, Chao; Qian, Yanning; Liu, Wentao

2016-11-17

Tolerance seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine. The microglial cell line BV-2 cells and mouse brain-derived endothelial cell line bEnd3 cells were used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signaling was assayed by western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using tail-flick tests. We found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin. Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore, systemic administration of metformin significantly blocked morphine-induced microglial activation in the spinal cord and then attenuated the development of chronic morphine tolerance in mice. Metformin significantly attenuated morphine antinociceptive tolerance by suppressing morphine-induced microglial activation through increasing AMPK phosphorylation.

[Behavioural studies during the gestational-lactation period in morphine treated rats].

PubMed

Sobor, Melinda; Timár, Júlia; Riba, Pál; Király, Kornél P; Al-Khrasani, Mahmoud; Gyarmati, Zsuzsanna; Fürst, Zsuzsanna

2013-12-01

Opioids impair the maternal behaviour of experimental animals. The effect of morphine on maternal behaviour in rat dams treated chronically with morphine during the whole pregnancy and lactation has not been yet analysed systematically. The aim of our work was to investigate the behavioural effects of moderate dose morphine administered constantly in the whole perinatal period in rats. Nulliparous female rats were treated with 10 mg/kg morphine s.c. once daily, from the day of mating. Maternal behaviour was observed, the effects of acute morphine treatment on the maternal behaviour and whether this effect could be antagonised by naloxone were also investigated. Physical and other behavioural (anxiety-like signals in elevated plus maze, changes in locomotor activity) withdrawal signs precipitated by naloxone were registered. After weaning sensitivity to the rewarding effect of morphine was measured by conditioned place preference and to the aversive effect of naloxone by conditioned place aversion tests. Antinociceptive test on tail-flick apparatus was performed to investigate the changes in morphine antinociceptive effects due to chronic morphine treatment. Maternal behaviour was significantly impaired in morphine-treated dams. This effect of morphine lasted c.a. 2-3 hours a day, it showed dose-dependency and was enhanced in MO-treated group (sensitisation). Only weak physical and no other behavioural (anxiety-like behaviour or hypolocomotion) withdrawal signs were precipitated by naloxone. The positive reinforcing effect of morphine and aversive effect of naloxone were markedly increased on conditioned place paradigm. Significant antinociceptive tolerance was not seen. Although human drug abuse can be hardly modelling under experimental circumstances, our constant, relatively moderate dose morphine treatment administered once daily during the whole pregnancy and lactation resulted in several subtle behavioural changes in dams. In perinatally opioid-exposed offspring short- and long-term behavioural disturbances can be detected which is well-known from literature. Besides direct pharmacological effects of morphine impaired maternal responsiveness and pup care could play a role in these disturbances.

Effect of Nimodipine on Morphine-related Withdrawal Syndrome in Rat Model: An Observational Study

PubMed Central

Mishra, Pravash Ranjan; Barik, Mayadhar; Ray, Subrata Basu

2017-01-01

Objective: To observe the effect of L-type calcium channel blocker like nimodipine on morphine's withdrawal when it was administered continuously along with morphine versus a single bolus dose of nimodipine, which was administered at the end of the experiment before the precipitation of withdrawal reaction in morphine-dependent rats. Materials and Methods: Four groups of adult male Wistar rats were rendered morphine dependent by subcutaneous injections of morphine at a dose of 10 mg/kg for 10 days. Nimodipine 10 mg/kg intraperitoneally (ip) administered to one group once daily before morphine administration in the entire experimental period, and another group received nimodipine only once at the end of the experiment as a single bolus dose 2 mg/kg before the administration of naloxone. Naloxone 3 mg/kg was administered ip to all the groups to precipitate withdrawal reactions. The withdrawal reactions were evaluated and scored as per the Gellert and Holtzman global withdrawal rating scale. Results: Nimodipine when administered as a single bolus dose before naloxone administration in morphine-dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period. Conclusion: We discovered that nimodipine helps in attenuating the severity of morphine withdrawal having potential role encountered during pharmacotherapy with morphine management of opioid dependence, well memory, impairement, cell signaling and phosphorylation of neuron. PMID:28553371

Effect of Nimodipine on Morphine-related Withdrawal Syndrome in Rat Model: An Observational Study.

PubMed

Mishra, Pravash Ranjan; Barik, Mayadhar; Ray, Subrata Basu

2017-01-01

To observe the effect of L-type calcium channel blocker like nimodipine on morphine's withdrawal when it was administered continuously along with morphine versus a single bolus dose of nimodipine, which was administered at the end of the experiment before the precipitation of withdrawal reaction in morphine-dependent rats. Four groups of adult male Wistar rats were rendered morphine dependent by subcutaneous injections of morphine at a dose of 10 mg/kg for 10 days. Nimodipine 10 mg/kg intraperitoneally (ip) administered to one group once daily before morphine administration in the entire experimental period, and another group received nimodipine only once at the end of the experiment as a single bolus dose 2 mg/kg before the administration of naloxone. Naloxone 3 mg/kg was administered ip to all the groups to precipitate withdrawal reactions. The withdrawal reactions were evaluated and scored as per the Gellert and Holtzman global withdrawal rating scale. Nimodipine when administered as a single bolus dose before naloxone administration in morphine-dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period. We discovered that nimodipine helps in attenuating the severity of morphine withdrawal having potential role encountered during pharmacotherapy with morphine management of opioid dependence, well memory, impairement, cell signaling and phosphorylation of neuron.

Morphine treatment enhances glutamatergic input onto neurons of the nucleus accumbens via both disinhibitory and stimulating effect.

PubMed

Yuan, Kejing; Sheng, Huan; Song, Jiaojiao; Yang, Li; Cui, Dongyang; Ma, Qianqian; Zhang, Wen; Lai, Bin; Chen, Ming; Zheng, Ping

2017-11-01

Drug addiction is a chronic brain disorder characterized by the compulsive repeated use of drugs. The reinforcing effect of repeated use of drugs on reward plays an important role in morphine-induced addictive behaviors. The nucleus accumbens (NAc) is an important site where morphine treatment produces its reinforcing effect on reward. However, how morphine treatment produces its reinforcing effect on reward in the NAc remains to be clarified. In the present study, we studied the influence of morphine treatment on the effects of DA and observed whether morphine treatment could directly change glutamatergic synaptic transmission in the NAc. We also explored the functional significance of morphine-induced potentiation of glutamatergic synaptic transmission in the NAc at behavioral level. Our results show that (1) morphine treatment removes the inhibitory effect of DA on glutamatergic input onto NAc neurons; (2) morphine treatment potentiates glutamatergic input onto NAc neurons, especially the one from the basolateral amygdala (BLA) to the NAc; (3) blockade of glutamatergic synaptic transmission in the NAc or ablation of projection neurons from BLA to NAc significantly decreases morphine treatment-induced increase in locomotor activity. These results suggest that morphine treatment enhances glutamatergic input onto neurons of the NAc via both disinhibitory and stimulating effect and therefore increases locomotor activity. © 2016 Society for the Study of Addiction.

Does Maternal Buprenorphine Dose Affect Severity or Incidence of Neonatal Abstinence Syndrome?

PubMed

Wong, Jacqueline; Saver, Barry; Scanlan, James M; Gianutsos, Louis Paul; Bhakta, Yachana; Walsh, James; Plawman, Abigail; Sapienza, David; Rudolf, Vania

2018-06-13

To measure the incidence, onset, duration, and severity of neonatal abstinence syndrome (NAS) in infants born to mothers receiving buprenorphine and to assess the association between buprenorphine dose and NAS outcomes. We reviewed charts of all mother-infant pairs maintained on buprenorphine who delivered in our hospital from January 1, 2000 to April 1, 2016. In 89 infants, NAS incidence requiring morphine was 43.8%. Means for morphine-treated infants included: 55.2 hours to morphine start, 15.9 days on morphine, and 20 days hospital stay. NAS requiring morphine treatment occurred in 48.5% and 41.4% of infants of mothers receiving ≤8 mg/d buprenorphine versus >8 mg/d, respectively (P = 0.39). We found no significant associations of maternal buprenorphine dose with peak NAS score, NAS severity requiring morphine, time to morphine start, peak morphine dose, or days on morphine. Among the other factors examined, only exclusive breastfeeding was significantly associated with neonatal outcomes, specifically lower odds of morphine treatment (odds ratio 0.24, P = 0.003). These findings suggest higher buprenorphine doses can be prescribed to pregnant women receiving medication therapy for addiction without increasing NAS severity. Our finding of reduced risk of NAS requiring morphine treatment also suggests breastfeeding is both safe and beneficial for these infants and should be encouraged.

Agmatine reduces only peripheral-related behavioral signs, not the central signs, of morphine withdrawal in nNOS deficient transgenic mice.

PubMed

Aricioglu, Feyza; Paul, Ian A; Regunathan, Soundar

2004-01-09

Agmatine inhibits morphine tolerance/dependence and potentiates morphine analgesia. This study was designed to investigate whether neuronal nitric oxide mediates the actions of agmatine in morphine dependence by using mice lacking a functional form of this enzyme. Mice received agmatine just after the morphine pellet implantation for 3 days twice daily or single injection 30 min before naloxone. In both genotypes treated for 3 days with morphine pellets, naloxone administration precipitated clear signs of withdrawal. Both acute and chronic administration of agmatine reduced withdrawal signs in wild type mice and reduced only peripheral signs of morphine dependence in neuronal nitric oxide synthase knockout mice. Withdrawal signs, that are related to central nervous system activity were not affected. These findings indicate that neuronal nitric oxide synthase partly mediates the effects of agmatine in morphine physical dependence.

Effects of Shilajit on the development of tolerance to morphine in mice.

PubMed

Tiwari, P; Ramarao, P; Ghosal, S

2001-03-01

Effects of concomitant administration of Processed Shilajit (PS, 0.1 and 1 mg/kg, i.p.), in Swiss mice were evaluated on the development of tolerance to morphine induced analgesia in the hot plate test. Chronic administration of morphine (10 mg/kg, i.p., b.i.d.) to mice over a duration of 10 days resulted in the development of tolerance to the analgesic effect of morphine. Concomitant administration of PS with morphine, from day 6 to day 10, resulted in a significant inhibition of the development of tolerance to morphine (10 mg/kg, i.p.) induced analgesia. Processed Shilajit per se, in the doses used, did not elicit any significant analgesia in mice; nor did the chronic concomitant administration of Processed Shilajit alter the morphine-induced analgesia. These findings with Processed Shilajit indicate its potential as a prospective modifier of analgesic tolerance to morphine. Copyright 2001 John Wiley & Sons, Ltd.

Morphine, but not Trauma, Sensitizes to Systemic Acinetobacter baumannii Infection

PubMed Central

Breslow, Jessica M.; Monroy, M. Alexandra; Daly, John M.; Meissler, Joseph J.; Gaughan, John; Adler, Martin W.; Eisenstein, Toby K.

2014-01-01

Acinetobacter baumannii is an important nosocomial pathogen in civilian intensive care units. Recently the incidence has increased in wounded military personnel. Morphine is documented in numerous animal studies to be immunosuppressive and to sensitize to infection. The hypotheses were tested that morphine, administered for analgesia in the battlefield, predisposes to Acinetobacter infection, and that the opioid may have an additive or synergistic effect with trauma. To test these hypotheses, an intraperitoneal infection model was established in mice using several Acinetobacter strains. Morphine administered for 48 hr by implantation of a slow-release morphine pellet increased mortality compared to animals receiving a placebo pellet, an effect that was blocked by the mu-opioid receptor antagonist, naltrexone. Acinetobacter burdens in the blood, spleens, livers, and lungs of morphine-treated mice, were significantly higher than those in placebo-treated animals, confirming that mortality was due to potentiated growth of the bacteria. There were also elevated levels of pro-inflammatory cytokines in morphine-treated versus placebo-treated mice. Morphine caused a reduction in the total number of cells in the peritoneal cavity, a decrease in the percentage and total numbers of neutrophils, and a decrease in the total number of macrophages. Morphine treatment also suppressed levels of the neutrophil-inducing molecules, IL-17A and KC/CXCL1. However, IL-17A−/− mice given morphine were not sensitized to Acintobacter infection to a greater degree than similarly treated wild-type mice. Trauma alone did not sensitize to Acinetobacter infection, and there was no additive effect between morphine and trauma. These results support the hypothesis that morphine potentiates Acinetobacter infection. PMID:21826405

The Neuroprotection of Low-Dose Morphine in Cellular and Animal Models of Parkinson’s Disease Through Ameliorating Endoplasmic Reticulum (ER) Stress and Activating Autophagy

PubMed Central

Wang, Bing; Su, Cun-Jin; Liu, Teng-Teng; Zhou, Yan; Feng, Yu; Huang, Ya; Liu, Xu; Wang, Zhi-Hong; Chen, Li-Hua; Luo, Wei-Feng; Liu, Tong

2018-01-01

Parkinson’s disease (PD) is a common neurodegenerative disease characterized the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Brain endogenous morphine biosynthesis was reported to be impaired in PD patients and exogenous morphine attenuated 6-hydroxydopamine (6-OHDA)-induced cell death in vitro. However, the mechanisms underlying neuroprotection of morphine in PD are still unclear. In the present study, we investigated the neuroprotective effects of low-dose morphine in cellular and animal models of PD and the possible underlying mechanisms. Herein, we found 6-OHDA and rotenone decreased the mRNA expression of key enzymes involved in endogenous morphine biosynthesis in SH-SY5Y cells. Incubation of morphine prevented 6-OHDA-induced apoptosis, restored mitochondrial membrane potential, and inhibited the accumulation of intracellular reactive oxygen species (ROS) in SH-SY5Y cells. Furthermore, morphine attenuated the 6-OHDA-induced endoplasmic reticulum (ER) stress possible by activating autophagy in SH-SY5Y cells. Finally, oral application of low-dose morphine significantly improved midbrain tyrosine hydroxylase (TH) expression, decreased apomorphine-evoked rotation and attenuated pain hypersensitivity in a 6-OHDA-induced PD rat model, without the risks associated with morphine addiction. Feeding of low-dose morphine prolonged the lifespan and improved the motor function in several transgenic Drosophila PD models in gender, genotype, and dose-dependent manners. Overall, our results suggest that neuroprotection of low-dose morphine may be mediated by attenuating ER stress and oxidative stress, activating autophagy, and ameliorating mitochondrial function. PMID:29731707

Morphine, but not trauma, sensitizes to systemic Acinetobacter baumannii infection.

PubMed

Breslow, Jessica M; Monroy, M Alexandra; Daly, John M; Meissler, Joseph J; Gaughan, John; Adler, Martin W; Eisenstein, Toby K

2011-12-01

Acinetobacter baumannii is an important nosocomial pathogen in civilian intensive care units. Recently the incidence has increased in wounded military personnel. Morphine is documented in numerous animal studies to be immunosuppressive and to sensitize to infection. The hypotheses were tested that morphine, administered for analgesia in the battlefield, predisposes to Acinetobacter infection, and that the opioid may have an additive or synergistic effect with trauma. To test these hypotheses, an intraperitoneal infection model was established in mice using several Acinetobacter strains. Morphine administered for 48 h by implantation of a slow-release morphine pellet increased mortality compared to animals receiving a placebo pellet, an effect that was blocked by the mu-opioid receptor antagonist, naltrexone. Acinetobacter burdens in the blood, spleens, livers, and lungs of morphine-treated mice, were significantly higher than those in placebo-treated animals, confirming that mortality was due to potentiated growth of the bacteria. There were also elevated levels of pro-inflammatory cytokines in morphine-treated versus placebo-treated mice. Morphine caused a reduction in the total number of cells in the peritoneal cavity, a decrease in the percentage and total numbers of neutrophils, and a decrease in the total number of macrophages. Morphine treatment also suppressed levels of the neutrophil-inducing molecules, IL-17A and KC/CXCL1. However, IL-17A(-/-) mice given morphine were not sensitized to Acintobacter infection to a greater degree than similarly treated wild-type mice. Trauma alone did not sensitize to Acinetobacter infection, and there was no additive effect between morphine and trauma. These results support the hypothesis that morphine potentiates Acinetobacter infection.

Suppression of transmission of nociceptive impulses by morphine

PubMed Central

Duggan, A.W.; Hall, J.G.; Headley, P.M.

1977-01-01

1 In spinal cats anaesthetized with α-chloralose, a study was made of the effects of morphine and naloxone, administered electrophoretically from micropipettes, on the responses of dorsal horn neurones to noxious (raising of skin temperature above 45°C) and innocuous (deflection of hairs) peripheral stimuli. 2 Administered near cell bodies, morphine reduced the nociceptive responses of only 2 of 37 cells. Excitation occurred more commonly than depression and abnormalities in action potentials were commonly observed following ejection of morphine. None of these effects of morphine was antagonized by electrophoretically applied naloxone. 3 Administered in the substantia gelatinosa from one micropipette while recording responses of deeper neurones with a second micropipette, morphine reduced the nociceptive responses of 15 of 19 neurones. Firing in response to deflection of hairs was not reduced by morphine. Depression of nociceptive responses by morphine was long lasting (>20 minutes). Naloxone ejected into the substantia gelatinosa or given intravenously in doses as low as 0.1 mg/kg antagonized the effects of morphine. The effectiveness of this dose of intravenous naloxone suggests that the concentrations of morphine in the substantia gelatinosa which reduced nociceptive responses were not unlike those present after analgesic doses of systemic morphine. Naloxone alone, and excitant and depressant amino acids ejected into the substantia gelatinosa had little effect on cell firing. 4 Both the selective action of morphine on nociceptive responses and the reversal of this action by intravenous naloxone suggest that the opiate receptor present in the substantia gelatinosa is relevant to analgesia produced by opiates given systemically. PMID:199311

Differential Changes in Expression of Stress- and Metabolic-Related Neuropeptides in the Rat Hypothalamus during Morphine Dependence and Withdrawal

PubMed Central

Núnez, Cristina; Zelei, Edina; Polyák, Ágnes; Milanés, M. Victoria

2013-01-01

Chronic morphine treatment and naloxone precipitated morphine withdrawal activates stress-related brain circuit and results in significant changes in food intake, body weight gain and energy metabolism. The present study aimed to reveal hypothalamic mechanisms underlying these effects. Adult male rats were made dependent on morphine by subcutaneous implantation of constant release drug pellets. Pair feeding revealed significantly smaller weight loss of morphine treated rats compared to placebo implanted animals whose food consumption was limited to that eaten by morphine implanted pairs. These results suggest reduced energy expenditure of morphine-treated animals. Chronic morphine exposure or pair feeding did not significantly affect hypothalamic expression of selected stress- and metabolic related neuropeptides - corticotropin-releasing hormone (CRH), urocortin 2 (UCN2) and proopiomelanocortin (POMC) compared to placebo implanted and pair fed animals. Naloxone precipitated morphine withdrawal resulted in a dramatic weight loss starting as early as 15–30 min after naloxone injection and increased adrenocorticotrophic hormone, prolactin and corticosterone plasma levels in morphine dependent rats. Using real-time quantitative PCR to monitor the time course of relative expression of neuropeptide mRNAs in the hypothalamus we found elevated CRH and UCN2 mRNA and dramatically reduced POMC expression. Neuropeptide Y (NPY) and arginine vasopressin (AVP) mRNA levels were transiently increased during opiate withdrawal. These data highlight that morphine withdrawal differentially affects expression of stress- and metabolic-related neuropeptides in the rat hypothalamus, while relative mRNA levels of these neuropeptides remain unchanged either in rats chronically treated with morphine or in their pair-fed controls. PMID:23805290

Modulation of morphine antinociceptive tolerance and physical dependence by co-administration of simvastatin.

PubMed

Mansouri, Mohammad Taghi; Khodayar, Mohammad Javad; Tabatabaee, Amirhossein; Ghorbanzadeh, Behnam; Naghizadeh, Bahareh

2015-10-01

Statins, 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, are widely used in the management of different diseases beyond their primary indication for lowering cholesterol. Previous studies have demonstrated the neuroprotective effects of simvastatin in different animal models. In the present study, we examined the effects of simvastatin (30, 60, 100 and 300mg/kg, p.o.) on the development and expression of morphine-induced tolerance and dependence in mice. For the induction of morphine tolerance and dependence, mice were twice daily treated with morphine (10mg/kg, s.c.) for 5 consecutive days. Tolerance was evaluated by the hot-plate test and physical dependence by naloxone challenge, on the sixth day. The results showed that oral administration of simvastatin produced antinociceptive activity in a dose-dependent way. Co-administration of simvastatin with morphine did not affect the acute morphine-induced analgesia (10mg/kg, s.c.). However, repeated co-administration of simvastatin with morphine significantly attenuated the development of tolerance to the analgesic effect of morphine and inhibited the naloxone (5mg/kg, s.c.)-precipitated withdrawal signs (jumping and body weight loss). Also, simvastatin at doses of 100 and 300mg/kg attenuated the expression of morphine-induced tolerance and dependence. These data indicated that, while simvastatin can alleviate both development and expression of morphine-induced tolerance, it cannot enhance morphine-induced antinociception. Taken together, simvastatin may be used as an adjutant therapeutic agent in combination with morphine and or other opioids in patients with severe chronic pain. Copyright © 2015 Elsevier Inc. All rights reserved.

Oral Morphine Use in South India: A Population-Based Study

PubMed Central

Karim, Safiya; Booth, Christopher M.

2017-01-01

Purpose Access to opioids for pain control is recognized as an urgent issue in low- and middle-income countries. Here we report temporal and regional trends in morphine use in Kerala, India. Methods Oral morphine use data for the State of Kerala (2012 to 2015) was used to describe temporal trends, regional variation, and provider characteristics. Total morphine use was calculated for each district of Kerala to derive an annual per capita use rate (milligrams per capita). Each provider was classified as government, private, nongovernment organization (NGO), or NGO partnership. Results Oral morphine use for Kerala was 1.32 mg/capita and increased over the study period 27% (from 1.23 mg/capita to 1.56 mg/capita). There was substantial variation in morphine use across districts (range, 0.49 mg/capita to 2.97 mg/capita; six-fold difference). This variation increased over time (19-fold difference in 2015). In 2015, 31% of morphine providers (51 of 167) were government institutions; they delivered 48% of total morphine in Kerala. Corresponding data for other providers are private institutions, 23% of centers and 13% of morphine; NGOs, 41% of centers and 34% of morphine; and NGO partnerships, 5% of centers and 4% of morphine. From 2012 to 2015, the total number of centers increased by 35%, from 124 to 167. Conclusion Oral morphine use has increased over time in Kerala but remains substantially lower than estimated need. There is significant geographic variation of use. Efforts are needed to improve palliative care in Kerala and to reduce regional disparities in access to opioids. PMID:29244992

Effects of carprofen and morphine on the minimum alveolar concentration of isoflurane in dogs.

PubMed

Ko, Jeff C H; Weil, Ann B; Inoue, Tomohito

2009-01-01

The minimum alveolar concentration (MAC) of isoflurane in dogs was determined following carprofen (2.2 mg/kg per os) alone, morphine (1 mg/kg intravenously) alone, carprofen and morphine, and no drug control in eight healthy adult dogs. Isoflurane MAC following administration of morphine alone (0.81%+/-0.18%) or carprofen and morphine (0.68%+/-0.31%) was significantly less than the control MAC (1.24%+/-0.15%). Isoflurane MAC after carprofen alone (1.13%+/-0.13%) was not significantly different from the control value. Results indicated that administration of morphine alone or in combination with carprofen significantly reduced the MAC of isoflurane in dogs. The isoflurane MAC reduction was additive between the effects of carprofen and morphine.

Effect of prenatal restraint stress and morphine co-administration on plasma vasopressin concentration and anxiety behaviors in adult rat offspring.

PubMed

Nakhjiri, Elnaz; Saboory, Ehsan; Roshan-Milani, Shiva; Rasmi, Yousef; Khalafkhani, Davod

2017-03-01

Stressful events and exposure to opiates during gestation have important effects on the later mental health of the offspring. Anxiety is among the most common mental disorders. The present study aimed to identify effects of prenatal restraint stress and morphine co-administration on plasma vasopressin concentration (PVC) and anxiety behaviors in rats. Pregnant rats were divided into four groups (n = 6, each): saline, morphine, stress + saline and stress + morphine treatment. The stress procedure consisted of restraint twice per day, two hours per session, for three consecutive days starting on day 15 of pregnancy. Rats in the saline and morphine groups received either 0.9% saline or morphine intraperitoneally on the same days. In the morphine/saline + stress groups, rats were exposed to restraint stress and received either morphine or saline intraperitoneally. All offspring were tested in an elevated plus maze (EPM) on postnatal day 90 (n = 6, each sex), and anxiety behaviors of each rat were recorded. Finally, blood samples were collected to determine PVC. Prenatal morphine exposure reduced anxiety-like behaviors. Co-administration of prenatal stress and morphine increased locomotor activity (LA) and PVC. PVC was significantly lower in female offspring of the morphine and morphine + stress groups compared with males in the same group, but the opposite was seen in the saline + stress group. These data emphasize the impact of prenatal stress and morphine on fetal neuroendocrine development, with long-term changes in anxiety-like behaviors and vasopressin secretion. These changes are sex specific, indicating differential impact of prenatal stress and morphine on fetal neuroendocrine system development. Lay Summary Pregnant women are sometimes exposed to stressful and painful conditions which may lead to poor outcomes for offspring. Opiates may provide pain and stress relief to these mothers. In this study, we used an experimental model of maternal exposure to stress and morphine in pregnant rats. The findings indicated that maternal stress increased anxiety in offspring while morphine decreased such effects, but had negative effects on the levels of a hormone controlling blood pressure, and activity of offspring. Hence morphine should not be used in pregnancy for pain and stress relief.

S-adenosyl methionine (SAM) attenuates the development of tolerance to analgesic activity of morphine in rats.

PubMed

Katyal, Jatinder; Kumar, Hemant; Joshi, Dinesh; Gupta, Yogendra Kumar

2017-04-03

Development of tolerance to analgesic effect, on chronic administration of morphine, limits its clinical usefulness in pain management. S-adenosyl methionine (SAM) used for arthritis and approved as a supplement in many countries including United States was evaluated for reducing morphine tolerance. Male 'Wistar' rats were used. The analgesic activity was determined using tail flick analgesiometer (Columbus Instruments, USA). Rats given morphine (7mg/kg), intraperitoneally (i.p.), once daily for 5days developed tolerance to analgesic effect. To evaluate the effect of SAM on morphine tolerance, SAM 800mg/kg was administered orally (p.o.), 45min prior to each dose of morphine. The analgesic activity of SAM and opioidergic component in its activity was also evaluated. Co-administration of morphine and SAM reversed morphine tolerance. SAM exhibited analgesic effect after repeated administration which was reversed by naloxone administration. Since safety of SAM on chronic use is documented it can be a good option in morphine tolerance. Role in drug addiction and withdrawal should also be evaluated. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibition of the ubiquitin-proteasome activity prevents glutamate transporter degradation and morphine tolerance.

PubMed

Yang, Liling; Wang, Shuxing; Lim, Grewo; Sung, Backil; Zeng, Qing; Mao, Jianren

2008-12-01

Glutamate transporters play a crucial role in physiological glutamate homeostasis and neurotoxicity. Recently, we have shown that downregulation of glutamate transporters after chronic morphine exposure contributed to the development of morphine tolerance. In the present study, we examined whether regulation of the glutamate transporter expression with the proposed proteasome inhibitor MG-132 would contribute to the development of tolerance to repeated intrathecal (twice daily x 7 days) morphine administration in rats. The results showed that MG-132 (5 nmol) given intrathecally blocked morphine-induced glutamate transporter downregulation and the decrease in glutamate uptake activity within the spinal cord dorsal horn. Co-administration of morphine (15 nmol) with MG-132 (vehicle=1<2.5<5=10 nmol) also dose-dependently prevented the development of morphine tolerance in rats. These findings suggest that prevention of spinal glutamate transporter downregulation may regulate the glutamatergic function that has been implicated in the development of morphine tolerance. The possible relationship between MG-132-mediated regulation of glutamate transporters, ubiquitin-proteasome system, and the cellular mechanisms of morphine tolerance is discussed in light of these findings.

Morphine-induced kinetic alterations of choline acetyltransferase of the rat caudate nucleus

PubMed Central

Datta, K.; Wajda, I. J.

1972-01-01

1. In order to explain the decrease of choline acetyltransferase (2.3.1.6.) activity observed in the caudate nucleus of morphine-treated rats, partially purified preparations of the enzyme were used in kinetic studies, with choline as substrate. 2. The apparent Michaelis constant for the enzyme obtained from normal rats was found to be 0·9 mM choline; this value doubled when the animals were killed one hour after a single injection of morphine (30 mg/kg). When the rats were injected daily for 4 or 15 days, and killed one hour after the last injection, the apparent Km value was 2·1 mM in each case. Prolonged daily treatment with morphine, followed by 48 h withdrawal, or by administration of 4 mg/kg of naloxone (given half an hour after the last injection of morphine) resulted in apparent Km values of 1·3-1·5 mM of choline, suggesting a gradual return to the lower, normal substrate requirement. Vmax changes were insignificant. 3. The effect of morphine added in vitro to different enzyme preparations was also studied. The Km values of 0·9 mM, in the enzyme isolated from normal rats, increased to 2·0 after incubation in vitro with 12·5 mM morphine. Similar increases were found in enzymes obtained from rats 48 h after the withdrawal of morphine or from rats injected with naloxone after prolonged morphine treatment. The high apparent Km values, found in enzyme obtained from animals killed one hour after the last dose of morphine, did not change upon incubation with 12·5 mM morphine. A similar pattern of Km changes was noticed after incubation with 25 mM acetylcholine. 4. An increase of 32% in acetylcholine (ACh) level was found in the caudate nucleus one hour after subcutaneous injection of 30 mg/kg of morphine. Return to normal values was observed when morphine was administered daily. After two to three weeks of daily treatment and subsequent withdrawal from morphine for 48 h, the levels of ACh were normal. If the daily treated rats were given naloxone within half an hour of the last injection of morphine, and killed 30 min later, the levels of ACh remained normal. 5. Fifty per cent inhibition of enzyme activity was observed upon in vitro incubation with 75 mM acetylcholine, or with 25 mM morphine. The same degree of inhibition was noticed when the enzyme was obtained from normal or from morphine-treated rats. PMID:5041452

Morphine administration during low ovarian hormone stage results in transient over expression of fear memories in females.

PubMed

Perez-Torres, Emily M; Ramos-Ortolaza, Dinah L; Morales, Roberto; Santini, Edwin; Rios-Ruiz, Efrain J; Torres-Reveron, Annelyn

2015-01-01

Acute exposure to morphine after a traumatic event reduces trauma related symptoms in humans and conditioned fear expression in male rats. We aimed to determine whether acute administration of morphine alters consolidation of fear learning and extinction. Male and female rats in proestrus and metaestrus (high and low ovarian hormones respectively) underwent fear conditioning and received saline or morphine (2.5 mg/kg s.c.). The next day they underwent extinction. Results showed increased freezing during extinction only in the morphine metaestrus group while morphine did not affect males or proestrus females. Recall of extinction was similar on all groups. On a second experiment, a subset of rats conditioned during metaestrus was administered morphine prior to extinction producing no effects. We then measured mu opioid receptor (MOR) expression in the amygdala and periaqueductal gray (PAG) at the end of extinction (day 2). In males and proestrus females, morphine caused an increase in MOR in the amygdala but no in the PAG. In metaestrus females, morphine did not change MOR expression in either structure. These data suggests that ovarian hormones may interact with MORs in the amygdala to transiently alter memory consolidation. Morphine given after trauma to females with low ovarian hormones might increase the recall of fear responses, making recovery harder.

Overexpression of Thioredoxin-1 Blocks Morphine-Induced Conditioned Place Preference Through Regulating the Interaction of γ-Aminobutyric Acid and Dopamine Systems.

PubMed

Li, Xiang; Huang, Mengbing; Yang, Lihua; Guo, Ningning; Yang, Xiaoyan; Zhang, Zhimin; Bai, Ming; Ge, Lu; Zhou, Xiaoshuang; Li, Ye; Bai, Jie

2018-01-01

Morphine is one kind of opioid, which is currently the most effective widely utilized pain relieving pharmaceutical. Long-term administration of morphine leads to dependence and addiction. Thioredoxin-1 (Trx-1) is an important redox regulating protein and works as a neurotrophic cofactor. Our previous study showed that geranylgeranylaceton, an inducer of Trx-1 protected mice from rewarding effects induced by morphine. However, whether overexpression of Trx-1 can block morphine-induced conditioned place preference (CPP) in mice is still unknown. In this study, we first examined whether overexpression of Trx-1 affects the CPP after morphine training and further examined the dopamine (DA) and γ-aminobutyric acid (GABA) systems involved in rewarding effects. Our results showed that morphine-induced CPP was blocked in Trx-1 overexpression transgenic (TG) mice. Trx-1 expression was induced by morphine in the ventral tegmental area (VTA) and nucleus accumbens (NAc) in wild-type (WT) mice, which was not induced in Trx-1 TG mice. The DA level and expressions of tyrosine hydroxylase (TH) and D1 were induced by morphine in WT mice, which were not induced in Trx-1 TG mice. The GABA level and expression of GABA B R were decreased by morphine, which were restored in Trx-1 TG mice. Therefore, Trx-1 may play a role in blocking CPP induced by morphine through regulating the expressions of D1, TH, and GABA B R in the VTA and NAc.

Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord.

PubMed

Dai, Wen-Ling; Xiong, Feng; Yan, Bing; Cao, Zheng-Yu; Liu, Wen-Tao; Liu, Ji-Hua; Yu, Bo-Yang

2016-12-22

Tolerance induced by morphine remains a major unresolved problem and significantly limits its clinical use. Recent evidences have indicated that dopamine D2 receptor (D2DR) is likely to be involved in morphine-induced antinociceptive tolerance. However, its exact effect and molecular mechanism remain unknown. In this study we examined the effect of D2DR on morphine antinociceptive tolerance in mice spinal cord. Chronic morphine treatment significantly increased levels of D2DR in mice spinal dorsal horn. And the immunoreactivity of D2DR was newly expressed in neurons rather than astrocytes or microglia both in vivo and in vitro. Blockade of D2DR with its antagonist (sulpiride and L-741,626, i.t.) attenuated morphine antinociceptive tolerance without affecting basal pain perception. Sulpiride (i.t.) also down-regulated the expression of phosphorylation of NR1, PKC, MAPKs and suppressed the activation of astrocytes and microglia induced by chronic morphine administration. Particularly, D2DR was found to interact with μ opioid receptor (MOR) in neurons, and chronic morphine treatment enhanced the MOR/D2DR interactions. Sulpiride (i.t.) could disrupt the MOR/D2DR interactions and attenuate morphine tolerance, indicating that neuronal D2DR in the spinal cord may be involved in morphine tolerance possibly by interacting with MOR. These results may present new opportunities for the treatment and management of morphine-induced antinociceptive tolerance which often observed in clinic.

Morphine-induced changes in acetylcholine release in the interpeduncular nucleus and relationship to changes in motor behavior in rats

PubMed Central

Taraschenko, Olga D.; Rubbinaccio, Heather Y.; Shulan, Joseph M.; Glick, Stanley D.; Maisonneuve, Isabelle M.

2007-01-01

Owing to multiple anatomical connections and functional interactions between the habenulo-interpeduncular and the mesolimbic pathways, it has been proposed that these systems could together mediate the reinforcing properties of addictive drugs. 18-Methoxycoronaridine, an agent that reduces morphine self-administration and attenuates dopamine sensitization in the nucleus accumbens in response to repeated morphine, has been shown to produce these effects by acting in the medial habenula and interpeduncular nucleus. Acetylcholine, one of the predominant neurotransmitters in the interpeduncular nucleus, may be a major determinant of these interactions. To determine if and how morphine acts in the interpeduncular nucleus, the effects of acute and repeated administration of morphine on extracellular acetylcholine levels in this brain area were assessed. In addition, the motor behavior of rats receiving repeated morphine administration was monitored during microdialysis sessions. Acutely, morphine produced a biphasic effect on extracellular acetylcholine levels in the interpeduncular nucleus such that low and high doses of morphine (i.e., 5 and 20 mg/kg i.p.) significantly increased and decreased acetylcholine levels, respectively. Repeated administration of the same doses of morphine resulted in tolerance to the inhibitory but not to the stimulatory effects; tolerance was accompanied by sensitization to morphine-induced changes in locomotor activity and stereotypic behavior. The latter results suggest that tolerance to morphine's effect on the cholinergic habenulo-interpeduncular pathway is related to its sensitizing effects on the mesostriatal dopaminergic pathways. PMID:17544456

Effects of paclitaxel on mechanical sensitivity and morphine reward in male and female C57Bl6 mice

PubMed Central

Neelakantan, Harshini; Ward, Sara Jane; Walker, Ellen Ann

2016-01-01

This study evaluated the hypothesis that a paclitaxel treatment regimen sufficient to produce mechanical allodynia would alter sensitivities of male and female mice to the conditioned rewarding and reinforcing effects of morphine. Saline or paclitaxel were administered on days 1, 3, 5, and 7 in male and female C57Bl/6 mice to induce morphine-reversible mechanical allodynia as measured by the Von Frey filament test. Paclitaxel treatment did not change sensitivity to morphine conditioned place preference (CPP) relative to saline treatment in either male or female mice. Morphine produced peak self-administration under a fixed ratio-1 schedule of reinforcement for 0.03 mg/kg morphine per infusion in female mice and 0.1 mg/kg morphine per infusion in male mice. During the progressive ratio experiments, saline treatment in male mice decreased the number of morphine infusions for 12 days whereas the paclitaxel-treated male mice maintained responding for morphine similar to baseline levels during the same time period. However, paclitaxel did not have an overall effect on the reinforcing efficacy of morphine assessed over a limited dose range during the course of the repeated self-administration. These results suggest that the reward-related behavioral effects of morphine are overall not robustly altered by the presence of paclitaxel treatment under the current dosing regimen, with the exception of maintaining a small yet significant higher baseline than saline treatment during the development of allodynia in male mice. PMID:27929349

Effects of voluntary exercise on anxiety-like behavior and voluntary morphine consumption in rat pups borne from morphine-dependent mothers during pregnancy.

PubMed

Haydari, Sakineh; Miladi-Gorji, Hossein; Mokhtari, Amin; Safari, Manouchehr

2014-08-22

Exposure to morphine during pregnancy produced long-term effects in offspring behaviors. Recent studies have shown that voluntary exercise decreases the severity of anxiety behaviors in both morphine-dependent and withdrawn rats. Thus, the aims of the present study were to examine whether maternal exercise decreases prenatal dependence-induced anxiety and also, voluntary consumption of morphine in animal models of craving in rat pups. Pregnant rats were made dependent by chronic administration of morphine in drinking water simultaneously with access to a running wheel that lasted at least 21 days. Then, anxiety-like behaviors using the elevated plus-maze (EPM) and voluntary consumption of morphine using a two-bottle choice paradigm (TBC) were tested in male rat pups. The results showed that the rat pups borne from exercising morphine-dependent mothers exhibited an increase in EPM open arm time (P<0.0001) and entries (P<0.05) as compared with the sedentary groups. In animal models of craving showed that voluntary consumption of morphine in the rat pups borne from exercising morphine-dependent mothers was less in the second (P<0.032) and third (P<0.014) periods of intake as compared with the sedentary group. This study showed that maternal exercise decreases the severity of the anxiogenic-like behaviors and voluntary consumption of morphine in rat pups. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Administration of the glial cell modulator, minocycline, in the nucleus accumbens attenuated the maintenance and reinstatement of morphine-seeking behavior.

PubMed

Arezoomandan, Reza; Haghparast, Abbas

2016-03-01

Relapse to drug use is one of the most difficult clinical problems in treating addiction. Glial activation has been linked with the drug abuse, and the glia modulators such as minocycline can modulate the drug abuse effects. The aim of the present study was to determine whether minocycline could attenuate the maintenance and reinstatement of morphine. Conditioned place preference (CPP) was induced by subcutaneous injection of morphine (5 mg/kg) for 3 days. Following the acquisition of the CPP, the rats were given daily bilateral intra-NAc injections of either minocycline (1, 5, and 10 μg/0.5 μL) or saline (0.5 μL). The animals were tested for conditioning score 60 min after each injection. To induce the reinstatement, a priming dose of morphine (1 mg/kg) was injected 1 day after the final extinction day. The morphine-induced CPP lasted for 7 days after cessation of morphine treatment. Our data revealed that a priming dose of morphine could reinstate the extinguished morphine-induced CPP. Daily intra-accumbal injection of minocycline during the extinction period blocked the maintenance of morphine CPP and also attenuated the priming-induced reinstatement. Our findings indicated that minocycline could facilitate the extinction and attenuate the reinstatement of morphine. These results provided new evidence that minocycline might be considered as a promising therapeutic agent for the treatment of several symptoms associated with morphine abuse.

Antidiuretic effect of morphine in the rat: tolerance and physical dependence.

PubMed Central

Huidobro, F

1978-01-01

1 Injection of rats with morphine or methadone, before they received a water load equivalent to 5% of their body weight, produced a dose-dependent antidiuretic effect. Following the antidiuresis, urine was eliminated with kinetics similar to control untreated rats. 2 The antidiuretic effect of morphine or methadone was blocked by naloxone administered before the opiate, or reversed when given after the opiate. 3 Rats implanted with morphine pellets developed a marked degree of tolerance to the antidiuretic effect of morphine. Tolerance was also obtained on injection of three daily doses of morphine or methadone over two days. 4 Withdrawal symptoms were precipitated by naloxone in rats implanted with pellets of morphine; under these conditions the animals showed a marked reduction in urine production as compared to naive rats. PMID:568501

Fatty acid amide hydrolase-morphine interaction influences ventilatory response to hypercapnia and postoperative opioid outcomes in children.

PubMed

Chidambaran, Vidya; Pilipenko, Valentina; Spruance, Kristie; Venkatasubramanian, Raja; Niu, Jing; Fukuda, Tsuyoshi; Mizuno, Tomoyuki; Zhang, Kejian; Kaufman, Kenneth; Vinks, Alexander A; Martin, Lisa J; Sadhasivam, Senthilkumar

2017-01-01

Fatty acid amide hydrolase (FAAH) degrades anandamide, an endogenous cannabinoid. We hypothesized that FAAH variants will predict risk of morphine-related adverse outcomes due to opioid-endocannabinoid interactions. In 101 postsurgical adolescents receiving morphine analgesia, we prospectively studied ventilatory response to 5% CO 2 (HCVR), respiratory depression (RD) and vomiting. Blood was collected for genotyping and morphine pharmacokinetics. We found significant FAAH-morphine interaction for missense (rs324420) and several regulatory variants, with HCVR (p < 0.0001) and vomiting (p = 0.0339). HCVR was more depressed in patients who developed RD compared with those who did not (p = 0.0034), thus FAAH-HCVR association predicts risk of impending RD from morphine use. FAAH genotypes predict risk for morphine-related adverse outcomes.

Using a Morphine Equivalence Metric to Quantify Opioid Consumption: Examining the Capacity to Provide Effective Treatment of Debilitating Pain at the Global, Regional, and Country Levels

PubMed Central

Gilson, Aaron M.; Maurer, Martha A.; Ryan, Karen M.; Cleary, James F.; Rathouz, Paul J.

2014-01-01

Context Morphine has been considered the gold standard for treating moderate to severe pain, although many new opioid products and formulations have been marketed in the last two decades and should be considered when examining opioid consumption. Understanding opioid consumption is improved by using an equianalgesic measure that controls for the strengths of all examined opioids. Objectives The research objective was to utilize a morphine equivalence metric to determine the extent that morphine consumption relates to the total consumption of all other study opioids. Methods A Morphine Equivalence (ME) metric was created for morphine and for the aggregate consumption of each study opioid (Total ME), adjusted for country population to allow for uniform equianalgesic comparisons. Graphical and statistical evaluations of morphine use and Total ME consumption trends (between 1980 and 2009) were made for the global and geographic regional levels, and for selected developed and developing countries. Results Global morphine consumption rose dramatically in the early 1980s but has been significantly outpaced by Total ME since 1996. As expected, the extent of morphine and Total ME consumption varied notably among regions, with the Americas, Europe, and Oceania regions accounting for the highest morphine use and Total ME in 2009. Developing and least developed countries, compared to developed countries, demonstrated lower overall Total ME consumption. Conclusion Generally, worldwide morphine use has not increased at the rate of Total ME, especially in recent years. Examining a country's ability to effectively manage moderate to severe pain should extend beyond morphine to account for all available potent opioids. PMID:23017614

Extinction of opiate reward reduces dendritic arborization and c-Fos expression in the nucleus accumbens core.

PubMed

Leite-Morris, Kimberly A; Kobrin, Kendra L; Guy, Marsha D; Young, Angela J; Heinrichs, Stephen C; Kaplan, Gary B

2014-04-15

Recurrent opiate use combined with environmental cues, in which the drug was administered, provokes cue-induced drug craving and conditioned drug reward. Drug abuse craving is frequently linked with stimuli from a prior drug-taking environment via classical conditioning and associative learning. We modeled the conditioned morphine reward process by using acquisition and extinction of conditioned place preference (CPP) in C57BL/6 mice. Mice were trained to associate a morphine injection with a drug context using a classical conditioning paradigm. In morphine conditioning (0, 0.25, 0.5, 1, 5, or 10 mg/kg) experimental mice acquired a morphine CPP dose response with 10mg/kg as most effective. During morphine CPP extinction experiments, mice were divided into three test groups: morphine CPP followed by extinction training, morphine CPP followed by sham extinction, and saline controls. Extinction of morphine CPP developed within one extinction experiment (4 days) that lasted over two more trials (another 8 days). However, the morphine CPP/sham extinction group retained a place preference that endured through all three extinction trials. Brains were harvested following CPP extinction and processed using Golgi-Cox impregnation. Changes in dendritic morphology and spine quantity were examined in the nucleus accumbens (NAc) Core and Shell neurons. In the NAcCore only, morphine CPP/extinguished mice produced less dendritic arborization, and a decrease in neuronal activity marker c-Fos compared to the morphine CPP/sham extinction group. Extinction of morphine CPP is associated with decreased structural complexity of dendrites in the NAcCore and may represent a substrate for learning induced structural plasticity relevant to addiction. Published by Elsevier B.V.

Methadone Reverses Analgesic Tolerance Induced by Morphine Pretreatment

PubMed Central

Posa, Luca; Accarie, Alison; Marie, Nicolas

2016-01-01

Background: Opiates such as morphine are the most powerful analgesics, but their protracted use is restrained by the development of tolerance to analgesic effects. Recent works suggest that tolerance to morphine might be due to its inability to promote mu opioid receptor endocytosis, and the co-injection of morphine with a mu opioid receptor internalizing agonist like [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin reduces tolerance to morphine. So far, no studies have been conducted to evaluate the ability of methadone to reduce morphine tolerance in morphine-pretreated animals, a treatment sequence that could be encountered in opiate rotation protocol. We investigated the ability of methadone (a mu opioid receptor internalizing agonist used in therapy) to reverse morphine tolerance and the associated cellular mechanisms in the periaqueductal gray matter, a region involved in pain control. Methods: We measured analgesic response following a challenge dose of morphine in the hot plate test and investigated regulation of mu opioid receptor (coupling and endocytosis) and some cellular mechanisms involved in tolerance such as adenylate cyclase superactivation and changes in N-methyl-d-aspartate receptor subunits expression and phosphorylation state. Results: A chronic treatment with morphine promoted tolerance to its analgesic effects and was associated with a lack of mu opioid receptor endocytosis, adenylate cyclase overshoot, NR2A and NR2B downregulation, and phosphorylation of NR1. We reported that a methadone treatment in morphine-treated mice reversed morphine tolerance to analgesia by promoting mu opioid receptor endocytosis and blocking cellular mechanisms of tolerance. Conclusions: Our data might lead to rational strategies to tackle opiate tolerance in the frame of opiate rotation. PMID:26390873

Comparison of epidural morphine versus intramuscular morphine for postoperative analgesia.

PubMed

Baftiu, Nehat; Hadri, Burhan; Mustafa, Aziz

2010-01-01

To compare effects and side effects or complications of epidural versus intramuscularly administered morphine for relieve of postoperative pain. In the first group (epidural) analgesia is achieved by application of morphine through epidural catheter. To the amount of morphine is added physiological solution until 10 ml of total volume of the mixture is achieved. This mixture is given to 150 patients, by epidural route before the exit from the operation room. Epidural catheter is removed after 48 hours. Second group (intramuscular) analgesia is realized by application of 10 mg of morphine by intramuscular route. Morphine is injected at the end of surgery. Pain is assessed with combination of verbal categorical scale and visual analog scale. Verbal categorical scale used is 8 points scale and contains words of Tursky: 0 no pain, 1 very low pain, 2 week pain, 3 mild pain, 4 moderate pain, 5 strong pain, 6 severe pain, 7 untolerated pain. Awareness is assed during first 24 hours. For this Reynolds 4 points scale is used: awaked 1, somnolent 2, sleepy 3, deep sleep 4. Pain assessed by visual analog scale (VAS) is 15.17-29.62 in the epidural group patients versus 26.39-70.83 in intramuscular group. Variation of respiration rate in both groups is not significant 22.21 +/- 4.23 and 23.98 +/- 2.72 in minute, in epidural and intramuscular morphine groups, respectively. PaCO2 and PaO2 values are similar without significant variation 35.34 +/- 4.72 mmHg in the epidural morphine group and 31.3 +/- 3.21 mmHg in intramuscular morphine group. Epidural administration of morphine provides better analgesia in quality, since it is deeper, longer in duration and with less inhibitory supra-spinal actions when compared to intramuscular administered morphine.

Opiate alkaloids in Ascaris suum.

PubMed

Pryor, S C; Putnam, Jennifer; Hoo, Nanyamka

2004-01-01

The parasitic worm Ascaris suum contains the opiate alkaloids morphine and morphine-6-glucuronide as determined by HPLC coupled to electrochemical detection and by gas chromatography/mass spectrometry. The level of morphine in muscle tissue of female and male is 252 +/- 32.68, 1168 +/- 278 and 180 +/- 23.47 (ng/g of wet tissue), respectively. The level of M6G in muscle tissue of female and male is 167 +/- 28.37 and 92 +/- 11.45 (ng/g of wet tissue), respectively. Furthermore, Ascaris maintained for 5 days contained a significant amount of morphine, as did their medium, demonstrating their ability to synthesize the opiate alkaloid. The anatomic distribution of morphine was examined by indirect immunofluorescent staining and HPLC of various tissues dissected from male and female adult worms. Immunofluorescence revealed morphine in the subcuticle layers, in the animals' nerve chords and in the female reproductive organs. Morphine was found to be most prevalent in the muscle tissue and there is significantly more morphine in females than males, probably due to the large amounts in the female uterus. Morphine (10(-9) M) and morphine-6-glucuronide (10(-9) M) stimulated the release of NO from Ascaris muscle tissue. Naloxone (10(-7) M), and L-NAME (10(-6) M) blocked (P < 0.005) morphine-stimulated NO release from A. suum muscle. CTOP (10(-7) M) did not block morphine's NO release. However, naloxone could not block M6G stimulated NO release by muscle tissue, whereas CTOP (10(-7) M) blocked its release. These findings were in seeming contradiction to our inability to isolate a mu opiate receptor messenger RNA by RT-PCR using a human mu primer. This suggests that a novel mu opiate receptor was present and selective toward M6G.

Memantine and dizocilpine interactions with antinociceptive or discriminative stimulus effects of morphine in rats after acute or chronic treatment with morphine

PubMed Central

Chen, Yukun; Evola, Marianne

2013-01-01

Rationale Memantine is a N-methyl-d-aspartic acid receptor (NMDAR) channel blocker that binds to dizocilpine sites and appears well tolerated during chronic use. Published studies suggest NMDAR antagonists prevent development of tolerance to effects of morphine by blocking NMDAR hyperactivation. Objectives We sought to compare effects of memantine to those of the more frequently studied dizocilpine and to evaluate memantine as a potential adjunct to modify tolerance to mu-opioid receptor agonists. Methods Sprague–Dawley rats were trained to discriminate morphine (3.2 mg/kg) and saline under fixed ratio 15 schedules of food delivery. Potency and maximal stimulus or rate-altering effects of cumulative doses of morphine were examined 30 min after pretreatment with dizocilpine (0.032–0.1 mg/kg) or memantine (5–10 mg/kg) and after chronic treatment with combinations of dizocilpine or memantine and morphine, 10 mg/kg twice daily, for 6 to 14 days. Effects of dizocilpine or memantine on morphine antinociception were examined in a 55 °C water tail-withdrawal assay with drug treatments parallel to those in discrimination studies. Results Acutely, memantine attenuated while dizocilpine potentiated the stimulus and antinociceptive effects of morphine. Neither chronic dizocilpine nor memantine blocked tolerance to the stimulus effects of morphine. In contrast, combined-treatment with dizocilpine (0.1 mg/kg) blocked tolerance to antinociceptive effects of lower (0.1∼3.2 mg/kg) but not higher doses of morphine, whereas memantine did not block tolerance. Conclusions Memantine and dizocilpine interacted differently with morphine, possibly due to different NMDAR binding profiles. The lack of memantine-induced changes in morphine tolerance suggests memantine may not be a useful adjunct in chronic pain management. PMID:22864944

Pleiotrophin modulates morphine withdrawal but has no effects on morphine-conditioned place preference.

PubMed

Gramage, Esther; Vicente-Rodríguez, Marta; Herradón, Gonzalo

2015-09-14

Pleiotrophin (PTN) is a neurotrophic factor with important functions in addiction and neurodegenerative disorders. Morphine administration induces an increase in the expression of PTN and Midkine (MK), the only other member of this family of cytokines, in brain areas related with the addictive effects of drug of abuse, like the Ventral Tegmental Area or the hippocampus. In spite of previous studies showing that PTN modulates amphetamine and ethanol rewarding effects, and that PTN is involved in morphine-induced analgesia, it was still unknown if the rewarding effects of morphine may be regulated by endogenous PTN. Thus, we aim to study the role of PTN in the reward and physical dependence induced by morphine. We used the Conditioned Place Preference (CPP) paradigm in PTN genetically deficient (PTN-/-) and wild type (WT) mice to assess the rewarding effects of morphine in absence of endogenous PTN. Second, to study if PTN may be involved in morphine physical dependence, naloxone-precipitated withdrawal syndrome was induced in PTN-/- and WT morphine dependent mice. Although the increase in the time spent in the morphine-paired compartment after conditioning tended to be more pronounced in PTN-/- mice, statistical significance was not achieved. The data suggest that PTN does not exert an important role in morphine reward. However, our results clearly indicate that PTN-/- mice develop a more severe withdrawal syndrome than WT mice, characterized as a significant increase in the time standing and in the total incidences of forepaw licking, forepaw tremors, wet dog shake and writhing. The data presented here suggest that PTN is a novel genetic factor that plays a role in morphine withdrawal syndrome. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

D1- and D2-like dopamine receptors in the CA1 region of the hippocampus are involved in the acquisition and reinstatement of morphine-induced conditioned place preference.

PubMed

Assar, Nasim; Mahmoudi, Dorna; Farhoudian, Ali; Farhadi, Mohammad Hasan; Fatahi, Zahra; Haghparast, Abbas

2016-10-01

The hippocampus plays a vital role in processing contextual memories and reward related learning tasks, such as conditioned place preference (CPP). Among the neurotransmitters in the hippocampus, dopamine is deeply involved in reward-related processes. This study assessed the role of D1- and D2-like dopamine receptors within the CA1 region of the hippocampus in the acquisition and reinstatement of morphine-CPP. To investigate the role of D1 and D2 receptors in morphine acquisition, the animals received different doses of D1- and/or D2-like dopamine receptor antagonists (SCH23390 and sulpiride, respectively) into the CA1, 5min before the administration of morphine (5mg/kg, subcutaneously) during a 3-days conditioning phase. To evaluate the involvement of these receptors in morphine reinstatement, the animals received different doses of SCH23390 or sulpiride (after extinction period) 5min before the administration of a low dose of morphine (1mg/kg) in order to reinstate the extinguished morphine-CPP. Conditioning scores were recorded by Ethovision software. The results of this study showed that the administration of SCH23390 or sulpiride, significantly decreased the acquisition of morphine-CPP. Besides, the injection of these antagonists before the administration of a priming dose of morphine, following the extinction period, decreased the reinstatement of morphine-CPP in sacrificed rats. However, the effect of sulpiride on the acquisition and reinstatement of morphine-CPP was more significant than that of SCH23390. These findings suggested that D1- and D2-like dopamine receptors in the CA1 are involved in the acquisition and reinstatement of morphine-CPP, and antagonism of these receptors can reduce the rewarding properties of morphine. Copyright © 2016 Elsevier B.V. All rights reserved.

Oral Analgesics Utilization for Children With Musculoskeletal Injury (OUCH Trial): An RCT.

PubMed

Le May, Sylvie; Ali, Samina; Plint, Amy C; Mâsse, Benoit; Neto, Gina; Auclair, Marie-Christine; Drendel, Amy L; Ballard, Ariane; Khadra, Christelle; Villeneuve, Edith; Parent, Stefan; McGrath, Patrick J; Leclair, Grégoire; Gouin, Serge

2017-11-01

Musculoskeletal injuries (MSK-Is) are a common and painful condition among children that remains poorly treated in the emergency department (ED). We aimed to test the efficacy of a combination of an anti-inflammatory drug with an opioid for pain management of MSK-I in children presenting to the ED. In this randomized, double-blinded, placebo-controlled trial, we enrolled children between 6 and 17 years presenting to the ED with an MSK-I and a pain score >29 mm on the visual analog scale (VAS). Participants were randomly assigned to oral morphine (0.2 mg/kg) + ibuprofen (10 mg/kg) (morphine + ibuprofen) or morphine (0.2 mg/kg) + placebo of ibuprofen or ibuprofen (10 mg/kg) + placebo of morphine. Primary outcome was children with VAS pain score <30 mm at 60 minutes postmedication administration. A total of 501 participants were enrolled and 456 were included in primary analyses (morphine + ibuprofen = 177; morphine = 188; ibuprofen = 91). Only 29.9% (morphine + ibuprofen), 29.3% (morphine), and 33.0% (ibuprofen) of participants achieved the primary outcome ( P = .81). Mean VAS pain reduction at 60 minutes were -18.7 (95% confidence interval [CI]: -21.9 to -16.6) (morphine + ibuprofen), -17.0 (95% CI: -20.0 to -13.9) (morphine), -18.6 (95% CI: -22.9 to -14.2) (ibuprofen) ( P = .69). Children in the morphine + ibuprofen group ( P < .001) and in the morphine group ( P < .001) experienced more side effects than those in the ibuprofen group. No serious adverse event was reported. Combination of morphine with ibuprofen did not provide adequate pain relief for children with MSK-I in the ED. None of the study medication provided an optimal pain management because most of children did not reach a mild pain score (NCT02064894). Copyright © 2017 by the American Academy of Pediatrics.

Spinal glucocorticoid receptor‑regulated chronic morphine tolerance may be through extracellular signal‑regulated kinase 1/2.

PubMed

Zhai, Mei-Li; Chen, Yi; Liu, Chong; Wang, Jian-Bo; Yu, Yong-Hao

2018-05-23

Opioid use has been limited in the treatment of chronic pain due to their side effects, including analgesic tolerance. Previous studies demonstrated that glucocorticoid receptors (GRs) may be involved in the development of chronic morphine tolerance; however, the mechanism remains unknown. It was hypothesized that the expression of spinal phosphorylated mitogen‑activated protein kinase [MAPK; phosphorylated extracellular signal‑regulated kinase (ERK)] is regulated through the spinal GRs, following chronic treatment with morphine. In the first experiment, the experimental rats were randomly divided into four groups: Control, morphine, morphine+GR antagonist mifepristone (RU38486) and morphine+GR agonist dexamethasone (Dex). Each group was treated with continuous intrathecal (IT) injection of the drugs for 6 days. The expression of GRs and MAPK 3/1 (p‑ERK 1/2) in the spinal dorsal horn was detected by western blot analysis and immunofluorescence staining. In the second experiment, the MAPK inhibitor PD98059 was added and the rats were randomly divided into four groups: Control, morphine, PD98059+morphine and PD98059+morphine+Dex. The continuous IT injection lasted for 7 days in each group. For all experiments, the tail flick test was conducted 30 min following administration every day to assess the thermal hyperalgesia of the rats. The experimental results demonstrated that there was a co‑existence of GRs and p‑ERK 1/2 in the spinal cord dorsal horn by double immunofluorescence staining. The GR antagonist RU38486 attenuated the morphine analgesia tolerance by inhibiting the expression of GR and increasing the expression of p‑ERK. The MAPK inhibitor PD98059 increased the effect of morphine tolerance and prolonged the duration of morphine tolerance. The present results suggest that spinal GRs may serve an important role in the development of morphine tolerance through the ERK signaling pathway.

False-positive buprenorphine EIA urine toxicology results due to high dose morphine: a case report.

PubMed

Tenore, Peter L

2012-01-01

In monitoring a patient with chronic pain who was taking high-dose morphine and oxycodone with weekly urine enzymatic immunoassay (EIA) toxicology testing, the authors noted consistent positives for buprenorphine. The patient was not taking buprenorphine, and gas chromatography/mass spectroscopy (GCMS) testing on multiple samples revealed no buprenorphine, indicating a case of false-positive buprenorphine EIAs in a high-dose opiate case. The authors discontinued oxycodone for a period of time and then discontinued morphine. Urine monitoring with EIAs and GCMS revealed false-positive buprenorphine EIAs, which remained only when the patient was taking morphine. When taking only oxycodone and no morphine, urine samples became buprenorphine negative. When morphine was reintroduced, false-positive buprenorphine results resumed. Medical practitioners should be aware that high-dose morphine (with morphine urine levels turning positive within the 15,000 to 28,000 mg/mL range) may produce false-positive buprenorphine EIAs with standard urine EIA toxicology testing.

Enhancement of the contact hypersensitivity reaction by acute morphine administration at the elicitation phase.

PubMed

Nelson, C J; How, T; Lysle, D T

1999-11-01

The present study investigated the effects of morphine on the irritant contact sensitivity (ICS) and contact hypersensitivity (CHS) reaction. ICS was induced by croton oil application on the pinnae of naïve rats. Morphine injected prior to croton oil application did not affect the ICS response when assessed by measurements of pinnae thickness. CHS was induced by applying the antigen 2,4-dinitro-1-fluorobenzene (DNFB) to the pinnae of rats sensitized to DNFB. Rats received an injection of morphine prior to either initial antigen exposure (sensitization) or antigen reexposure (challenge). Morphine prior to challenge, but not sensitization, resulted in a pronounced enhancement of the CHS response as measured by pinna thickness. Quantitative PCR also showed increased IFN-gamma mRNA levels in the inflamed tissue of morphine-treated rats. Naltrexone blocked the morphine-induced enhancement of the CHS response. The differential effects of morphine suggest that opioids have a more pronounced effect on in vivo immune responses that involve immunological memory. Copyright 1999 Academic Press.

Effect of 12-monoketocholic acid on modulation of analgesic action of morphine and tramadol.

PubMed

Kuhajda, Ivan; Posa, Mihalj; Jakovljević, Vida; Ivetić, Vesna; Mikov, Momir

2009-01-01

This work is concerned with the potential promotive action of 12-monoketocholic acid (12-MKC) on the analgesic effect of morphine and tramadol. The investigation was carried out on laboratory Wistar rats divided into five test groups, each treated with either morphine (2 mg/kg), tramadol (9.6 mg/kg), 12-MKC (2 mg/kg), morphine + 12-MKC, or tramadol + 12-MKC, the control group receiving physiological solution (2 mg/kg). The effect of 12-MKC on the analgesic action of morphine and tramadol was determined by radiation heat method. Morphine and tramadol, given in equimolar doses, did not show significant difference in the degree of analgesia. In combination with morphine, 12-MKC increased significantly the analgesic effect compared with the group treated with morphine alone. However, 12-MKC caused no change in the action of tramadol. The 5-day intravenous application of 12-MKC in combination with the two analgesics caused no changes in the biochemical parameters nor pathohistological changes in the liver parenchyma of tested animals.

Continuous intravenous morphine infusion for postoperative analgesia following posterior spinal fusion for idiopathic scoliosis.

PubMed

Poe-Kochert, Connie; Tripi, Paul A; Potzman, Jennifer; Son-Hing, Jochen P; Thompson, George H

2010-04-01

A retrospective study of postoperative pain management. Evaluate the efficacy and safety of continuous intravenous morphine infusion for postoperative pain management in patients with idiopathic scoliosis (IS) undergoing posterior spinal fusion (PSF) and segmental spinal instrumentation (SSI). Postoperative pain is a common problem following surgery for IS. There are no published reports regarding the use of a continuous intravenous morphine infusion for this patient population. We retrospectively reviewed data regarding 339 consecutive patients with IS who underwent PSF and SSI between 1992 and 2006. All patients received intrathecal morphine after the induction of general anesthesia. Following surgery, preordered morphine infusion (0.01 mg/kg/h) was started at first reported pain. The infusion rate was titrated based on vital signs, visual analog scale (VAS) pain scores (0-10), and clinical status. It was continued until patients were able to take oral analgesics. We reviewed intrathecal morphine dosage, VAS pain scores through the third postoperative day, interval to start of morphine infusion, total morphine requirements in the first 48 hours, and any adverse reactions (nausea/vomiting, pruritus, respiratory depression, and pediatric intensive care unit admission). Mean intrathecal morphine dose was 15.5 +/- 3.9 microg/kg and mean interval to start of the intravenous morphine infusion was 17.5 +/- 5 hours. Mean VAS pain scores were 3.1, 4.5, 4.5, and 4.6 at 12 hours, 1, 2, and 3 days after surgery, respectively.The total mean morphine dose in the first 48 hours postoperatively was 0.03 +/- 0.01 mg/kg/h. Total morphine received was 1.44 +/- 0.5 mg/kg. Nausea/vomiting and pruritus, related to the morphine infusion occurred in 45 patients (13.3%) and 14 patients (4.1%), respectively. No patients had respiratory depression or required Pediatric Intensive Care Unit admission. A low frequency of adverse events and a mean postoperative VAS pain score of 5 or less demonstrate that a continuous postoperative morphine infusion is a safe and effective method of pain management in patients with IS following PSF and SSI.

Hair testing in postmortem diagnosis of substance abuse: An unusual case of slow-release oral morphine abuse in an adolescent.

PubMed

Baillif-Couniou, Valérie; Kintz, Pascal; Sastre, Caroline; Pok, Phak-Rop Pos; Chèze, Marjorie; Pépin, Gilbert; Leonetti, Georges; Pelissier-Alicot, Anne-Laure

2015-11-01

Morphine sulfate misuse is essentially observed among regular heroin injectors. To our knowledge, primary addiction to morphine sulfate is exceptional, especially among young adolescents. A 13-year-old girl, with no history of addiction, was found dead with three empty blisters of Skenan(®) LP 30 mg at her side. Opiates were detected in biological fluids and hair by chromatographic methods. Blood analyses confirmed morphine overdose (free morphine: 428 ng/mL; total morphine: 584 ng/mL) and segmental hair analysis confirmed regular exposure over several months (maximum morphine concentration 250 pg/mg). Suspecting the victim's mother of recreational use of Skenan(®), the magistrate ordered analysis of her hair, with negative results. From an epidemiological viewpoint, this case of oral morphine sulfate abuse in an adolescent with no previous history suggests the emergence of a new trend of morphine sulfate consumption. From a toxicological viewpoint, it demonstrates the value of hair testing, which documented the victim's regular exposure and made an important contribution to the police investigation. Copyright © 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Acupuncture suppresses reinstatement of morphine-seeking behavior induced by a complex cue in rats.

PubMed

Lee, Bong Hyo; Lim, Sung Chul; Jeon, Hyeon Jeong; Kim, Jae Su; Lee, Yun Kyu; Lee, Hyun Jong; In, Sunghyun; Kim, Hee Young; Yoon, Seong Shoon; Yang, Chae Ha

2013-08-26

Morphine causes physical and psychological dependence for individuals after repeated-use. Above all, our previous study showed that acupuncture attenuated reinstatement of morphine-seeking behavior induced by pharmacological cue. In this study, we investigated whether acupuncture could suppress the reinstatement of morphine-seeking behavior induced by the combination of environmental and pharmacological cues and the possible neuronal involvement. Male Sprague-Dawley rats were trained to self-administer morphine (1.0 mg/kg) for 3 weeks. Following the withdrawal phase (7 days), the effects of acupuncture on reinstatement of morphine-seeking behavior were investigated. For the investigation of neuronal involvement, the GABAA receptor antagonist bicuculline and the GABAB receptor antagonist SCH 50911 were pre-treated. Morphine-seeking behavior induced by combination of re-exposure to the operant chamber and morphine injection was suppressed perfectly by acupuncture at SI5, but not at the control acupoint LI5 and this effect was blocked by pre-treatment with the GABA receptor antagonists. This study suggests that acupuncture at SI5 can be considered as a predominant therapy for the reinstatement of morphine-seeking behavior in humans. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Effects of microRNA-223 on morphine analgesic tolerance by targeting NLRP3 in a rat model of neuropathic pain

PubMed Central

Xie, Xiao-Juan; Ma, Li-Gang; Xi, Kai; Fan, Dong-Mei; Li, Jian-Guo; Zhang, Quan; Zhang, Wei

2017-01-01

Objective To investigate the effects of microRNA-223 on morphine analgesic tolerance by targeting NLRP3 in a rat model of neuropathic pain. Methods Our study selected 100 clean grade healthy Sprague-Dawley adult male rats weighing 200 to 250 g. After establishment of a rat model of chronic constriction injury, these rats were divided into 10 groups (10 rats in each group): the normal control, sham operation, chronic constriction injury, normal saline, morphine, miR-223, NLRP3, miR-223 + morphine, NLRP3 + morphine, and miR-223 + NLRP3 + morphine groups. The real-time quantitative polymerase chain reaction assay, Western blotting, and enzyme-linked immunosorbent assay were used for detecting the mRNA and protein expressions of NLRP3, apoptosis-associated speck-like protein, Caspase-1, Interleukin (IL)-1β, and IL-18 in sections of lumbar spinal cord. Immunohistochemistry was applied for detecting the positive rates of NLRP3, apoptosis-associated speck-like protein, Caspase-1, IL-1β, and IL-18. Results The paw withdrawal threshold and percentage maximum possible effect (%MPE) were higher in chronic constriction injury group when compared with the normal control and sham operation groups. Behavioral tests showed that compared with the chronic constriction injury and normal saline groups, the morphine and miR-223 + morphine groups showed obvious analgesic effects. Expressions of miR-223 in the miR-223, miR-223 + morphine, and miR-223 + NLRP3 + morphine were significantly higher than those in the chronic constriction injury, normal saline, and morphine groups. Compared with chronic constriction injury, normal saline and morphine groups, the mRNA and protein expressions of NLRP3, apoptosis-associated speck-like protein, Caspase-1, IL-1β, and IL-18 were significantly decreased in the miR-223 and miR-223 + morphine groups, while mRNA and protein expressions of NLRP3, apoptosis-associated speck-like protein, Caspase-1, IL-1β, and IL-18 were significantly increased in the NLRP3 and NLRP3 + morphine group. Conclusion Our study provides strong evidence that miR-223 could suppress the activities of NLRP3 inflammasomes (NLRP3, apoptosis-associated speck-like protein, and Caspase-1) to relieve morphine analgesic tolerance in rats by down-regulating NLRP3. PMID:28580822

The effect of IVPCA morphine on post-hysterectomy bowel function.

PubMed

Chan, Kuang-Cheng; Cheng, Ya-Jung; Huang, Guang-Ta; Wen, Yuan-Jui; Lin, Chen-Jung; Chen, Li-Kuei; Sun, Wei-Zen

2002-06-01

Although morphine has been shown to induce bowel dysfunction in a dose-dependent fashion, in most relevant studies it was investigated in single bolus injection. Recently, intravenous morphine via patient-controlled analgesia (IVPCA) has been widely used to provide analgesia by divided bolus doses on patients' demand with satisfactory effects. This approach, by reducing the peak serum surge, largely resembles the pharmacokinetic and pharmacodynamic advantage of continuous infusion. There is yet no report on the investigation of its effect on post-operative bowel dysfunction. Fifty-one women who underwent abdominal total hysterectomy (ATH) due to uterine myoma were enrolled to investigate the association between the doses of morphine consumption by PCA and the time of first passage of flatus. In all patients morphine was administered intravenously via a PCA pump immediately after recovery from general anesthesia. We found that 49 out of 51 patients (96%) exhibited mild pain with IVPCA morphine. They had consumed an average dose of 16.9 mg morphine (range, 0-46 mg) upon the first passage of flatus which occurred 2036.4 min (average) post-operatively. There was no correlation between the dose of morphine and the time of first passage of flatus (r = 0.053, P > 0.05). The absence of suppression of bowel movement by IVPCA morphine for post-operative pain control suggests that favorable pharmacokinetic profile of IVPCA can help reduce the morphine-induced bowel dysfunction at its therapeutic level.

Comparison of Morphine, Morphine-Lidocaine, and Morphine-Lidocaine-Ketamine Infusions in Dogs Using an Incision-Induced Pain Model.

PubMed

Chiavaccini, Ludovica; Claude, Andrew K; Meyer, Robert E

We aimed to compare antinociceptive effects of IV infusions of morphine (M), morphine-lidocaine (ML), or morphine-lidocaine-ketamine (MLK) combined, in a mild-to-moderate pain model in dogs. Eighteen adult hounds were heavily sedated with IV morphine (0.2 mg/kg) and dexmedetomidine to undergo thoracic skin incisions. After reversal, dogs were randomly assigned to receive loading doses of lidocaine and ketamine (MLK), lidocaine and saline (ML), or equivalent volume of saline (M), followed by 18 hr constant infusions of morphine (0.12 mg/kg/hr), lidocaine (3 mg/kg/hr) and ketamine (0.6 mg/kg/hr); morphine (0.12 mg/kg/hr) and lidocaine (3 mg/kg/hr); or morphine (0.12 mg/kg/hr), respectively. Pain was assessed with Short Form Glasgow Composite Measure Pain Scale and mechanical nociception with von Frey filaments (VFFS). Data were analyzed with linear mixed model on ranks. Independently of treatment, Short Form Glasgow Composite Measure Pain Scale was significantly higher than baseline for 24 hr (p < .0001), while VFFS was significantly lower than baseline for 48 hr post-recovery (p < .0001), with no difference between MLK and M groups. The ML group recorded significantly lower VFFS (p = .02) than the M group for the entire study. In conclusion, there was no significant analgesic difference between MLK and M alone.

Delay discounting of oral morphine and sweetened juice rewards in dependent and non-dependent rats.

PubMed

Harvey-Lewis, Colin; Perdrizet, Johnna; Franklin, Keith B J

2014-07-01

Opioid-dependent humans are reported to show accelerated delay discounting of opioid rewards when compared to monetary rewards. It has been suggested that this may reflect a difference in discounting of consumable and non-consumable goods not specific to dependent individuals. Here, we evaluate the discounting of similar morphine and non-morphine oral rewards in dependent and non-dependent rats We first tested the analgesic and rewarding effects of our morphine solution. In a second experiment, we assigned rats randomly to either dependent or non-dependent groups that, 30 min after daily testing, received 30 mg/kg subcutaneous dose of morphine, or saline, respectively. Delay discounting of drug-free reward was examined prior to initiation of the dosing regimen. We tested discounting of the morphine reward in half the rats and retested the discounting of the drug-free reward in the other half. All tests were run 22.5 h after the daily maintenance dose. Rats preferred the morphine cocktail to the drug-free solution and consumed enough to induce significant analgesia. The control quinine solution did not produce these effects. Dependent rats discounted morphine rewards more rapidly than before dependence and when compared to discounting drug-free rewards. In non-dependent rats both reward types were discounted similarly. These results show that morphine dependence increases impulsiveness specifically towards a drug reward while morphine experience without dependence does not.

Morphine- and CaMKII dependent enhancement of GIRK channel signaling in hippocampal neurons

PubMed Central

Nassirpour, Rounak; Bahima, Laia; Lalive, Arnaud L.; Lüscher, Christian; Luján, Rafael; Slesinger, Paul A.

2010-01-01

G protein-gated inwardly rectifying potassium (GIRK) channels, which help control neuronal excitability, are important for the response to drugs of abuse. Here, we describe a novel pathway for morphine-dependent enhancement of GIRK channel signaling in hippocampal neurons. Morphine treatment for ~20 h increased the colocalization of GIRK2 with PSD95, a dendritic spine marker. Western blot analysis and quantitative immuno-electron microscopy revealed an increase in GIRK2 protein and targeting to dendritic spines. In vivo administration of morphine also produced an upregulation of GIRK2 protein in the hippocampus. The mechanism engaged by morphine required elevated intracellular Ca2+ and was insensitive to pertussis toxin, implicating opioid receptors that may couple to Gq G proteins. met-enkephalin, but not the μ-selective (DAMGO) and δ-selective (DPDPE) opioid receptor agonists, mimicked the effect of morphine suggesting involvement of a heterodimeric opioid receptor complex. Peptide (KN-93) inhibition of CaMKII prevented the morphine-dependent change in GIRK localization while expression of a constitutively activated form of CaMKII mimicked the effects of morphine. Coincident with an increase in GIRK2 surface expression, functional analyses revealed that morphine-treatment increased the size of serotonin-activated GIRK currents and Ba2+-sensitive basal K+ currents in neurons. These results demonstrate plasticity in neuronal GIRK signaling that may contribute to the abusive effects of morphine. PMID:20926668

Fatty acid amide hydrolase–morphine interaction influences ventilatory response to hypercapnia and postoperative opioid outcomes in children

PubMed Central

Chidambaran, Vidya; Pilipenko, Valentina; Spruance, Kristie; Venkatasubramanian, Raja; Niu, Jing; Fukuda, Tsuyoshi; Mizuno, Tomoyuki; Zhang, Kejian; Kaufman, Kenneth; Vinks, Alexander A; Martin, Lisa J; Sadhasivam, Senthilkumar

2017-01-01

Aim: Fatty acid amide hydrolase (FAAH) degrades anandamide, an endogenous cannabinoid. We hypothesized that FAAH variants will predict risk of morphine-related adverse outcomes due to opioid–endocannabinoid interactions. Patients & methods: In 101 postsurgical adolescents receiving morphine analgesia, we prospectively studied ventilatory response to 5% CO2 (HCVR), respiratory depression (RD) and vomiting. Blood was collected for genotyping and morphine pharmacokinetics. Results: We found significant FAAH–morphine interaction for missense (rs324420) and several regulatory variants, with HCVR (p < 0.0001) and vomiting (p = 0.0339). HCVR was more depressed in patients who developed RD compared with those who did not (p = 0.0034), thus FAAH–HCVR association predicts risk of impending RD from morphine use. Conclusion: FAAH genotypes predict risk for morphine-related adverse outcomes. PMID:27977335

Opiate and non-opiate aspects of morphine induced seizures.

PubMed

Frenk, H; Liban, A; Balamuth, R; Urca, G

1982-12-16

The intraperitoneal administration of morphine hydrochloride at doses of 300 mg/kg produced analgesia, catalepsy, and electrographic spiking in rats that developed into electrographic seizure patterns after approximately 2.5 h. Whereas naltrexone (12 mg/kg) reversed analgesia and catalepsy, and diminished electrographic spiking, it precipitated electrographic seizure activity similar to that observed following intraperitoneal morphine alone. These seizures were accompanied by behavioral convulsions. No tolerance to these seizures developed with repeated paired administration of morphine and naltrexone or in morphine tolerant rats, but rather potentiation was observed. The epileptogenic effects were found to be potentiated in amygdaloid kindled rats, as well. It was concluded that morphine at these doses activates two different epileptogenic mechanisms, one mediated by opiate receptors, the other not. The possibility of the simultaneous activation of a morphine sensitive anticonvulsant mechanism is discussed.

Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part I.

PubMed

Armstrong, Scott C; Cozza, Kelly L

2003-01-01

Pharmacokinetic drug-drug interactions with morphine, hydromorphone, and oxymorphone are reviewed in this column. Morphine is a naturally occurring opiate that is metabolized chiefly through glucuronidation by uridine diphosphate glucuronosyl transferase (UGT) enzymes in the liver. These enzymes produce an active analgesic metabolite and a potentially toxic metabolite. In vivo drug-drug interaction studies with morphine are few, but they do suggest that inhibition or induction of UGT enzymes could alter morphine and its metabolite levels. These interactions could change analgesic efficacy. Hydromorphone and oxymorphone, close synthetic derivatives of morphine, are also metabolized primarily by UGT enzymes. Hydromorphone may have a toxic metabolite similar to morphine. In vivo drug-drug interaction studies with hydromorphone and oxymorphone have not been done, so it is difficult to make conclusions with these drugs.

Music therapy inhibits morphine-seeking behavior via GABA receptor and attenuates anxiety-like behavior induced by extinction from chronic morphine use.

PubMed

Kim, Ki Jin; Lee, Sang Nam; Lee, Bong Hyo

2018-05-01

Morphine is a representative pain killer. However, repeated use tends to induce addiction. Music therapy has been gaining interest as a useful type of therapy for neuropsychiatric diseases. The present study examined whether Korean traditional music (KT) could suppress morphine-seeking behavior and anxiety-like behavior induced by extinction from chronic morphine use and additionally investigated a possible neuronal mechanism. Male Sprague-Dawley rats were trained to intravenously self-administer morphine hydrochloride (1.0 mg/kg) using a fixed ratio 1 schedule in daily 2 h session during 3 weeks. After training, rats who established baseline (variation less than 20% of the mean of infusion for 3 consecutive days) underwent extinction. Music was played twice a day during extinction. In the second experiment, the selective antagonists of GABA A and GABA B receptors were treated before the last playing to investigate the neuronal mechanism focusing on the GABA receptor pathway. Another experiment of elevated plus maze was performed to investigate whether music therapy has an anxiolytic effect at the extinction phase. KT but not other music (Indian road or rock music) reduced morphine-seeking behavior induced by a priming challenge with morphine. And, this effect was blocked by the GABA receptor antagonists. In addition, KT showed anxiolytic effects against withdrawal from morphine. Results of this study suggest that KT suppresses morphine-seeking behavior via GABA receptor pathway. In addition, KT showed to have anxiolytic effects, suggesting it has bi-directional effects on morphine. Copyright © 2018 Elsevier B.V. All rights reserved.

Ethanol Reversal of Cellular Tolerance to Morphine in Rat Locus Coeruleus Neurons

PubMed Central

Llorente, Javier; Withey, Sarah; Rivero, Guadalupe; Cunningham, Margaret; Cooke, Alex; Saxena, Kunal; McPherson, Jamie; Oldfield, Sue; Dewey, William L.; Bailey, Chris P.; Kelly, Eamonn; Henderson, Graeme

2013-01-01

Consumption of ethanol is a considerable risk factor for death in heroin overdose. We sought to determine whether a mildly intoxicating concentration of ethanol could alter morphine tolerance at the cellular level. In rat locus coeruleus (LC) neurons, tolerance to morphine was reversed by acute exposure of the brain slice to ethanol (20 mM). Tolerance to the opioid peptide [d-Ala2,N-MePhe4,Gly-ol]-enkephalin was not reversed by ethanol. Previous studies in LC neurons have revealed a role for protein kinase C (PKC)α in μ-opioid receptor (MOPr) desensitization by morphine and in the induction and maintenance of morphine tolerance, but we have been unable to demonstrate that 20 mM ethanol produces significant inhibition of PKCα. The ability of ethanol to reverse cellular tolerance to morphine in LC neurons was absent in the presence of the phosphatase inhibitor okadaic acid, indicating that dephosphorylation is involved. In human embryonic kidney 293 cells expressing the MOPr, ethanol reduced the level of MOPr phosphorylation induced by morphine. Ethanol reversal of tolerance did not appear to result from a direct effect on MOPr since acute exposure to ethanol (20 mM) did not modify the affinity of binding of morphine to the MOPr or the efficacy of morphine for G-protein activation as measured by guanosine 5′-O-(3-[35S]thio)triphosphate binding. Similarly, ethanol did not affect MOPr trafficking. We conclude that acute exposure to ethanol enhances the effects of morphine by reversing the processes underlying morphine cellular tolerance. PMID:23716621

Effect of Tamoxifen and Brain-Penetrant Protein Kinase C and c-Jun N-Terminal Kinase Inhibitors on Tolerance to Opioid-Induced Respiratory Depression in Mice

PubMed Central

Withey, Sarah L.; Hill, Rob; Lyndon, Abigail; Dewey, William L.; Kelly, Eamonn

2017-01-01

Respiratory depression is the major cause of death in opioid overdose. We have previously shown that prolonged treatment of mice with morphine induces profound tolerance to the respiratory-depressant effects of the drug (Hill et al., 2016). The aim of the present study was to investigate whether tolerance to opioid-induced respiratory depression is mediated by protein kinase C (PKC) and/or c-Jun N-terminal kinase (JNK). We found that although mice treated for up to 6 days with morphine developed tolerance, as measured by the reduced responsiveness to an acute challenge dose of morphine, administration of the brain-penetrant PKC inhibitors tamoxifen and calphostin C restored the ability of acute morphine to produce respiratory depression in morphine-treated mice. Importantly, reversal of opioid tolerance was dependent on the nature of the opioid ligand used to induce tolerance, as these PKC inhibitors did not reverse tolerance induced by prolonged treatment of mice with methadone nor did they reverse the protection to acute morphine-induced respiratory depression afforded by prolonged treatment with buprenorphine. We found no evidence for the involvement of JNK in morphine-induced tolerance to respiratory depression. These results indicate that PKC represents a major mechanism underlying morphine tolerance, that the mechanism of opioid tolerance to respiratory depression is ligand-dependent, and that coadministration of drugs with PKC-inhibitory activity and morphine (as well as heroin, largely metabolized to morphine in the body) may render individuals more susceptible to overdose death by reversing tolerance to the effects of morphine. PMID:28130265

Morphine regulates Argonaute 2 and TH expression and activity but not miR-133b in midbrain dopaminergic neurons.

PubMed

García-Pérez, Daniel; López-Bellido, Roger; Hidalgo, Juana M; Rodríguez, Raquel E; Laorden, Maria Luisa; Núñez, Cristina; Milanés, Maria Victoria

2015-01-01

Epigenetic changes such as microRNAs (miRs)/Ago2-induced gene silencing represent complex molecular signature that regulate cellular plasticity. Recent studies showed involvement of miRs and Ago2 in drug addiction. In this study, we show that changes in gene expression induced by morphine and morphine withdrawal occur with concomitant epigenetic modifications in the mesolimbic dopaminergic (DA) pathway [ventral tegmental area (VTA)/nucleus accumbens (NAc) shell], which is critically involved in drug-induced dependence. We found that acute or chronic morphine administration as well as morphine withdrawal did not modify miR-133b messenger RNA (mRNA) expression in the VTA, whereas Ago2 protein levels were decreased and increased in morphine-dependent rats and after morphine withdrawal, respectively. These changes were paralleled with enhanced and decreased NAc tyrosine hydroxylase (TH) protein (an early DA marker) in morphine-dependent rats and after withdrawal, respectively. We also observed changes in TH mRNA expression in the VTA that could be related to Ago2-induced translational repression of TH mRNA during morphine withdrawal. However, the VTA number of TH-positive neurons suffered no alterations after the different treatment. Acute morphine administration produced a marked increase in TH activity and DA turnover in the NAc (shell). In contrast, precipitated morphine withdrawal decreased TH activation and did not change DA turnover. These findings provide new information into the possible correlation between Ago2/miRs complex regulation and DA neurons plasticity during opiate addiction. © 2013 Society for the Study of Addiction.

Acute Morphine, Chronic Morphine, and Morphine Withdrawal Differently Affect Pleiotrophin, Midkine, and Receptor Protein Tyrosine Phosphatase β/ζ Regulation in the Ventral Tegmental Area.

PubMed

García-Pérez, Daniel; Laorden, M Luisa; Milanés, M Victoria

2017-01-01

Pleiotrophin (PTN) and midkine (MK) are secreted growth factors and cytokines, proposed to be significant neuromodulators with multiple neuronal functions. PTN and MK are generally related with cell proliferation, growth, and differentiation by acting through different receptors. PTN or MK, signaling through receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ), lead to the activation of extracellular signal-regulated kinases (ERKs) and thymoma viral proto-oncogene (Akt), which induce morphological changes and modulate addictive behaviors. Besides, there is increasing evidence that during the development of drug addiction, astrocytes contribute to the synaptic plasticity by synthesizing and releasing substances such as cytokines. In the present work, we studied the effect of acute morphine, chronic morphine, and morphine withdrawal on PTN, MK, and RPTPβ/ζ expression and on their signaling pathways in the ventral tegmental area (VTA). Present results indicated that PTN, MK, and RPTPβ/ζ levels increased after acute morphine injection, returned to basal levels during chronic opioid treatment, and were upregulated again during morphine withdrawal. We also observed an activation of astrocytes after acute morphine injection and during opiate dependence and withdrawal. In addition, immunofluorescence analysis revealed that PTN, but not MK, was overexpressed in astrocytes and that dopaminergic neurons expressed RPTPβ/ζ. Interestingly, p-ERK 1/2 levels during chronic morphine and morphine withdrawal correlated RPTPβ/ζ expression. All these observations suggest that the neuroprotective and behavioral adaptations that occur during opiate addiction could be, at least partly, mediated by these cytokines.

Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine

PubMed Central

Hill, Rob; Lyndon, Abi; Withey, Sarah; Roberts, Joanne; Kershaw, Yvonne; MacLachlan, John; Lingford-Hughes, Anne; Kelly, Eamonn; Bailey, Chris; Hickman, Matthew; Henderson, Graeme

2016-01-01

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO2 in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths. PMID:26171718

Protective Effect of Bacoside-A against Morphine-Induced Oxidative Stress in Rats

PubMed Central

Sumathi, T.; Nathiya, V. C.; Sakthikumar, M.

2011-01-01

In the present study, we investigated the protective effect of bacoside-A the active principle isolated from the plant Bacopa monniera against oxidative damage induced by morphine in rat brain. Morphine intoxicated rats received 10-160 mg/kg b.w. of morphine hydrochloride intraperitoneally for 21 days. Bacoside-A pretreated rats were administered with bacoside-A (10 mg/kg b.w/day) orally, 2 h before the injection of morphine for 21 days. Pretreatment with bacoside-A has shown to possess a significant protective role against morphine induced brain oxidative damage in the antioxidant status (total reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase and lipid peroxidation) and membrane bound ATP-ases(Na+/K+ATPase. Ca2+ and Mg2+ ATPases) activities in rat. The results of the present study indicate that bacoside-A protects the brain from oxidative stress induced by morphine. PMID:22707825

Protective Effect of Bacoside-A against Morphine-Induced Oxidative Stress in Rats.

PubMed

Sumathi, T; Nathiya, V C; Sakthikumar, M

2011-07-01

In the present study, we investigated the protective effect of bacoside-A the active principle isolated from the plant Bacopa monniera against oxidative damage induced by morphine in rat brain. Morphine intoxicated rats received 10-160 mg/kg b.w. of morphine hydrochloride intraperitoneally for 21 days. Bacoside-A pretreated rats were administered with bacoside-A (10 mg/kg b.w/day) orally, 2 h before the injection of morphine for 21 days. Pretreatment with bacoside-A has shown to possess a significant protective role against morphine induced brain oxidative damage in the antioxidant status (total reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase and lipid peroxidation) and membrane bound ATP-ases(Na(+)/K(+)ATPase. Ca(2+) and Mg(2+) ATPases) activities in rat. The results of the present study indicate that bacoside-A protects the brain from oxidative stress induced by morphine.

Laccase catalyzed elimination of morphine from aqueous systems.

PubMed

Huber, Daniela; Bleymaier, Klaus; Pellis, Alessandro; Vielnascher, Robert; Daxbacher, Andreas; Greimel, Katrin J; Guebitz, Georg M

2018-05-25

Pharmaceuticals contaminate the environment for several reasons, including metabolic excretion after intake, industrial waste and improper disposal. The narcotic drug morphine is commonly utilized for chronic pain management, and the distribution of morphine in aqueous systems and in waste waters is of high concern. Here, the removal of morphine by a laccase from Myceliophthora thermophila both in its free form as well as immobilized on Accurel MP1000 beads was investigated. Complete morphine elimination was achieved within 30 min for the free and the immobilized enzyme (70% bound protein) for concentrations between 1 and 1,000 mg L -1 according to LC-TOF mass spectrometry analysis. Higher morphine concentrations up to 60 g L -1 were also tested and total elimination was achieved within 6 h. Therefore, laccases are ideal candidates for removing morphine from aqueous systems. Copyright © 2018 Elsevier B.V. All rights reserved.

Implication of cyclin-dependent kinase 5 in the development of psychological dependence on and behavioral sensitization to morphine.

PubMed

Narita, Minoru; Shibasaki, Masahiro; Nagumo, Yasuyuki; Narita, Michiko; Yajima, Yoshinori; Suzuki, Tsutomu

2005-06-01

In the present study, we investigated the role of cyclin-dependent kinase 5 (cdk5) in the brain dynamics changed by repeated in vivo treatment with morphine. The level of phosphorylated-cdk5 was significantly increased in the cingulate cortex of mice showing the morphine-induced rewarding effect. Under these conditions, roscovitine, a cdk5 inhibitor, given intracerebroventricularly (i.c.v.) caused a dose-dependent and significant inhibition of the morphine-induced rewarding effect. In addition, the dose-response effect of the morphine-induced rewarding effect was dramatically attenuated in cdk5 heterozygous (+/-) knockout mice. Furthermore, the development of behavioral sensitization by intermittent administration of morphine was virtually abolished in cdk5 (+/-) mice. These findings suggest that the induction and/or activation of cdk5 are implicated in the development of psychological dependence on morphine.

Morphine 6 glucuronide stimulates nitric oxide release in mussel neural tissues: evidence for a morphine 6 glucuronide opiate receptor subtype.

PubMed

Mantione, K; Zhu, W; Rialas, C; Casares, F; Cadet, P; Franklin, A L; Tonnesen, J; Stefano, G B

2002-03-01

We have previously demonstrated that Mytilus edulis pedal ganglia contain opiate alkaloids, i.e., morphine and morphine 6 glucuronide (M6G), as well as mu opiate receptor subtype fragments exhibiting high sequence similarity to those found in mammals. Now we demonstrate that M6G stimulates pedal ganglia constitutive nitric oxide (NO) synthase (cNOS)-derived NO release at identical concentrations and to similar peak levels as morphine. However, the classic opiate antagonist, naloxone, only blocked the ability of morphine to stimulate cNOS-derived NO release and not that of M6G. CTOP, a mu-specific antagonist, blocked the ability of M6G to induce cNOS-derived NO release as well as that of morphine, suggesting that a novel mu opiate receptor was present and selective toward M6G. In examining a receptor displacement analysis, both opiate alkaloids displaced [3H]-dihydromorphine binding to the mu opiate receptor subtype. However, morphine exhibited a twofold higher affinity, again suggesting that a novel mu opiate receptor may be present.

AMPA receptor positive allosteric modulators attenuate morphine tolerance and dependence.

PubMed

Hu, Xiaoyu; Tian, Xuebi; Guo, Xiao; He, Ying; Chen, Haijun; Zhou, Jia; Wang, Zaijie Jim

2018-04-25

Development of opioid tolerance and dependence hinders the use of opioids for the treatment of chronic pain. In searching for the mechanism and potential intervention for opioid tolerance and dependence, we studied the action of two positive allosteric modulators of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR PAMs). In mice treated with morphine (100 mg/kg, s.c.), acute morphine tolerance and dependence developed in 4-6 h. Treatment with aniracetam, a well-established AMPAR PAM, was able to completely prevent and reverse the development of acute antinociceptive tolerance to morphine. Partial, but significant, effects of aniracetam on acute morphine induced-physical dependence were also observed. Moreover, aniracetam significantly reversed the established morphine tolerance and dependence in a chronic model of morphine tolerance and dependence produced by intermittent morphine (10 mg/kg, s.c. for 5d). In addition, HJC0122, a new AMPAR PAM was found to have similar effects as aniracetam but with a higher potency. These previously undisclosed actions of AMPAR PAMs are intriguing and may shed lights on understanding the APMA signaling pathway in opioid addiction. Moreover, these data suggest that AMPAR PAMs may have utility in preventing and treating morphine tolerance and dependence. Copyright © 2018. Published by Elsevier Ltd.

Ethnicity and OPRM variant independently predict pain perception and patient-controlled analgesia usage for post-operative pain.

PubMed

Tan, Ene-choo; Lim, Eileen C P; Teo, Yik-ying; Lim, Yvonne; Law, Hai-yang; Sia, Alex T

2009-06-23

Morphine consumption can vary widely between individuals even for identical surgical procedures. As mu-opioid receptor (OPRM1) is known to modulate pain perception and mediate the analgesic effects of opioid compounds in the central nervous system, we examined the influence of two OPRM polymorphisms on acute post-operative pain and morphine usage in women undergoing elective caesarean delivery. Data on self-reported pain scores and amount of total morphine use according to patient-controlled analgesia were collected from 994 women from the three main ethnic groups in Singapore. We found statistically significant association of the OPRM 118A>G with self-administered morphine during the first 24-hour postoperative period both in terms of total morphine (p = 1.7 x 10(-5)) and weight-adjusted morphine (p = 6.6 x 10(-5)). There was also significant association of this OPRM variant and time-averaged self-rated pain scores (p = 0.024). OPRM 118G homozygotes used more morphine and reported higher pain scores than 118A carriers. Other factors which influenced pain score and morphine usage include ethnicity, age and paying class. Our results suggest that ethnicity and OPRM 118A>G genotype are independent and significant contributors to variation in pain perception and postoperative morphine use in patients undergoing cesarean delivery.

Inhibition of Histone Deacetylases Attenuates Morphine Tolerance and Restores MOR Expression in the DRG of BCP Rats.

PubMed

He, Xiao-Tao; Zhou, Kai-Xiang; Zhao, Wen-Jun; Zhang, Chen; Deng, Jian-Ping; Chen, Fa-Ming; Gu, Ze-Xu; Li, Yun-Qing; Dong, Yu-Lin

2018-01-01

The easily developed morphine tolerance in bone cancer pain (BCP) significantly hindered its clinical use. Increasing evidence suggests that histone deacetylases (HDACs) regulate analgesic tolerance subsequent to continuous opioid exposure. However, whether HDACs contribute to morphine tolerance in the pathogenesis of BCP is still unknown. In the current study, we explored the possible engagement of HDACs in morphine tolerance during the pathogenesis of BCP. After intra-tibia tumor cell inoculation (TCI), we found that the increased expression of HDACs was negatively correlated with the decreased expression of MOR in the DRG following TCI. The paw withdrawal threshold (PWT) and percentage maximum possible effects (MPEs) decreased rapidly in TCI rats when morphine was used alone. In contrast, the concomitant use of SAHA and morphine significantly elevated the PWT and MPEs of TCI rats compared to morphine alone. Additionally, we found that SAHA administration significantly elevated MOR expression in the DRG of TCI rats with or without morphine treatment. Moreover, the TCI-induced increase in the co-expression of MOR and HDAC1 in neurons was significantly decreased after SAHA administration. These results suggest that HDACs are correlated with the downregulation of MOR in the DRG during the pathogenesis of BCP. Inhibition of HDACs using SAHA can be used to attenuate morphine tolerance in BCP.

Inhibition of CaMKII activity in the nucleus accumbens shell blocks the reinstatement of morphine-seeking behavior in rats.

PubMed

Liu, Zhuo; Zhang, Jian-Jun; Liu, Xiao-Dong; Yu, Long-Chuan

2012-06-19

The Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) may be a core component in the common molecular pathways for drug addiction. Moreover, studies using animal models of drug addiction have demonstrated that changing CaMKII activity or expression influences animals' responses to the drugs of abuse. Here, we explored the roles of CaMKII in the nucleus accumbens (NAc) shell in the extinction and reinstatement of morphine-seeking behavior. Rats were trained to obtain intravenous morphine infusions through poking hole on a fixed-ratio one schedule. Selective CaMKII inhibitor myristoylated autocamtide-2-inhibitory peptide (myr-AIP) was injected into the NAc shell of rats after the acquisition of morphine self-administration (SA) or before the reinstatement test. The results demonstrated that injection of myr-AIP after acquisition of morphine SA did not influence morphine-seeking in the following extinction days and the number of days spent for reaching extinction criterion. However, pretreatment with myr-AIP before the reinstatement test blocked the reinstatement of morphine-seeking behavior induced by morphine-priming. Our results strongly indicate that CaMKII activity in the NAc shell is essential to the relapse to morphine-seeking. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Analgesic effect of the electromagnetic resonant frequencies derived from the NMR spectrum of morphine.

PubMed

Verginadis, Ioannis I; Simos, Yannis V; Velalopoulou, Anastasia P; Vadalouca, Athina N; Kalfakakou, Vicky P; Karkabounas, Spyridon Ch; Evangelou, Angelos M

2012-12-01

Exposure to various types of electromagnetic fields (EMFs) affects pain specificity (nociception) and pain inhibition (analgesia). Previous study of ours has shown that exposure to the resonant spectra derived from biologically active substances' NMR may induce to live targets the same effects as the substances themselves. The purpose of this study is to investigate the potential analgesic effect of the resonant EMFs derived from the NMR spectrum of morphine. Twenty five Wistar rats were divided into five groups: control group; intraperitoneal administration of morphine 10 mg/kg body wt; exposure of rats to resonant EMFs of morphine; exposure of rats to randomly selected non resonant EMFs; and intraperitoneal administration of naloxone and simultaneous exposure of rats to the resonant EMFs of morphine. Tail Flick and Hot Plate tests were performed for estimation of the latency time. Results showed that rats exposed to NMR spectrum of morphine induced a significant increase in latency time at time points (p < 0.05), while exposure to the non resonant random EMFs exerted no effects. Additionally, naloxone administration inhibited the analgesic effects of the NMR spectrum of morphine. Our results indicate that exposure of rats to the resonant EMFs derived from the NMR spectrum of morphine may exert on animals similar analgesic effects to morphine itself.

Acute food deprivation reverses morphine-induced locomotion deficits in M5 muscarinic receptor knockout mice.

PubMed

Steidl, Stephan; Lee, Esther; Wasserman, David; Yeomans, John S

2013-09-01

Lesions of the pedunculopontine tegmental nucleus (PPT), one of two sources of cholinergic input to the ventral tegmental area (VTA), block conditioned place preference (CPP) for morphine in drug-naïve rats. M5 muscarinic cholinergic receptors, expressed by midbrain dopamine neurons, are critical for the ability of morphine to increase nucleus accumbens dopamine levels and locomotion, and for morphine CPP. This suggests that M5-mediated PPT cholinergic inputs to VTA dopamine neurons critically contribute to morphine-induced dopamine activation, reward and locomotion. In the current study we tested whether food deprivation, which reduces PPT contribution to morphine CPP in rats, could also reduce M5 contributions to morphine-induced locomotion in mice. Acute 18-h food deprivation reversed the phenotypic differences usually seen between non-deprived wild-type and M5 knockout mice. That is, food deprivation increased morphine-induced locomotion in M5 knockout mice but reduced morphine-induced locomotion in wild-type mice. Food deprivation increased saline-induced locomotion equally in wild-type and M5 knockout mice. Based on these findings, we suggest that food deprivation reduces the contribution of M5-mediated PPT cholinergic inputs to the VTA in morphine-induced locomotion and increases the contribution of a PPT-independent pathway. The contributions of cholinergic, dopaminergic and GABAergic neurons to the effects of acute food deprivation are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Neonatal morphine exposure in very preterm infants-cerebral development and outcomes.

PubMed

Steinhorn, Rachel; McPherson, Christopher; Anderson, Peter J; Neil, Jeffrey; Doyle, Lex W; Inder, Terrie

2015-05-01

To investigate the association of morphine exposure in very preterm infants with cerebral volumes and neurodevelopmental outcome from birth through middle childhood. Observational study of very preterm infants in the Victorian Infant Brain Study cohort. A total of 230 infants born <30 weeks' gestational age or <1250 g were recruited from all admissions to the neonatal intensive care unit of the Royal Women's Hospital. Fifty-seven (25%) infants received morphine analgesia during their neonatal intensive care unit stay at the attending physician's discretion. Primary outcomes were regional brain volumes at term and 7 years; neurobehavioral performance at term; and cognitive, motor, emotional, behavioral, communication, and executive function scores at age 2 and 7 years. Linear regressions were used to compare outcomes between participants who did and did not receive morphine. At term, preterm infants who received morphine had similar rates of gray matter injury to no-morphine infants, but a trend toward smaller cortical volumes in the orbitofrontal (Pleft=.002, Pright=.01) and subgenual (Pleft=.01) regions. At 7 years, cortical volumes did not differ between groups. At 2 years, morphine-exposed children were more likely to show behavioral dysregulation (P=.007) than no-morphine children, but at 7 years no detrimental impacts of morphine on neurobehavioral outcome were observed. Low-dose morphine analgesia received during neonatal intensive care was associated with early alterations in cerebral structure and short-term neurobehavioral problems that did not persist into childhood. Copyright © 2015 Elsevier Inc. All rights reserved.

[Morphine in the treatment of acute pulmonary oedema].

PubMed

Ellingsrud, Christoffer; Agewall, Stefan

2014-12-09

Morphine is still used in Norway and the rest of Europe as part of the treatment for pulmonary oedema, but the scientific basis for this is tenuous. In this article we assess the literature that supports and challenges the use of morphine in cases of pulmonary oedema. The article is based on a literature search in Medline and EMBASE and on the articles which form the basis of Norwegian and international guidelines. Morphine has been used for several decades in cases of pulmonary oedema due to the anxiolytic and vasodilatory properties of the drug. Vasodilation caused by morphine has been described in other patient groups, but there is little evidence in the literature to suggest that morphine causes vasodilation in patients with pulmonary oedema. Non-specific depression of the central nervous system is probably the most significant factor for the changes in haemodynamics in pulmonary oedema. Retrospective studies have shown both negative and neutral effects in acute decompensated heart failure. There are no reliable clinical studies that document better prognosis from the use of morphine. Based on the available studies, the possibility cannot be excluded that the use of morphine results in increased mortality among patients with acute pulmonary oedema. In addition, there is little evidence that the vasodilatory properties of morphine are of any significance for this condition. The benefits and risks of using morphine in cases of acute pulmonary oedema are still unclear, but so far there is little evidence to support the beneficial use of the drug.

Pharmacological evidence for the role of nitric oxide in the modulation of stress-induced anxiety by morphine in rats.

PubMed

Anand, Rashmi; Gulati, Kavita; Ray, Arunabha

2012-02-15

The present study evaluated the effects of the opioid agonist, morphine on stress induced anxiogenesis and the possible involvement of nitric oxide (NO) in such effects in rats. Acute restraint stress consistently induced an anxiety-like response in the elevated plus maze test, i.e. reduced number of open arm entries and time spent in the open arms as compared to controls. Pretreatment with morphine (1 and 5mg/kg), attenuated the restraint stress induced anxiogenic response in a dose related manner. Restraint stress induced neurobehavioral suppression was associated with reductions in brain NO oxidation products (NOx) levels, which were also reversed with morphine. Interaction studies showed that sub-effective doses of morphine and l-arginine (a NO precursor) had synergistic effects on stress induced elevated plus maze activity and brain NOx, whereas, l-NAME (a NO synthase inhibitor) neutralized these effects of morphine. Repeated restraint stress (×5) induced adaptative changes as evidenced by normalization of behavioral suppression and elevations in brain NOx, as compared to acute stress. Pretreatment with morphine in combination with repeated stress (×5) showed potentiating effects in the induction of behavioral adaptation in the elevated plus maze and elevations in brain NOx, as compared to repeated stress alone. Further, l-NAME, when administered prior to morphine, blocked this effect of morphine on stress adaptation. These results suggest differential morphine-NO interactions during acute and repeated restraint stress. Copyright © 2011 Elsevier B.V. All rights reserved.

Effects of endurance, resistance, and concurrent exercise on learning and memory after morphine withdrawal in rats.

PubMed

Zarrinkalam, Ebrahim; Heidarianpour, Ali; Salehi, Iraj; Ranjbar, Kamal; Komaki, Alireza

2016-07-15

Continuous morphine consumption contributes to the development of cognitive disorders. This work investigates the impacts of different types of exercise on learning and memory in morphine-dependent rats. Forty morphine-dependent rats were randomly divided into five groups: sedentary-dependent (Sed-D), endurance exercise-dependent (En-D), strength exercise-dependent (St-D), and combined (concurrent) exercise-dependent (Co-D). Healthy rats were used as controls (Con). After 10weeks of regular exercise (endurance, strength, and concurrent; each five days per week), spatial and aversive learning and memory were assessed using the Morris water maze and shuttle box tests. The results showed that morphine addiction contributes to deficits in spatial learning and memory. Furthermore, each form of exercise training restored spatial learning and memory performance in morphine-dependent rats to levels similar to those of healthy controls. Aversive learning and memory during the acquisition phase were not affected by morphine addiction or exercise, but were significantly decreased by morphine dependence. Only concurrent training returned the time spent in the dark compartment in the shuttle box test to control levels. These findings show that different types of exercise exert similar effects on spatial learning and memory, but show distinct effects on aversive learning and memory. Further, morphine dependence-induced deficits in cognitive function were blocked by exercise. Therefore, different exercise regimens may represent practical treatment methods for cognitive and behavioral impairments associated with morphine-related disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Antagonism of the morphine-induced locomotor activation of mice by fructose: comparison with other opiates and sugars, and sugar effects on brain morphine.

PubMed

Brase, D A; Ward, C R; Bey, P S; Dewey, W L

1991-01-01

The mouse locomotor activation test of opiate action in a 2+2 dose parallel line assay was used in a repeated testing paradigm to determine the test, opiate and hexose specificities of a previously reported antagonism of morphine-induced antinocociception by hyperglycemia. In opiate specificity studies, fructose (5 g/kg, i.p.) significantly reduced the potency ratio for morphine and methadone, but not for levorphanol, meperidine or phenazocine when intragroup comparisons were made. In intergroup comparisons, fructose significantly reduced the potencies of levorphanol and phenazocine, but not methadone or meperidine. In hexose/polyol specificity studies, tagatose and fructose significantly reduced the potency ratio for morphine, whereas glucose, galactose, mannose and the polyols, sorbitol and xylitol, caused no significant decrease in potency. Fructose, tagatose, glucose and mannose (5 g/kg, i.p.) were tested for effects on brain morphine levels 30 min after morphine (60 min after sugar), and all four sugars significantly increased brain morphine relative to saline-pretreated controls. It is concluded that the antagonism of morphine by acute sugar administration shows specificity for certain sugars and occurs despite sugar-induced increases in the distribution of morphine to the brain. Furthermore, the effects of fructose show an opiate specificity similar to that of glucose on antinociception observed previously in our laboratory, except that methadone was also significantly inhibited in the present study, when a repeated-testing experimental design was used.

Effect of Tamoxifen and Brain-Penetrant Protein Kinase C and c-Jun N-Terminal Kinase Inhibitors on Tolerance to Opioid-Induced Respiratory Depression in Mice.

PubMed

Withey, Sarah L; Hill, Rob; Lyndon, Abigail; Dewey, William L; Kelly, Eamonn; Henderson, Graeme

2017-04-01

Respiratory depression is the major cause of death in opioid overdose. We have previously shown that prolonged treatment of mice with morphine induces profound tolerance to the respiratory-depressant effects of the drug (Hill et al., 2016). The aim of the present study was to investigate whether tolerance to opioid-induced respiratory depression is mediated by protein kinase C (PKC) and/or c-Jun N-terminal kinase (JNK). We found that although mice treated for up to 6 days with morphine developed tolerance, as measured by the reduced responsiveness to an acute challenge dose of morphine, administration of the brain-penetrant PKC inhibitors tamoxifen and calphostin C restored the ability of acute morphine to produce respiratory depression in morphine-treated mice. Importantly, reversal of opioid tolerance was dependent on the nature of the opioid ligand used to induce tolerance, as these PKC inhibitors did not reverse tolerance induced by prolonged treatment of mice with methadone nor did they reverse the protection to acute morphine-induced respiratory depression afforded by prolonged treatment with buprenorphine. We found no evidence for the involvement of JNK in morphine-induced tolerance to respiratory depression. These results indicate that PKC represents a major mechanism underlying morphine tolerance, that the mechanism of opioid tolerance to respiratory depression is ligand-dependent, and that coadministration of drugs with PKC-inhibitory activity and morphine (as well as heroin, largely metabolized to morphine in the body) may render individuals more susceptible to overdose death by reversing tolerance to the effects of morphine. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

siRNA capsulated brain-targeted nanoparticles specifically knock down OATP2B1 in mice: a mechanism for acute morphine tolerance suppression.

PubMed

Yang, Zi-Zhao; Li, Li; Wang, Lu; Xu, Ming-Cheng; An, Sai; Jiang, Chen; Gu, Jing-Kai; Wang, Zai-Jie Jim; Yu, Lu-Shan; Zeng, Su

2016-09-15

Regulating main brain-uptake transporter of morphine may restrict its tolerance generation, then modify its antinociception. In this study, more than 2 fold higher intracellular uptake concentrations for morphine and morphine-6-glucuronide (M6G) were observed in stable expression cells, HEK293-hOATP2B1 than HEK293-MOCK. Specifically, the Km value of morphine to OATP2B1 (57.58 ± 8.90 μM) is 1.4-time more than that of M6G (80.31 ± 21.75 μM); Cyclosporine A (CsA), an inhibitor of OATP2B1, can inhibit their intracellular accumulations with IC50 = 3.90 ± 0.50 μM for morphine and IC50 = 6.04 ± 0.86 μM for M6G, respectively. To further investigate the role of OATP2B1 in morphine brain transport and tolerance, the novel nanoparticles of DGL-PEG/dermorphin capsulated siRNA (OATP2B1) were applied to deliver siRNA into mouse brain. Along with OATP2B1 depressed, a main reduction was found for each of morphine or M6G in cerebrums or epencephalons of acute morphine tolerance mice. Furthermore, calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) in mouse prefrontal cortex (mPFC) underwent dephosphorylation at Thr286. In conclusion, OATP2B1 downregulation in mouse brain can suppress tolerance via blocking morphine and M6G brain transport. These findings might help to improve the pharmacological effects of morphine.

siRNA capsulated brain-targeted nanoparticles specifically knock down OATP2B1 in mice: a mechanism for acute morphine tolerance suppression

PubMed Central

Yang, Zi-Zhao; Li, Li; Wang, Lu; Xu, Ming-Cheng; An, Sai; Jiang, Chen; Gu, Jing-Kai; Wang, Zai-Jie Jim; Yu, Lu-Shan; Zeng, Su

2016-01-01

Regulating main brain-uptake transporter of morphine may restrict its tolerance generation, then modify its antinociception. In this study, more than 2 fold higher intracellular uptake concentrations for morphine and morphine-6-glucuronide (M6G) were observed in stable expression cells, HEK293-hOATP2B1 than HEK293-MOCK. Specifically, the Km value of morphine to OATP2B1 (57.58 ± 8.90 μM) is 1.4-time more than that of M6G (80.31 ± 21.75 μM); Cyclosporine A (CsA), an inhibitor of OATP2B1, can inhibit their intracellular accumulations with IC50 = 3.90 ± 0.50 μM for morphine and IC50 = 6.04 ± 0.86 μM for M6G, respectively. To further investigate the role of OATP2B1 in morphine brain transport and tolerance, the novel nanoparticles of DGL-PEG/dermorphin capsulated siRNA (OATP2B1) were applied to deliver siRNA into mouse brain. Along with OATP2B1 depressed, a main reduction was found for each of morphine or M6G in cerebrums or epencephalons of acute morphine tolerance mice. Furthermore, calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) in mouse prefrontal cortex (mPFC) underwent dephosphorylation at Thr286. In conclusion, OATP2B1 downregulation in mouse brain can suppress tolerance via blocking morphine and M6G brain transport. These findings might help to improve the pharmacological effects of morphine. PMID:27629937

Long-term effects of routine morphine infusion in mechanically ventilated neonates on children's functioning: five-year follow-up of a randomized controlled trial.

PubMed

de Graaf, Joke; van Lingen, Richard A; Simons, Sinno H P; Anand, Kanwaljeet J S; Duivenvoorden, Hugo J; Weisglas-Kuperus, Nynke; Roofthooft, Daniella W E; Groot Jebbink, Liesbeth J M; Veenstra, Ravian R; Tibboel, Dick; van Dijk, Monique

2011-06-01

Newborns on ventilatory support often receive morphine to induce analgesia. Animal experiments suggest that this may impair subsequent cognitive and behavioral development. There are sparse human data on long-term effects of neonatal morphine. We aimed to investigate the effects of continuous morphine administered in the neonatal period on the child's functioning. We conducted a follow-up study among 5-year-olds who, as mechanically ventilated neonates, had participated in a placebo-controlled trial on effects of morphine administration on pain and neurologic outcome. They were now tested on intelligence, visual motor integration, behavior, chronic pain, and health-related quality of life. Univariate analyses showed significantly lower overall intelligence quotient (IQ) scores for children who earlier had received morphine, that is, mean 94 (SD 14.5) versus 100 (SD 12.9) for those who received placebo (P = 0.049). Other between-group differences in outcomes were not found. The statistical difference disappeared after correction for treatment condition, open-label morphine consumption over the first 28 days, and a propensity score for clinically relevant co-variables in multiple regression analyses. However, scores on one IQ subtest, "visual analysis," were significantly negatively related to having received morphine and to open-label morphine consumption the first 28 days. The finding of a significant effect of morphine on the "visual analysis" IQ subtest calls for follow-up at a later age focusing on the higher-order neurocognitive functions. Morphine received in the neonatal period has negative effects on the child's cognitive functioning at the age of 5 years which warrants follow-up at a later age. Copyright © 2011 International Association for the Study of Pain. All rights reserved.

Critical role of toll-like receptor 9 in morphine and Mycobacterium tuberculosis-Induced apoptosis in mice.

PubMed

Chen, Lin; Shi, Wanliang; Li, Hui; Sun, Xiuli; Fan, Xionglin; Lesage, Gene; Li, Hui; Li, Yi; Zhang, Yi; Zhang, Xiumei; Zhang, Ying; Yin, Deling

2010-02-19

Although it is established that opioid and Mycobacterium tuberculosis are both public health problems, the mechanisms by which they affect lung functions remain elusive. We report here that mice subjected to chronic morphine administration and M. tuberculosis infection exhibited significant apoptosis in the lung in wild type mice as demonstrated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay. Morphine and M. tuberculosis significantly induced the expression of Toll-like receptor 9 (TLR9), a key mediator of innate immunity and inflammation. Interestingly, deficiency in TLR9 significantly inhibited the morphine and M. tuberculosis induced apoptosis in the lung. In addition, chronic morphine treatment and M. tuberculosis infection enhanced the levels of cytokines (TNF-alpha, IL-1beta, and IL-6) in wild type mice, but not in TLR9 knockout (KO) mice. The bacterial load was much lower in TLR9 KO mice compared with that in wild type mice following morphine and M. tuberculosis treatment. Morphine alone did not alter the bacterial load in either wild type or TLR9 KO mice. Moreover, administration of morphine and M. tuberculosis decreased the levels of phosphorylation of Akt and GSK3beta in the wild type mice, but not in TLR9 KO mice, suggesting an involvement of Akt/GSK3beta in morphine and M. tuberculosis-mediated TLR9 signaling. Furthermore, administration of morphine and M. tuberculosis caused a dramatic decrease in Bcl-2 level but increase in Bax level in wild type mice, but not in TLR9 KO mice, indicating a role of Bcl-2 family in TLR9-mediated apoptosis in the lung following morphine and M. tuberculosis administration. These data reveal a role for TLR9 in the immune response to opioids during M. tuberculosis infection.

Morphine Pharmacokinetics in Children With Down Syndrome Following Cardiac Surgery.

PubMed

Goot, Benjamin H; Kaufman, Jon; Pan, Zhaoxing; Bourne, David W A; Hickey, Francis; Twite, Mark; Galinkin, Jeffrey; Christians, Uwe; Zuk, Jeannie; da Cruz, Eduardo M

2018-05-01

To assess if morphine pharmacokinetics are different in children with Down syndrome when compared with children without Down syndrome. Prospective single-center study including subjects with Down syndrome undergoing cardiac surgery (neonate to 18 yr old) matched by age and cardiac lesion with non-Down syndrome controls. Subjects were placed on a postoperative morphine infusion that was adjusted as clinically necessary, and blood was sampled to measure morphine and its metabolites concentrations. Morphine bolus dosing was used as needed, and total dose was tracked. Infusions were continued for 24 hours or until patients were extubated, whichever came first. Postinfusion, blood samples were continued for 24 hours for further evaluation of kinetics. If patients continued to require opioid, a nonmorphine alternative was used. Morphine concentrations were determined using a unique validated liquid chromatography tandem-mass spectrometry assay using dried blood spotting as opposed to large whole blood samples. Morphine concentration versus time data was modeled using population pharmacokinetics. A 16-bed cardiac ICU at an university-affiliated hospital. Forty-two patients (20 Down syndrome, 22 controls) were enrolled. None. The pharmacokinetics of morphine in pediatric patients with and without Down syndrome following cardiac surgery were analyzed. No significant difference was found in the patient characteristics or variables assessed including morphine total dose or time on infusion. Time mechanically ventilated was longer in children with Down syndrome, and regarding morphine pharmacokinetics, the covariates analyzed were age, weight, presence of Down syndrome, and gender. Only age was found to be significant. This study did not detect a significant difference in morphine pharmacokinetics between Down syndrome and non-Down syndrome children with congenital heart disease.

Effect of morphine and lacosamide on levels of dopamine and 5-HIAA in brain regions of rats with induced hypoglycemia.

PubMed

Guzman, D Calderon; Garcia, E Hernandez; Mejia, G Barragan; Olguin, H Juarez; Gonzalez, J A Saldivar; Labra Ruiz, N A

2014-01-15

The study aimed to determine the effect of morphine and lacosamide on levels of dopamine and 5-HIAA in a hypoglycemic model. Female Wistar rats (n = 30), mean weight of 180 g were treated as follow: Group 1 (control) received 0.9% NaCl, Group II; morphine (10 mg kg(-1)), Group III; lacosamide (10 mg kg(-1)), Group IV; insulin (10 U.I. per rat), Group V; morphine (10 mg kg(-1))+insulin, Group VI; lacosamide (10 mg kg(-1))+ insulin. All administrations were made intraperitoneally every 24 h, for 5 days. Animals were sacrificed after the last dose to measure the levels of glucose in blood; dopamine and 5-HIAA in cortex, hemispheres and cerebellum/medulla oblongata regions. Levels of glucose decreased significantly in animals treated with morphine, lacosamide and all groups that received insulin alone or combined with respect to control group. Levels of Dopamine diminished significantly in cortex and increased significantly in hemispheres of animals that received morphine. In cortex, 5-HIAA increase significantly in the groups treated with morphine, morphine+insulin and lacosamide+insulin, however a significant decrease of the same substance was witnessed in cerebellum and medulla oblongata of animals that received morphine or lacosamide plus insulin. GSH increased significantly in cortex and cerebellum/medulla oblongata of animals treated with morphine and lacosamide alone or combined with insulin. Lipid peroxidation decreased significantly in cortex and cerebellum/medulla oblongata of groups that received lacosamide alone or combined with insulin. These results indicate that hypoglycemia induced changes in cellular regulation while morphine and lacosamide are accompanied by biochemical responses.

Effect of morphine on the growth rate of Calliphora stygia (Fabricius) (Diptera: Calliphoridae) and possible implications for forensic entomology.

PubMed

George, Kelly A; Archer, Melanie S; Green, Lauren M; Conlan, Xavier A; Toop, Tes

2009-12-15

Insect specimens collected from decomposing bodies enable forensic entomologists to estimate the minimum post-mortem interval (PMI). Drugs and toxins within a corpse may affect the development rate of insects that feed on them and it is vital to quantify these effects to accurately calculate minimum PMI. This study investigated the effects of morphine on growth rates of the native Australian blowfly, Calliphora stygia (Fabricius) (Diptera: Calliphoridae). Several morphine concentrations were incorporated into pet mince to simulate post-mortem concentrations in morphine, codeine and/or heroin-dosed corpses. There were four treatments for feeding larvae; T 1: control (no morphine); T 2: 2 microg/g morphine; T 3: 10 microg/g morphine; and T 4: 20 microg/g morphine. Ten replicates of 50 larvae were grown at 22 degrees C for each treatment and their development was compared at four comparison intervals; CI 1: 4-day-old larvae; CI 2: 7-day-old larvae; CI 3: pupae; and CI 4: adults. Length and width were measured for larvae and pupae, and costae and tibiae were measured for adults. Additionally, day of pupariation, day of adult eclosion, and survivorship were calculated for each replicate. The continued presence of morphine in meat was qualitatively verified using high-performance liquid chromatography with acidic potassium permanganate chemiluminescence detection. Growth rates of C. stygia fed on morphine-spiked mince did not differ significantly from those fed on control mince for any comparison interval or parameter measured. This suggests that C. stygia is a reliable model to use to accurately age a corpse containing morphine at any of the concentrations investigated.

Effectiveness of morphine, fentanyl, and methoxyflurane in the prehospital setting.

PubMed

Middleton, Paul M; Simpson, Paul M; Sinclair, Gary; Dobbins, Timothy A; Math, B; Bendall, Jason C

2010-01-01

To compare the effectiveness of intravenous (IV) morphine, intranasal (IN) fentanyl, and inhaled methoxyflurane when administered by paramedics to patients with moderate to severe pain. We conducted a retrospective comparative study of adult patients with moderate to severe pain treated by paramedics from the Ambulance Service of New South Wales who received IV morphine, IN fentanyl, or inhaled methoxyflurane either alone or in combination between January 1, 2004, and November 30, 2006. We used multivariate logistic regression to analyze data extracted from a clinical database containing routinely entered information from patient health care records. The primary outcome measure was effective analgesia, defined as a reduction in pain severity of > or = 30% of initial pain score using an 11-point verbal numeric rating scale (VNRS-11). The study population comprised 52,046 patients aged between 16 and 100 years with VNRS-11 scores of > or = 5. All analgesic agents were effective in the majority of patients (81.8%, 80.0%, and 59.1% for morphine, fentanyl, and methoxyflurane, respectively). There was very strong evidence that methoxyflurane was inferior to both morphine and fentanyl (p < 0.0001). There was strong evidence that morphine was more effective than fentanyl (p = 0.002). There was no evidence that combination analgesia was better than either fentanyl or morphine alone. Inhaled methoxyflurane, IN fentanyl, and IV morphine are all effective analgesic agents in the out-of-hospital setting. Morphine and fentanyl are significantly more effective analgesic agents than methoxyflurane. Morphine appears to be more effective than IN fentanyl; however, the benefit of IV morphine may be offset to some degree by the ability to administer IN fentanyl without the need for IV access.

Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age?

PubMed

de Graaf, Joke; van Lingen, Richard A; Valkenburg, Abraham J; Weisglas-Kuperus, Nynke; Groot Jebbink, Liesbeth; Wijnberg-Williams, Barbara; Anand, Kanwaljeet J S; Tibboel, Dick; van Dijk, Monique

2013-03-01

Morphine is widely used to treat severe pain in neonatal intensive care unit patients. Animal studies suggest adverse long-term side effects of neonatal morphine, but a follow-up study of 5-year-old children who participated in a morphine-placebo controlled trial as newborns found no such effects on the child's general functioning. This study indicated that morphine may negatively affect response inhibition, a domain of executive functions. Therefore, we performed a second follow-up study in the same population at the age of 8 to 9 years, focused on the child's general functioning in terms of intelligence, visual motor integration, and behavior and on executive functions. Children in the morphine group showed significantly less externalizing problems according to the parents but more internalizing behavior according to the teachers, but only after adjustment for intelligence quotient (IQ), potential confounders using a propensity score, and additional open-label morphine. Morphine-treated children showed significantly fewer problems with executive functions in daily life as rated by parents for the subscales inhibition and organization of materials and for planning/organizing as rated by the teachers. After adjustment for IQ and the propensity score, executive functioning as rated by the parents remained statistically significantly better in the morphine-treated group. The influence of the additional morphine given was not of a significant influence for any of the outcome variables. Overall, the present study demonstrates that continuous morphine infusion of 10 μg/kg/h during the neonatal period does not harm general functioning and may even have a positive influence on executive functions at 8 to 9 years. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Intrathecal morphine for analgesia in children undergoing selective dorsal rhizotomy.

PubMed

Dews, T E; Schubert, A; Fried, A; Ebrahim, Z; Oswalt, K; Paranandi, L

1996-03-01

Selective dorsal root rhizotomy is performed for relief of spasticity in children with cerebral palsy. Postoperative pain relief can be provided by intrathecal morphine administered at the time of the procedure. We sought to define an optimal dose of intrathecal morphine in children undergoing selective rhizotomy, through a randomized, double-blinded prospective trial. After institutional approval and parental written informed consent, 27 patients, ages 3-10 years, were randomized to receive 10, 20, or 30 micrograms.kg-1 (Groups A, B, and C, respectively) of preservative-free morphine administered intrathecally by the surgeon after dural closure. Postoperatively, vital signs, pulse oximetry, and pain intensity scores were recorded hourly for 24 hr. Supplemental intravenous morphine was administered postoperatively according to a predetermined schedule based on pain scores. There was considerable individual variability in the time to initial morphine dosing and cumulative supplemental morphine dose. Time to first supplemental morphine dose was not different between groups. When compared to Groups A and B, cumulative 6-hr supplemental morphine dose was significantly lower in Group C (38.6 +/- 47 micrograms versus 79.1 +/- 74 and 189.6 +/- 126 for Groups A and B, respectively). By 12 hr, cumulative supplemental morphine dose was similar in Groups A and C. Group B consistently had a higher supplemental dose requirement than Groups A and C at 6, 12, and 18 hr. By 24 hr, there was no difference in cumulative dose among groups. Postoperative pain scores and the incidence of respiratory events, nausea, vomiting and pruritus were comparable among groups. These data suggest that intrathecal morphine at 30 micrograms.kg-1 provides the most intense analgesia at 6 hr following selective dorsal root rhizotomy, but was otherwise comparable to the 10 micrograms.kg-1 dose.

Transitional Study of Patient-Controlled Analgesia Morphine With Ketorolac to Patient-Controlled Analgesia Morphine With Parecoxib Among Donors in Adult Living Donor Liver Transplantation: A Single-Center Experience.

PubMed

Lim, K-I; Liu, C-K; Chen, C-L; Wang, C-H; Huang, C-J; Cheng, K-W; Wu, S-C; Shih, T-H; Yang, S-C; Lee, Y-E; Jawan, B; Juang, S-E

2016-05-01

In this study, as our center transitions from using patient-controlled analgesia (PCA) morphine with intravenous (IV) ketorolac to PCA morphine with IV parecoxib, the two regimens are compared in terms of quality of pain control. Post-operative pain management sheets were collected retrospectively among the living donors of liver transplantation during this transitional period. Group parecoxib was given plain PCA morphine. A single dose of IV parecoxib 40 mg was given 30 minutes before the end of surgery. Group ketorolac was given PCA morphine pre-mixed ketorolac with a concentration of 1.87 mg/mL. Daily and total morphine consumption, Visual Analog Score (VAS), and number of rescue attempts made up to 3 post-operative days, together with satisfaction score and incidence of side effects of PCA usage, were analyzed and compared by means of the Mann-Whitney U test; a value of P < .05 was regarded as significant, and data are given as mean ± SD. Fifty patients were analyzed; group 1 comprised 21 patients and group 2 comprised 29 patients. There was no difference between group 1 and group 2 in terms of daily VAS. PCA morphine requirements were significantly lower at day 2 and day 3 in group 1. However, the total overall morphine usage and satisfactory score was not statistically different (P = .863, P = .052). A single dose of IV parecoxib 40 mg can provide satisfactory pain control when paired with PCA morphine for donors undergoing living donor liver transplantation. The use of parecoxib in the multimodal analgesia regimen has similar efficacy, with possibly less morphine consumption, when compared with ketorolac. Copyright © 2016 Elsevier Inc. All rights reserved.

AN IL-1 RECEPTOR ANTAGONIST BLOCKS A MORPHINE-INDUCED ATTENUATION OF LOCOMOTOR RECOVERY AFTER SPINAL CORD INJURY

PubMed Central

Hook, Michelle A.; Washburn, Stephanie N.; Moreno, Georgina; Woller, Sarah A.; Puga, Denise; Lee, Kuan H.; Grau, James W.

2010-01-01

Morphine is one of the most commonly prescribed medications for the treatment of chronic pain after a spinal cord injury (SCI). Despite widespread use, however, little is known about the secondary consequences of morphine use after SCI. Unfortunately, our previous studies show that administration of a single dose of morphine, in the acute phase of a moderate spinal contusion injury, significantly attenuates locomotor function, reduces weight gain, and produces symptoms of paradoxical pain (Hook et al., 2009). The current study focused on the cellular mechanisms that mediate these effects. Based on data from other models, we hypothesized that pro-inflammatory cytokines might play a role in the morphine-induced attenuation of function. Experiment 1 confirmed that systemic morphine (20 mg/kg) administered one day after a contusion injury significantly increased expression levels of spinal IL-1β 24 hrs later. Experiment 2 extended these findings, demonstrating that a single dose of morphine (90 µg, i.t.) applied directly onto the spinal cord increased expression levels of spinal IL-1β at both 30 min and 24 hrs after administration. Experiment 3 showed that administration of an interleukin-1 receptor antagonist (IL-1ra, i.t.) prior to intrathecal morphine (90 µg), blocked the adverse effects of morphine on locomotor recovery. Further, pre-treatment with 3 µg IL-1ra prevented the increased expression of at-level neuropathic pain symptoms that was observed 28 days later in the group treated with morphine-alone. However, the IL-1ra also had adverse effects that were independent of morphine. Treatment with the IL-1ra alone undermined recovery of locomotor function, potentiated weight loss and significantly increased tissue loss at the injury site. Overall, these data suggest that morphine disrupts a critical balance in concentrations of pro-inflammatory cytokines in the spinal cord, and this undermines recovery of function. PMID:20974246

Spinal antinociception of synthetic omega-conotoxin SO-3, a selective N-type neuronal voltage-sensitive calcium channel blocker, and its effects on morphine analgesia in chemical stimulus tests in rodent.

PubMed

Yan, Ling-Di; Liu, Yan-Li; Zhang, Lei; Dong, Hua-Jin; Zhou, Pei-Lan; Su, Rui-Bin; Gong, Ze-Hui; Huang, Pei-Tang

2010-06-25

SO-3, a novel Omega-superfamily conotoxin derived from Conus striatus, selectively inhibits N-type neuronal voltage-sensitive calcium channels. In current study, antinociception of SO-3 compared with MVIIA or morphine and its effects on morphine analgesia were investigated in rodent chemical stimulus tests after acute or repeated intrathecal administration. In mice acetic acid writhing test, similar to MVIIA, SO-3 caused dose- and time-dependent spinal antinociception with ED(50) of 0.25 microg/kg and t(1/2) of 4h, which was more potent and longer-acting than morphine. In rat formalin test after intrathecal bolus injection, SO-3 produced dose- and time-dependent antinociception by suppressing acute (ED(50), 1.79 microg/kg) and tonic phases (ED(50), 0.41 microg/kg), which was similar to MVIIA and approximately 10-fold potency and twice longer-acting of morphine in blocking tonic phase responses. After repeated intrathecal injections twice daily for 5 consecutive days, SO-3 produced analgesia without loss of potency whereas morphine produced analgesia tolerance in rat formalin test; further, SO-3 still produced potent analgesia in morphine-tolerant rats. SO-3 co-administered with morphine left-shift the dose-response curve of morphine in mice acetic acid writhing test and significantly potentiated morphine analgesia in rat formalin test. No changes in motor function were seen in mice or rats receiving antinociceptive doses of SO-3 whereas MVIIA caused motor dysfunction at doses of 1.0-2.0 microg/kg in rats. This study showed that (1) novel SO-3 produced potent and long-acting spinal antinociception without observable motor dysfunction, (2) SO-3 significantly potentiated morphine analgesia, (3) After repeated intrathecal administration, SO-3 produced neither tolerance nor cross-tolerance to morphine analgesia. (c) 2010 Elsevier B.V. All rights reserved.

Endogenous Morphine in SH-SY5Y Cells and the Mouse Cerebellum

PubMed Central

Taleb, Omar; Kemmel, Véronique; Laux, Alexis; Miehe, Monique; Delalande, François; Roussel, Guy; Van Dorsselaer, Alain; Metz-Boutigue, Marie-Hélène; Aunis, Dominique; Goumon, Yannick

2008-01-01

Background Morphine, the principal active agent in opium, is not restricted to plants, but is also present in different animal tissues and cell types, including the mammalian brain. In fact, its biosynthetic pathway has been elucidated in a human neural cell line. These data suggest a role for morphine in brain physiology (e.g., neurotransmission), but this hypothesis remains a matter of debate. Recently, using the adrenal neuroendocrine chromaffin cell model, we have shown the presence of morphine-6-glucuronide (M6G) in secretory granules and their secretion products, leading us to propose that these endogenous alkaloids might represent new neuroendocrine factors. Here, we investigate the potential function of endogenous alkaloids in the central nervous system. Methodology and Principal Findings Microscopy, molecular biology, electrophysiology, and proteomic tools were applied to human neuroblastoma SH-SY5Y cells (i) to characterize morphine and M6G, and (ii) to demonstrate the presence of the UDP-glucuronyltransferase 2B7 enzyme, which is responsible for the formation of M6G from morphine. We show that morphine is secreted in response to nicotine stimulation via a Ca2+-dependent mechanism involving specific storage and release mechanisms. We also show that morphine and M6G at concentrations as low as 10−10 M are able to evoke specific naloxone-reversible membrane currents, indicating possible autocrine/paracrine regulation in SH-SY5Y cells. Microscopy and proteomic approaches were employed to detect and quantify endogenous morphine in the mouse brain. Morphine is present in the hippocampus, cortex, olfactory bulb, and cerebellum at concentration ranging from 1.45 to 7.5 pmol/g. In the cerebellum, morphine immunoreactivity is localized to GABA basket cells and their termini, which form close contacts on Purkinje cell bodies. Conclusions/Significance The presence of morphine in the brain and its localization in particular areas lead us to conclude that it has a specific function in neuromodulation and/or neurotransmission. Furthermore, its presence in cerebellar basket cell termini suggests that morphine has signaling functions in Purkinje cells that remain to be discovered. PMID:18327293

Dose-dependent effects of morphine exposure on mRNA and microRNA (miR) expression in hippocampus of stressed neonatal mice.

PubMed

McAdams, Ryan M; McPherson, Ronald J; Beyer, Richard P; Bammler, Theo K; Farin, Frederico M; Juul, Sandra E

2015-01-01

Morphine is used to sedate critically ill infants to treat painful or stressful conditions associated with intensive care. Whether neonatal morphine exposure affects microRNA (miR) expression and thereby alters mRNA regulation is unknown. We tested the hypothesis that repeated morphine treatment in stress-exposed neonatal mice alters hippocampal mRNA and miR expression. C57BL/6 male mice were treated from postnatal day (P) 5 to P9 with morphine sulfate at 2 or 5 mg/kg ip twice daily and then exposed to stress consisting of hypoxia (100% N2 1 min and 100% O2 5 min) followed by 2h maternal separation. Control mice were untreated and dam-reared. mRNA and miR expression profiling was performed on hippocampal tissues at P9. Overall, 2 and 5 mg/kg morphine treatment altered expression of a total of 150 transcripts (>1.5 fold change, P<0.05) from which 100 unique mRNAs were recognized (21 genes were up- and 79 genes were down-regulated), and 5 mg/kg morphine affected 63 mRNAs exclusively. The most upregulated mRNAs were fidgetin, arginine vasopressin, and resistin-like alpha, and the most down-regulated were defensin beta 11, aquaporin 1, calmodulin-like 4, chloride intracellular channel 6, and claudin 2. Gene Set Enrichment Analysis revealed that morphine treatment affected pathways related to cell cycle, membrane function, signaling, metabolism, cell death, transcriptional regulation, and immune response. Morphine decreased expression of miR-204-5p, miR-455-3p, miR-448-5p, and miR-574-3p. Nine morphine-responsive mRNAs that are involved in neurodevelopment, neurotransmission, and inflammation are predicted targets of the aforementioned differentially expressed miRs. These data establish that morphine produces dose-dependent changes in both hippocampal mRNA and miR expression in stressed neonatal mice. If permanent, morphine-mediated neuroepigenetic effects may affect long-term hippocampal function, and this provides a mechanism for the neonatal morphine-related impairment of adult learning.

Morphine Glucuronidation and Elimination in Intensive Care Patients: A Comparison with Healthy Volunteers.

PubMed

Ahlers, Sabine J G M; Välitalo, Pyry A J; Peeters, Mariska Y M; Gulik, Laura van; van Dongen, Eric P A; Dahan, Albert; Tibboel, Dick; Knibbe, Catherijne A J

2015-11-01

Although morphine is used frequently to treat pain in the intensive care unit, its pharmacokinetics has not been adequately quantified in critically ill patients. We evaluated the glucuronidation and elimination clearance of morphine in intensive care patients compared with healthy volunteers based on the morphine and morphine-3-glucuronide (M3G) concentrations. A population pharmacokinetic model with covariate analysis was developed with the nonlinear mixed-effects modeling software (NONMEM 7.3). The analysis included 3012 morphine and M3G concentrations from 135 intensive care patients (117 cardiothoracic surgery patients and 18 critically ill patients), who received continuous morphine infusions adapted to individual pain levels, and 622 morphine and M3G concentrations from a previously published study of 20 healthy volunteers, who received an IV bolus of morphine followed by a 1-hour infusion. For morphine, a 3-compartment model best described the data, whereas for M3G, a 1-compartment model fits best. In intensive care patients with a normal creatinine concentration, a decrease of 76% was estimated in M3G clearance compared with healthy subjects, conditional on the M3G volume of distribution being the same in intensive care patients and healthy volunteers. Furthermore, serum creatinine concentration was identified as a covariate for both elimination clearance of M3G in intensive care patients and unchanged morphine clearance in all patients and healthy volunteers. Under the assumptions in the model, M3G elimination was significantly decreased in intensive care patients when compared with healthy volunteers, which resulted in substantially increased M3G concentrations. Increased M3G levels were even more pronounced in patients with increased serum creatinine levels. Model-based simulations show that, because of the reduction in morphine clearance in intensive care patients with renal failure, a 33% reduction in the maintenance dose would result in morphine serum concentrations equal to those in healthy volunteers and intensive care patients with normal renal function, although M3G concentrations remain increased. Future pharmacodynamic investigations are needed to identify target concentrations in this population, after which final dosing recommendations can be made.

The Environmental footprint of morphine: a life cycle assessment from opium poppy farming to the packaged drug

PubMed Central

McAlister, Scott; Ou, Yanjun; Neff, Elise; Hapgood, Karen; Story, David; Mealey, Philip; McGain, Forbes

2016-01-01

Objective To examine the environmental life cycle from poppy farming through to production of 100 mg in 100 mL of intravenous morphine (standard infusion bag). Design ‘Cradle-to-grave’ process-based life cycle assessment (observational). Settings Australian opium poppy farms, and facilities for pelletising, manufacturing morphine, and sterilising and packaging bags of morphine. Main outcome measures The environmental effects (eg, CO2 equivalent (‘CO2 e’) emissions and water use) of producing 100 mg of morphine. All aspects of morphine production from poppy farming, pelletising, bulk morphine manufacture through to final formulation. Industry-sourced and inventory-sourced databases were used for most inputs. Results Morphine sulfate (100 mg in 100 mL) had a climate change effect of 204 g CO2 e (95% CI 189 to 280 g CO2 e), approximating the CO2 e emissions of driving an average car 1 km. Water use was 7.8 L (95% CI 6.7– to 9.0 L), primarily stemming from farming (6.7 L). All other environmental effects were minor and several orders of magnitude less than CO2 e emissions and water use. Almost 90% of CO2 e emissions occurred during the final stages of 100 mg of morphine manufacture. Morphine's packaging contributed 95 g CO2 e, which accounted for 46% of the total CO2 e (95% CI 82 to 155 g CO2 e). Mixing, filling and sterilisation of 100 mg morphine bags added a further 86 g CO2 e, which accounted for 42% (95% CI 80 to 92 g CO2 e). Poppy farming (6 g CO2 e, 3%), pelletising and manufacturing (18 g CO2 e, 9%) made smaller contributions to CO2 emissions. Conclusions The environmental effects of growing opium poppies and manufacturing bulk morphine were small. The final stages of morphine production, particularly sterilisation and packaging, contributed to almost 90% of morphine's carbon footprint. Focused measures to improve the energy efficiency and sources for drug sterilisation and packaging could be explored as these are relevant to all drugs. Comparisons of the environmental effects of the production of other drugs and between oral and intravenous preparations are required. PMID:27798031

Morphine induced exacerbation of sepsis is mediated by tempering endotoxin tolerance through modulation of miR-146a

PubMed Central

Banerjee, Santanu; Meng, Jingjing; Das, Subhas; Krishnan, Anitha; Haworth, Justin; Charboneau, Richard; Zeng, Yan; Ramakrishnan, Sundaram; Roy, Sabita

2013-01-01

Development of tolerance to endotoxin prevents sustained hyper inflammation during systemic infections. Here we report for the first time that chronic morphine treatment tempers endotoxin tolerance resulting in persistent inflammation, septicemia and septic shock. Morphine was found to down-regulate endotoxin/LPS induced miR-146a and 155 in macrophages. However, only miR-146a over expression, but not miR-155 abrogates morphine mediated hyper-inflammation. Conversely, antagonizing miR-146a (but not miR-155) heightened the severity of morphine-mediated hyper-inflammation. These results suggest that miR-146a acts as a molecular switch controlling hyper-inflammation in clinical and/or recreational use of morphine. PMID:23756365

Brain Reward Circuits in Morphine Addiction

PubMed Central

Kim, Juhwan; Ham, Suji; Hong, Heeok; Moon, Changjong; Im, Heh-In

2016-01-01

Morphine is the most potent analgesic for chronic pain, but its clinical use has been limited by the opiate’s innate tendency to produce tolerance, severe withdrawal symptoms and rewarding properties with a high risk of relapse. To understand the addictive properties of morphine, past studies have focused on relevant molecular and cellular changes in the brain, highlighting the functional roles of reward-related brain regions. Given the accumulated findings, a recent, emerging trend in morphine research is that of examining the dynamics of neuronal interactions in brain reward circuits under the influence of morphine action. In this review, we highlight recent findings on the roles of several reward circuits involved in morphine addiction based on pharmacological, molecular and physiological evidences. PMID:27506251

Glial activation and midkine and pleiotrophin transcription in the ventral tegmental area are modulated by morphine administration.

PubMed

García-Pérez, Daniel; Luisa Laorden, M; Núñez, Cristina; Victoria Milanés, M

2014-09-15

Opiates cause persistent restructuring in the mesolimbic reward system. Although a possible role for midkine and pleiotrophin cytokines in the field of synaptic plasticity has been proposed, it has not been assessed whether morphine administration regulates astrogliosis and midkine and pleiotrophin transcription. We observed that single morphine injection and chronic morphine increased glial fibrillary acidic protein expression in the ventral tegmental area (VTA). Interestingly, single morphine injection and chronic morphine increased VTA midkine and pleiotrophin mRNA expression. Given these results, we hypothesize a role for these cytokines in mediating, at least in part, acute neuroprotective effects and chronic neurotrophic adaptations that contribute to drug dependence. Copyright © 2014 Elsevier B.V. All rights reserved.

Differential involvement of 3', 5'-cyclic adenosine monophosphate-dependent protein kinase in regulation of Fos and tyrosine hydroxylase expression in the heart after naloxone induced morphine withdrawal.

PubMed

Almela, Pilar; Cerezo, Manuela; González-Cuello, A; Milanés, M Victoria; Laorden, M Luisa

2007-01-01

We previously demonstrated that morphine withdrawal induced hyperactivity of the heart by the activation of noradrenergic pathways innervating the left and right ventricle, as evaluated by noradrenaline (NA) turnover and Fos expression. We investigated whether cAMP-dependent protein kinase (PKA) plays a role in this process by estimating changes in PKA immunoreactivity and the influence of inhibitor of PKA on Fos protein expression, tyrosine hydroxylase (TH) immunoreactivity levels and NA turnover in the left and right ventricle. Dependence on morphine was induced by a 7-day s.c. implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (5 mg/kg). When opioid withdrawal was precipitated, an increase in PKA immunoreactivity and phospho-CREB (cyclic AMP response element protein) levels were observed in the heart. Moreover, morphine withdrawal induces Fos expression, an enhancement of NA turnover and an increase in the total TH levels. When the selective PKA inhibitor HA-1004 was infused, concomitantly with morphine pellets, it diminished the increase in NA turnover and the total TH levels observed in morphine-withdrawn rats. However, this inhibitor neither modifies the morphine withdrawal induced Fos expression nor the increase of nonphosphorylated TH levels. The present findings indicate that an up-regulated PKA-dependent transduction pathway might contribute to the activation of the cardiac catecholaminergic neurons in response to morphine withdrawal and suggest that Fos is not a target of PKA at heart levels.

Morphine tolerance as a function of ratio schedule: response requirement or unit price?

PubMed

Hughes, Christine E; Sigmon, Stacey C; Pitts, Raymond C; Dykstra, Linda A

2005-05-01

Key pecking by 3 pigeons was maintained by a multiple fixed-ratio 10, fixed-ratio 30, fixed-ratio 90 schedule of food presentation. Components differed with respect to amount of reinforcement, such that the unit price was 10 responses per 1-s access to food. Acute administration of morphine, l-methadone, and cocaine dose-dependently decreased overall response rates in each of the components. When a rate decreasing dose of morphine was administered daily, tolerance, as measured by an increase in the dose that reduced response rates to 50% of control (i.e., the ED50 value), developed in each of the components; however, the degree of tolerance was smallest in the fixed-ratio 90 component (i.e., the ED50 value increased the least). When the l-methadone dose-effect curve was redetermined during the chronic morphine phase, the degree of cross-tolerance conferred to l-methadone was similar across components, suggesting that behavioral variables may not influence the degree of cross-tolerance between opioids. During the chronic phase, the cocaine dose-effect curve shifted to the right for 2 pigeons and to the left for 1 pigeon, which is consistent with predictions based on the lack of pharmacological similarity between morphine and cocaine. When the morphine, l-methadone, and cocaine dose-effect curves were redetermined after chronic morphine administration ended, the morphine and l-methadone ED50s replicated those obtained prior to chronic morphine administration. The morphine data suggest that the fixed-ratio value (i.e., the absolute output) determines the degree of tolerance and not the unit price.

Functionally Selective Signaling for Morphine and Fentanyl Antinociception and Tolerance Mediated by the Rat Periaqueductal Gray

PubMed Central

Morgan, Michael M.; Reid, Rachel A.; Saville, Kimber A.

2014-01-01

Functionally selective signaling appears to contribute to the variability in mechanisms that underlie tolerance to the antinociceptive effects of opioids. The present study tested this hypothesis by examining the contribution of G protein-coupled receptor kinase (GRK)/Protein kinase C (PKC) and C-Jun N-terminal kinase (JNK) activation on both the expression and development of tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray of the rat. Microinjection of morphine or fentanyl into the periaqueductal gray produced a dose-dependent increase in hot plate latency. Microinjection of the non-specific GRK/PKC inhibitor Ro 32-0432 into the periaqueductal gray to block mu-opioid receptor phosphorylation enhanced the antinociceptive effect of morphine but had no effect on fentanyl antinociception. Microinjection of the JNK inhibitor SP600125 had no effect on morphine or fentanyl antinociception, but blocked the expression of tolerance to repeated morphine microinjections. In contrast, a microinjection of Ro 32-0432 blocked the expression of fentanyl, but not morphine tolerance. Repeated microinjections of Ro 32-0432 blocked the development of morphine tolerance and inhibited fentanyl antinociception whether rats were tolerant or not. Repeated microinjections of SP600125 into the periaqueductal gray blocked the development of tolerance to both morphine and fentanyl microinjections. These data demonstrate that the signaling molecules that contribute to tolerance vary depending on the opioid and methodology used to assess tolerance (expression vs. development of tolerance). This signaling difference is especially clear for the expression of tolerance in which JNK contributes to morphine tolerance and GRK/PKC contributes to fentanyl tolerance. PMID:25503060

α-Terpineol attenuates morphine-induced physical dependence and tolerance in mice: role of nitric oxide.

PubMed

Parvardeh, Siavash; Moghimi, Mahsa; Eslami, Pegah; Masoudi, Alireza

2016-02-01

Dependence and tolerance to opioid analgesics are major problems limiting their clinical application. α-Terpineol is a monoterpenoid alcohol with neuroprotective effects which is found in several medicinal plants such as Myrtus communis, Laurus nobilis, and Stachys byzantina. It has been shown that some of these medicinal plants such as S. byzantina attenuate dependence and tolerance to morphine. Since α-terpineol is one of the bioactive phytochemical constituent of these medicinal plants, the present study was conducted to investigate the effects of α-terpineol on morphine-induced dependence and tolerance in mice. The mice were rendered dependent or tolerant to morphine by a 3-day administration schedule. The hot-plate test and naloxone-induced withdrawal syndrome were used to evaluate tolerance and dependence on morphine, respectively. To investigate a possible role for nitric oxide (NO) in the protective effect of α-terpineol, the NO synthase inhibitor, L-N(G)-nitroarginine methyl ester (L-NAME) and NO precursor, L-arginine, were used. Administration of α-terpineol (5, 10, and 20 mg/kg, IP) significantly decreased the number of jumps in morphine dependent animals. Moreover, α-terpineol (20 and 40 mg/kg, IP) attenuated tolerance to the analgesic effect of morphine. The inhibitory effects of α-terpineol on morphine-induced dependence and tolerance were enhanced by pretreatment with L-NAME (10 mg/kg, IP). However, L-arginine (300 mg/kg, IP) antagonized the protective effects of α-terpineol on dependence and tolerance to morphine. These findings indicate that α-terpineol prevents the development of dependence and tolerance to morphine probably through the influence on NO production.

Cardiorespiratory effects of epidural administration of morphine and fentanyl in dogs anesthetized with sevoflurane.

PubMed

Naganobu, Kiyokazu; Maeda, Noriaki; Miyamoto, Toru; Hagio, Mitsuyoshi; Nakamura, Tadashi; Takasaki, Mayumi

2004-01-01

To determine the cardiorespiratory effects of epidural administration of morphine alone and in combination with fentanyl in dogs anesthetized with sevoflurane. Prospective study. 6 dogs. Dogs were anesthetized with sevoflurane and allowed to breathe spontaneously. After a stable plane of anesthesia was achieved, morphine (0.1 mg/kg [0.045 mg/lb]) or a combination of morphine and fentanyl (10 microg/kg [4.5 microg/lb]) was administered through an epidural catheter, the tip of which was positioned at the level of L6 or L7. Cardiorespiratory variables were measured for 90 minutes. Epidural administration of morphine alone did not cause any significant changes in cardiorespiratory measurements. However, epidural administration of morphine and fentanyl induced significant decreases in diastolic and mean arterial blood pressures and total peripheral resistance. Stroke volume was unchanged, PaCO2 was significantly increased, and arterial pH and base excess were significantly decreased. Heart rate was significantly lower after epidural administration of morphine and fentanyl than after administration of morphine alone. None of the dogs had any evidence of urine retention, vomiting, or pruritus after recovery from anesthesia. Results suggest that epidural administration of morphine at a dose of 0.1 mg/kg in combination with fentanyl at a dose of 10 microg/kg can cause cardiorespiratory depression in dogs anesthetized with sevoflurane.

Blocking α4β2 and α7 nicotinic acetylcholine receptors inhibits the reinstatement of morphine-induced CPP by drug priming in mice.

PubMed

Feng, Bin; Xing, Jiang-hao; Jia, Dong; Liu, Shui-bing; Guo, Hong-ju; Li, Xiao-qiang; He, Xiao-sheng; Zhao, Ming-gao

2011-06-20

Investigating the interaction between nicotinic and opioid receptors is of great interest for both basic mechanistic and clinical reasons. Morphine and nicotine, two common drugs of abuse, share several behavioral and rewarding properties. However, little is known about the subtypes of nicotinic acetylcholine receptors (nAChR) in the reinstatement of morphine-induced conditioned place preference (CPP). In this study, we found that a non-specific nAChR agonist, nicotine (0.5mg/kg), had no effects on the reinstatement of morphine-induced CPP. However, we found that pretreatment with specific α(4)β(2) and α(7) nAChR subtype antagonists, dihydroxy-β-erithroidine (DHβE, 5mg/kg) and methyllycaconitine (MLA, 4 mg/kg), 20 min prior to administration of morphine, inhibited the reinstatement of morphine-induced CPP by drug priming in mice. Furthermore, depression of the reinstatement of morphine-induced CPP by a single DHβE or MLA treatment lasted at least three days later when the reinstatement was induced by morphine priming. The data suggest that specific nAChR subtypes, i.e., α(4)β(2) and α(7), may contribute to the reinstatement of morphine-induced CPP by drug priming in mice. Copyright © 2011 Elsevier B.V. All rights reserved.

Effect of baclofen on morphine-induced conditioned place preference, extinction, and stress-induced reinstatement in chronically stressed mice.

PubMed

Meng, Shanshan; Quan, Wuxing; Qi, Xu; Su, Zhiqiang; Yang, Shanshan

2014-01-01

A stress-induced increase in excitability can result from a reduction in inhibitory neurotransmission. Modulation of gamma-aminobutyric acid (GABA)ergic transmission is an effective treatment for drug seeking and relapse. This study investigated whether baclofen, a GABA(B) receptor agonist, had an impact on morphine-induced conditioned place preference (CPP), extinction, and stress-induced relapse in chronically stressed mice. Chronic stress was induced by restraining mice for 2 h for seven consecutive days. We first investigated whether chronic stress influenced morphine-induced CPP, extinction, and stress-induced relapse in the stressed mice. Next, we investigated whether three different doses of baclofen influenced chronic stress as measured by the expression of morphine-induced CPP. We chose the most effective dose for subsequent extinction and reinstatement experiments. Reinstatement of morphine-induced CPP was induced by a 6-min forced swim stress. Locomotor activity was also measured for each test. Chronic stress facilitated the expression of morphine-induced CPP and prolonged extinction time. Forced swim stress primed the reinstatement of morphine-induced CPP in mice. Baclofen treatment affected the impact of chronic stress on different phases of morphine-induced CPP. Our results showed that baclofen antagonized the effects of chronic stress on morphine-induced CPP. These findings suggest the potential clinical utility of GABA(B) receptor-positive modulators as an anti-addiction agent in people suffering from chronic stress.

Withdrawal of repeated morphine enhances histamine-induced scratching responses in mice.

PubMed

Abe, Kenji; Kobayashi, Kanayo; Yoshino, Saori; Taguchi, Kyoji; Nojima, Hiroshi

2015-04-01

An itch is experientially well known that the scratching response of conditions such as atopic dermatitis is enhanced under psychological stress. Morphine is typical narcotic drug that induces a scratching response upon local application as an adverse drug reaction. Although long-term treatment with morphine will cause tolerance and dependence, morphine withdrawal can cause psychologically and physiologically stressful changes in humans. In this study, we evaluated the effects of morphine withdrawal on histamine-induced scratching behavior in mice. Administration of morphine with progressively increasing doses (10-50 mg/kg, i.p.) was performed for 5 consecutive days. At 3, 24, 48, and 72 hr after spontaneous withdrawal from the final morphine dose, histamine was intradermally injected into the rostral part of the back and then the number of bouts of scratching in 60 min was recorded and summed. We found that at 24 hr after morphine withdrawal there was a significant increase in histamine-induced scratching behavior. The spinal c-Fos positive cells were also significantly increased. The relative adrenal weight increased and the relative thymus weight decreased, both significantly. Moreover, the plasma corticosterone levels changed in parallel with the number of scratching bouts. These results suggest that morphine withdrawal induces a stressed state and enhances in histamine-induced scratching behavior. Increased reaction against histamine in the cervical vertebrae will participate in this stress-induced itch enhancement.

Morphine affects HIV-induced inflammatory response without influencing viral replication in human monocyte-derived macrophages

PubMed Central

Dave, Rajnish S.

2011-01-01

Opiate-abusing individuals are in the top three risk-factor groups for HIV infection. In fact, almost 30% of HIV-infected individuals in the USA are reported to abuse opiates, highlighting the intersection of drugs of abuse with HIV/AIDS. Opiate-abusers are cognitively impaired and suffer from neurological dysfunctions that may lead to high-risk sexual behavior, poor adherence to antiretroviral regimens, and hepatitis-C virus infection. Collectively, these factors may contribute to accelerated HIV CNS disease progression. To understand the role of morphine in disease progression, we sought to determine whether morphine influences HIV-induced inflammation or viral replication in human monocyte-derived macrophages (h-mdms) and MAGI cells infected with HIV and exposed to morphine. Chronic morphine exposure of HIV-infected h-mdms led to significant alterations in secretion of IL-6 and MCP-2. Morphine enhanced IL-6 secretion and blunted MCP-2 secretion from HIV-infected h-mdms. However, exposure of HIV-infected h-mdms to morphine had no effect on TNF-α secretion. Morphine had no effect on later-stages of viral replication in HIV-infected h-mdms. Morphine had a potentially additive effect on the HIV-induced production of IL-6 and delayed HIV-induced MCP-2 production. These results suggest that in HIV-infected opiate abusers enhanced CNS inflammation might result even when HIV disease is controlled. PMID:22066570

Chorionic morphine, naltrexone and pentoxifylline effect on hypophyso-gonadal hormones of male rats.

PubMed

Moradi, M; Mahmoodi, M; Raoofi, A; Ghanbari, A

2015-01-01

Knowledge about harmful effects of morphine on hormone secretion seems to be necessary. The aim of the present study was to evaluate the effect of pentoxifylline on side effects derived by morphine on hypophyso-gonadal hormones of male rats. 32 male rats were divided into the 4 groups of OSS: control (received 40 g Sucrose/l drinking water and intraperitoneal injection of 1 l/kg normal saline), OMS: morphine group (received 0.4 mg/l + 40 g Sucrose/l in drinking water and intraperitoneal injection of 1 l/kg normal saline), NMS: morphine+naltrexane group (received 0.4 mg/l + 40 g Sucrose/l in drinking water and IP injection dose of 10 mg/kg/ml/day Naltrexane) and PMS: morphine + pentoxifylline group (received 0.4 mg/dl + 40 g Sucrose/l in drinking water and IP injection dose of 12 mg/kg/ml/day Pentoxifylline) for 56 days, respectively. Serum levels of testosterone, LH, FSH hormones were measured. Pentoxifylline increased serum levels of testosterone, LH, FSH hormones compared to control, morphine and morphine-naltrexane groups. Pentoxifylline has a significant efficacy for increasing serum levels of sexual hormones. Considering that Pentoxifylline is safe and cheap, with easy application, we suggest for the usage of this drug for improving semen parameter's quality before performing ART for the treatment of morphine addicts (Fig. 1, Ref. 31).

Reinstatement of Morphine-Induced Conditioned Place Preference in Mice by Priming Injections

PubMed Central

Do Couto, B. Ribeiro; Aguilar, M. A.; Manzanedo, C.; Rodríguez-Arias, M.; Miñarro, J.

2003-01-01

To construct a model of relapse of drug abuse in mice, the induction, we evaluated the extinction and reinstatement of morphine-induced place preference. In Experiment 1, we examined the effects of morphine (0, 2, 3, 5, 10, 20 and 40 mg/kg) in the conditioned place preference (CPP) paradigm. Mice showed CPP with 5, 10, 20 and 40 mg/kg. In Experiment 2, we evaluated the effects of two different extinction procedures. After conditioning with 40 mg/kg of morphine, the mice underwent daily extinction sessions of 60 or 15 min of duration. CPP was extinguished after seven and nine sessions, respectively. In Experiment 3, we tested the reinstating effects of several priming doses of morphine. Mice were conditioned with 40 mg/kg of morphine and underwent the daily 15 min extinction sessions until CPP was no longer evident. Then, the effects of morphine (0, 2, 3, 5, 10, 20, 40 mg/kg, i.p.) were evaluated. CPP was reinstated by doses from 5 mg/kg upward. The results show that morphine priming injections are effective in reactivating opiateseeking behavior in mice, and thus, the CPP paradigm might be useful to investigate the mechanisms underlying relapse of drug abuse. PMID:15152982

Comparison of the effects of magnesium and ketamine on postoperative pain and morphine consumption. A double-blind randomized controlled clinical study.

PubMed

Arıkan, Müge; Aslan, Bilge; Arıkan, Osman; Horasanlı, Eyüp; But, Abdulkadir

2016-01-01

To compare the effects of magnesium sulfate and ketamine on postoperative pain and total morphine consumption in a placebo-controlled design. One hundred and twenty women scheduled for total abdominal hysterectomy were included in this prospective, randomized, double-blind study. Postoperatively, when the Numeric Pain Rating Scale (NPRS) was four or more, IV-PCA morphine was applied to all patients. The patients were randomized into three groups: Group K ketamine, Group M magnesium, and Group C saline received as infusion. Total morphine consumption for 48h, pain scores, adverse effects, and patients' satisfaction were evaluated. Total morphine consumption was significantly lower in Group K (32.6±9.2 mg) than in Group M (58.9±6.5 mg) and in Group C (65.7±8.2 mg). The satisfaction level of patients in Group K was higher than the other two groups (p<0.05). Pruritus and nausea were observed more frequently in Group C. CONCLUSİON: The addition of ketamine to IV-PCA morphine reduces the total consumption of morphine without psychotic effects; however, magnesium did not influence morphine consumption.

Mechanisms of morphine enhancement of spontaneous seizure activity.

PubMed

Saboory, Ehsan; Derchansky, Miron; Ismaili, Mohammed; Jahromi, Shokrollah S; Brull, Richard; Carlen, Peter L; El Beheiry, Hossam

2007-12-01

High-dose opioid therapy can precipitate seizures; however, the mechanism of such a dangerous adverse effect remains poorly understood. The aim of our study was to determine whether the neuroexcitatory activity of high-dose morphine is mediated by selective stimulation of opioid receptors. Mice hippocampi were resected intact and bathed in low magnesium artificial cerebrospinal fluid to induce spontaneous seizure-like events recorded from CA1 neurons. Application of morphine had a biphasic effect on the recorded spontaneous seizure-like events. In a low concentration (10 microM), morphine depressed electrographic seizure activity. Higher morphine concentrations (30 and 100 microM) enhanced seizure activity in an apparent dose-dependent manner. Naloxone, a nonselective opiate antagonist blocked the proconvulsant action of morphine. Selective mu and kappa opiate receptor agonists and antagonists enhanced and suppressed the spontaneous seizure activity, respectively. On the contrary, delta opioid receptor ligands did not have an effect. The proseizure effect of morphine is mediated through selective stimulation of mu and kappa opiate receptors but not the activation of the delta receptor system. The observed dose-dependent mechanism of morphine neuroexcitation underscores careful adjustment and individualized opioid dosing in the clinical setting.

Study Design and Rationale of "A Multicenter, Open-Labeled, Randomized Controlled Trial Comparing MIdazolam Versus MOrphine in Acute Pulmonary Edema": MIMO Trial.

PubMed

Dominguez-Rodriguez, Alberto; Burillo-Putze, Guillermo; Garcia-Saiz, Maria Del Mar; Aldea-Perona, Ana; Harmand, Magali González-Colaço; Mirò, Oscar; Abreu-Gonzalez, Pedro

2017-04-01

Morphine has been used for several decades in cases of acute pulmonary edema (APE) due to the anxiolytic and vasodilatory properties of the drug. The non-specific depression of the central nervous system is probably the most significant factor for the changes in hemodynamics in APE. Retrospective studies have shown both negative and neutral effects in patients with APE and therefore some authors have suggested benzodiazepines as an alternative treatment. The use of intravenous morphine in the treatment of APE remains controversial. The MIdazolan versus MOrphine in APE trial (MIMO) is a multicenter, prospective, open-label, randomized study designed to evaluate the efficacy and safety of morphine in patients with APE. The MIMO trial will evaluate as a primary endpoint whether intravenous morphine administration improves clinical outcomes defined as in-hospital mortality. Secondary endpoint evaluation will be mechanical ventilation, cardiopulmonary resuscitation, intensive care unit admission rate, intensive care unit length of stay, and hospitalization length. In the emergency department, morphine is still used for APE in spite of poor scientific background data. The data from the MIMO trial will establish the effect-and especially the risk-when using morphine for APE.

Essential role for RGS9 in opiate action.

PubMed

Zachariou, Venetia; Georgescu, Dan; Sanchez, Nick; Rahman, Zia; DiLeone, Ralph; Berton, Olivier; Neve, Rachael L; Sim-Selley, Laura J; Selley, Dana E; Gold, Stephen J; Nestler, Eric J

2003-11-11

Regulators of G protein signaling (RGS) are a family of proteins known to accelerate termination of effector stimulation after G protein receptor activation. RGS9-2, a brain-specific splice variant of the RGS9 gene, is highly enriched in striatum and also expressed at much lower levels in periaqueductal gray and spinal cord, structures known to mediate various actions of morphine and other opiates. Morphine exerts its acute rewarding and analgesic effects by activation of inhibitory guanine nucleotide-binding regulatory protein-coupled opioid receptors, whereas chronic morphine causes addiction, tolerance to its acute analgesic effects, and profound physical dependence by sustained activation of these receptors. We show here that acute morphine administration increases expression of RGS9-2 in NAc and the other CNS regions, whereas chronic exposure decreases RGS9-2 levels. Mice lacking RGS9 show enhanced behavioral responses to acute and chronic morphine, including a dramatic increase in morphine reward, increased morphine analgesia with delayed tolerance, and exacerbated morphine physical dependence and withdrawal. These findings establish RGS9 as a potent negative modulator of opiate action in vivo, and suggest that opiate-induced changes in RGS9 levels contribute to the behavioral and neural plasticity associated with chronic opiate administration.

Analgesia induced by morphine microinjected into the nucleus raphe magnus: effects on tonic pain.

PubMed

Dualé, Christian; Sierralta, Fernando; Dallel, Radhouane

2007-07-01

One of the possible sites of action of the analgesic effect of morphine is the Nucleus Raphe Magnus, as morphine injected into this structure induces analgesia in transient pain models. In order to test if morphine in the Nucleus Raphe Magnus is also analgesic in a tonic pain model, 5 microg of morphine or saline (control) were microinjected into the Nucleus Raphe Magnus of the rat. Analgesic effects were assessed following nociceptive stimulation using transient heating of the tail (phasic pain) and subcutaneous orofacial injection of 1.5 % formalin (tonic pain). While morphine was strongly analgesic for the tail-flick response (p <0.0001 compared to control), analgesia on the response to formalin was also observed for both early (p = 0.007) and late responses (p = 0.02). However, the response to formalin was not completely blunted. These results suggest that the Nucleus Raphe Magnus is not the exclusive site of action of morphine-induced analgesia in clinical conditions.

Atg5- and Atg7-dependent autophagy in dopaminergic neurons regulates cellular and behavioral responses to morphine.

PubMed

Su, Ling-Yan; Luo, Rongcan; Liu, Qianjin; Su, Jing-Ran; Yang, Lu-Xiu; Ding, Yu-Qiang; Xu, Lin; Yao, Yong-Gang

2017-09-02

The molecular basis of chronic morphine exposure remains unknown. In this study, we hypothesized that macroautophagy/autophagy of dopaminergic neurons would mediate the alterations of neuronal dendritic morphology and behavioral responses induced by morphine. Chronic morphine exposure caused Atg5 (autophagy-related 5)- and Atg7 (autophagy-related 7)-dependent and dopaminergic neuron-specific autophagy resulting in decreased neuron dendritic spines and the onset of addictive behaviors. In cultured primary midbrain neurons, morphine treatment significantly reduced total dendritic length and complexity, and this effect could be reversed by knockdown of Atg5 or Atg7. Mice deficient for Atg5 or Atg7 specifically in the dopaminergic neurons were less sensitive to developing a morphine reward response, behavioral sensitization, analgesic tolerance and physical dependence compared to wild-type mice. Taken together, our findings suggested that the Atg5- and Atg7-dependent autophagy of dopaminergic neurons contributed to cellular and behavioral responses to morphine and may have implications for the future treatment of drug addiction.

The Cardiovascular Effects of Morphine THE PERIPHERAL CAPACITANCE AND RESISTANCE VESSELS IN HUMAN SUBJECTS

PubMed Central

Zelis, Robert; Mansour, Edward J.; Capone, Robert J.; Mason, Dean T.

1974-01-01

To evaluate the effects of morphine on the peripheral venous and arterial beds, 69 normal subjects were evaluated before and after the intravenous administration of 15 mg morphine. Venous tone was determined by three independent techniques in 22 subjects. The venous pressure measured in a hand vein during temporary circulatory arrest (isolated hand vein technique) fell from 20.2±1.4 to 13.4±0.9 mm Hg (P < 0.01) 10 min after morphine, indicating that a significant venodilation had occurred. With the acute occlusion technique, morphine induced a reduction in forearm venous tone from 12.8±1.1 to 7.9±2.3 mm Hg/ml/100 ml (P < 0.01). Although forearm venous volume at a pressure of 30 mm Hg (VV[30]) was increased from 2.26±0.17 to 2.55±0.26 ml/100 ml, measured by the equilibration technique, the change was not significant (P > 0.1). Of note is that the initial reaction to morphine was a pronounced venoconstriction, demonstrated during the first 1-2 min after the drug. (Isolated hand vein pressure increased to 37.2±5.4 mm Hg, P < 0.01). This rapidly subsided, and by 5 min a venodilation was evident. Morphine did not attenuate the venoconstrictor response to a single deep breath, mental arithmetic, or the application of ice to the forehead when measured by either the isolated hand vein technique or the equilibration technique. To evaluate the effects of morphine on the peripheral resistance vessels in 47 normal subjects, forearm blood flow was measured plethysmographically before and 10-15 min after the intravenous administration of 15 mg of morphine. Although mean systemic arterial pressure was unchanged, forearm blood flow increased from 2.92±0.28 to 3.96±0.46 ml/min/100 ml (P < 0.01), and calculated vascular resistance fell from 42.4±5.2 to 31.6±3.2 mm Hg/ml/min/100 ml (P < 0.01). When subjects were tilted to the 45° head-up position, morphine did not block the increase in total peripheral vascular resistance that occurs; however, it did significantly attenuate the forearm arteriolar constrictor response (before morphine, + 25.7±5.4; after morphine, + 13.7±5.3 mm Hg/ml/min/100 ml, P < 0.05). However, morphine did not block the post-Valsalva overshoot of blood pressure, nor did it block the increase in forearm vascular resistance produced by the application of ice to the forehead. Similarly, morphine did not block the arteriolar or venoconstrictor effects of intra-arterially administered norepinephrine. Morphine infused into the brachial artery in doses up to 200 μg/min produced no changes in ipsilateral forearm VV[30], forearm blood flow, or calculated forearm resistance. Intra-arterial promethazine, atropine, and propranolol did not block the forearm arteriolar dilator response to intravenous morphine; however, intra-arterial phentolamine abolished the response. These data suggest that in human subjects, morphine induces a peripheral venous and arteriolar dilation by a reflex reduction in sympathetic alpha adrenergic tone. Morphine does not appear to act as a peripheral alpha adrenergic blocking agent but seems to attenuate the sympathetic efferent discharge at a central nervous system level. Images PMID:4612057

Morphine potentiates seizures induced by GABA antagonists and attenuates seizures induced by electroshock in the rat.

PubMed

Foote, F; Gale, K

1983-11-25

In a naloxone-reversible, dose-dependent manner, morphine (10-50 mg/kg i.p.) protected against seizures induced by maximal electroshock and increased the incidence and severity of seizures induced by bicuculline, in rats. Morphine also potentiated seizures induced by isoniazid and by picrotoxin. Thus, opiate activity influences the expression of seizures in contrasting ways depending upon the mode of seizure induction. Since morphine consistently potentiated seizures induced by interference with GABA transmission, it appears that GABAergic systems may be of particular significance for the elucidation of the varied effects of morphine on seizure susceptibility.

The Environmental footprint of morphine: a life cycle assessment from opium poppy farming to the packaged drug.

PubMed

McAlister, Scott; Ou, Yanjun; Neff, Elise; Hapgood, Karen; Story, David; Mealey, Philip; McGain, Forbes

2016-10-21

To examine the environmental life cycle from poppy farming through to production of 100 mg in 100 mL of intravenous morphine (standard infusion bag). 'Cradle-to-grave' process-based life cycle assessment (observational). Australian opium poppy farms, and facilities for pelletising, manufacturing morphine, and sterilising and packaging bags of morphine. The environmental effects (eg, CO 2 equivalent ('CO 2 e') emissions and water use) of producing 100 mg of morphine. All aspects of morphine production from poppy farming, pelletising, bulk morphine manufacture through to final formulation. Industry-sourced and inventory-sourced databases were used for most inputs. Morphine sulfate (100 mg in 100 mL) had a climate change effect of 204 g CO 2 e (95% CI 189 to 280 g CO 2 e), approximating the CO 2 e emissions of driving an average car 1 km. Water use was 7.8 L (95% CI 6.7- to 9.0 L), primarily stemming from farming (6.7 L). All other environmental effects were minor and several orders of magnitude less than CO 2 e emissions and water use. Almost 90% of CO 2 e emissions occurred during the final stages of 100 mg of morphine manufacture. Morphine's packaging contributed 95 g CO 2 e, which accounted for 46% of the total CO 2 e (95% CI 82 to 155 g CO 2 e). Mixing, filling and sterilisation of 100 mg morphine bags added a further 86 g CO 2 e, which accounted for 42% (95% CI 80 to 92 g CO 2 e). Poppy farming (6 g CO 2 e, 3%), pelletising and manufacturing (18 g CO 2 e, 9%) made smaller contributions to CO 2 emissions. The environmental effects of growing opium poppies and manufacturing bulk morphine were small. The final stages of morphine production, particularly sterilisation and packaging, contributed to almost 90% of morphine's carbon footprint. Focused measures to improve the energy efficiency and sources for drug sterilisation and packaging could be explored as these are relevant to all drugs. Comparisons of the environmental effects of the production of other drugs and between oral and intravenous preparations are required. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Tolerance to the antinociceptive effects of chronic morphine requires c-Jun N-terminal kinase.

PubMed

Marcus, David J; Zee, Michael; Hughes, Alex; Yuill, Matthew B; Hohmann, Andrea G; Mackie, Ken; Guindon, Josée; Morgan, Daniel J

2015-06-12

Morphine and fentanyl are opioid analgesics in wide clinical use that act through the μ-opioid receptor (MOR). However, one limitation of their long-term effectiveness is the development of tolerance. Receptor desensitization has been proposed as a putative mechanism driving tolerance to G protein-coupled receptor (GPCR) agonists. Recent studies have found that tolerance to morphine is mediated by the c-Jun N-terminal Kinase (JNK) signaling pathway. The goal of the present study was to test the hypotheses that: 1) JNK inhibition will be antinociceptive on its own; 2) JNK inhibition will augment morphine antinociception and; 3) JNK mediates chronic tolerance for the antinociceptive effects of morphine using acute (hotplate and tail-flick), inflammatory (10 μl of formalin 2.5%) and chemotherapy (cisplatin 5 mg/kg ip once weekly)-induced neuropathic pain assays. We found that JNK inhibition by SP600125 (3 mg/kg) produces a greater antinociceptive effect than morphine (6 mg/kg) alone in the formalin test. Moreover, co-administration of morphine (6 mg/kg) with SP600125 (3 mg/kg) produced a sub-additive antinociceptive effect in the formalin test. We also show that pre-treatment with SP600125 (3 or 10 mg/kg), attenuates tolerance to the antinociceptive effects of morphine (10 mg/kg), but not fentanyl (0.3 mg/kg), in the tail-flick and hotplate tests. Pre-treatment with SP600125 also attenuates tolerance to the hypothermic effects of both morphine and fentanyl. We also examined the role of JNK in morphine tolerance in a cisplatin-induced model of neuropathic pain. Interestingly, treatment with SP600125 (3 mg/kg) alone attenuated mechanical and cold allodynia in a chemotherapy-induced pain model using cisplatin. Strikingly, SP600125 (3 mg/kg) pre-treatment prolonged the anti-allodynic effect of morphine by several days (5 and 7 days for mechanical and cold, respectively). These results demonstrate that JNK signaling plays a crucial role in mediating antinociception as well as chronic tolerance to the antinociceptive effects of morphine in acute, inflammatory, and neuropathic pain states. Thus, inhibition of JNK signaling pathway, via SP600125, represents an efficacious pharmacological approach to delay tolerance to the antinociceptive effects of chronic morphine in diverse pain models.

Hospital morphine preparation for abstinence syndrome in newborns exposed to buprenorphine or methadone.

PubMed

Colombini, Nathalie; Elias, Riad; Busuttil, Muriel; Dubuc, Myriam; Einaudi, Marie-Ange; Bues-Charbit, Martine

2008-06-01

This study was undertaken to evaluate the adequacy of a hospital formulated oral morphine preparation for management of neonatal abstinence syndrome (NAS) and to compare clinical features in infants exposed to methadone or buprenorphine in utero. Between October 1998 and October 2004 all infants born to mothers treated with buprenorphine or methadone during pregnancy were enrolled into this prospective study. Morphine hydrochloride solution (0.2 mg/ml) was prepared without preservatives under a flow laminar air box (class 100). Morphine solution: quantitative and qualitative HPLC analysis and microbiological study at regular intervals during storage at 4 degrees C for 6 months. Maternal characteristics: age, opiate dose during pregnancy. Neonatal characteristics: gestational age at delivery, birth weight, Lipsitz scores. Morphine dose: daily morphine dose, maximum morphine dose, duration of NAS, and duration of treatment required to achieve stable Lipsitz scores below 4. Kruskal-Wallis test for comparison of median values. Microbiological and HPLC analysis showed that the morphine preparation remained stable for 6 months at 4 degrees C. Nine methadone-exposed infants and 13 buprenorphine-exposed infants were included in the study. All infants presented NAS requiring treatment with the morphine solution. Lipsitz scores at birth were significantly different in the methadone and buprenorphine groups (P < 0.05). The methadone group required significantly higher doses of morphine preparation than the buprenorphine group during the first 38 days of treatment (P < 0.05): 0.435 +/- 0.150 mg/kg/day vs. 0.257 +/- 0.083 mg/kg/day. This hospital morphine solution is adequate for management of NAS. Preparations showed good stability and doses could be adjusted with a margin of 0.02 mg. The onset of NAS occurred within 24 h after birth in methadone-exposed infants (range 6-24 h) and within 48 h after birth in buprenorphine-exposed infants (range 24-168 h). Due to the possibility of delayed onset of NAS up to 7 days, infants born to mothers treated with buprenorphine should be kept in the hospital for an appropriate surveillance period. Treatment time was significantly longer (45 vs. 28 days) and the mean morphine doses were higher (1.7 fold) in methadone-exposed than buprenorphine-exposed infants.

Dose-Dependent Effects of Morphine Exposure on mRNA and microRNA (miR) Expression in Hippocampus of Stressed Neonatal Mice

PubMed Central

McAdams, Ryan M.; McPherson, Ronald J.; Beyer, Richard P.; Bammler, Theo K.; Farin, Frederico M.; Juul, Sandra E.

2015-01-01

Morphine is used to sedate critically ill infants to treat painful or stressful conditions associated with intensive care. Whether neonatal morphine exposure affects microRNA (miR) expression and thereby alters mRNA regulation is unknown. We tested the hypothesis that repeated morphine treatment in stress-exposed neonatal mice alters hippocampal mRNA and miR expression. C57BL/6 male mice were treated from postnatal day (P) 5 to P9 with morphine sulfate at 2 or 5 mg/kg ip twice daily and then exposed to stress consisting of hypoxia (100% N2 1 min and 100% O2 5 min) followed by 2h maternal separation. Control mice were untreated and dam-reared. mRNA and miR expression profiling was performed on hippocampal tissues at P9. Overall, 2 and 5 mg/kg morphine treatment altered expression of a total of 150 transcripts (>1.5 fold change, P<0.05) from which 100 unique mRNAs were recognized (21 genes were up- and 79 genes were down-regulated), and 5 mg/kg morphine affected 63 mRNAs exclusively. The most upregulated mRNAs were fidgetin, arginine vasopressin, and resistin-like alpha, and the most down-regulated were defensin beta 11, aquaporin 1, calmodulin-like 4, chloride intracellular channel 6, and claudin 2. Gene Set Enrichment Analysis revealed that morphine treatment affected pathways related to cell cycle, membrane function, signaling, metabolism, cell death, transcriptional regulation, and immune response. Morphine decreased expression of miR-204-5p, miR-455-3p, miR-448-5p, and miR-574-3p. Nine morphine-responsive mRNAs that are involved in neurodevelopment, neurotransmission, and inflammation are predicted targets of the aforementioned differentially expressed miRs. These data establish that morphine produces dose-dependent changes in both hippocampal mRNA and miR expression in stressed neonatal mice. If permanent, morphine–mediated neuroepigenetic effects may affect long-term hippocampal function, and this provides a mechanism for the neonatal morphine-related impairment of adult learning. PMID:25844808

The effect of O-1602, an atypical cannabinoid, on morphine-induced conditioned place preference and physical dependence.

PubMed

Alavi, Mohaddeseh Sadat; Hosseinzadeh, Hossein; Shamsizadeh, Ali; Roohbakhsh, Ali

2016-06-01

Previous studies show that some non-CB1/non-CB2 effects of cannabinoids are mediated through G protein coupled receptor 55 (GPR55). As this receptor is activated by some of cannabinoid receptor ligands and is involved in the modulation of pain, it was hypothesized that this receptor may also interact with opioids. This study examined the effect of atypical cannabinoid O-1602 as a GPR55 agonist on morphine-induced conditioned place preference (CPP) and physical dependence. We used a biased CPP model to evaluate the effect of O-1602 (0.2, 1 and 5mg/kg, intraperitoneal; ip) on the acquisition and expression of morphine-induced CPP in male mice. The locomotor activities of mice were also recorded. Moreover, repeated administration of morphine (50, 50 and 75mg/kg/day) for three days, induced physical dependence. The withdrawal signs such as jumps and diarrhea were precipitated by administration of naloxone (5mg/kg, ip). The effect of O-1602 on the development of morphine physical dependence was assessed by injection of O-1602 (0.2, 1 and 5mg/kg) before morphine administrations. Morphine (40mg/kg, subcutaneous; sc), but not O-1602 (5mg/kg) elicited significant preference in the post-conditioning phase. O-1602 at the doses of 0.2 and 1mg/kg, but not 5mg/kg reduced acquisition of morphine CPP with an increase in locomotor activity at the dose of 5mg/kg. O-1602 at the doses of 0.2, 1 and 5mg/kg also reduced expression of morphine CPP with an increase in locomotor activity at the dose of 5mg/kg. O-1602 had a significant inhibitory effect on development of morphine-induced physical dependence at the dose of 5mg/kg by decreasing jumps and diarrhea during withdrawal syndrome. The present results indicate that O-1602 decreased acquisition and expression of morphine CPP and inhibited development of morphine-induced physical dependence. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Morphine is associated with a delayed activity of oral antiplatelet agents in patients with ST-elevation acute myocardial infarction undergoing primary percutaneous coronary intervention.

PubMed

Parodi, Guido; Bellandi, Benedetta; Xanthopoulou, Ioanna; Capranzano, Piera; Capodanno, Davide; Valenti, Renato; Stavrou, Katerina; Migliorini, Angela; Antoniucci, David; Tamburino, Corrado; Alexopoulos, Dimitrios

2015-01-01

Morphine is recommended in patients with ST-segment-elevation myocardial infarction, including those undergoing primary percutaneous coronary intervention. Suboptimal antiplatelet effect during and after primary percutaneous coronary intervention is associated with increased thrombotic complications. It was hypothesized a potential drug-drug interaction between morphine and antiplatelet agents. We sought to assess platelet inhibition after a loading dose of the currently recommended antiplatelet agents in ST-segment-elevation myocardial infarction patients according to morphine use. Three hundred patients undergoing primary percutaneous coronary intervention receiving either prasugrel (n = 95) or ticagrelor (n = 205) loading dose had platelet reactivity assessed by VerifyNow 1, 2, and 4 hours after loading dose. Patients treated with morphine (n = 95; 32%) had a higher incidence of vomit (15% versus 2%; P = 0.001). P2Y12 reactivity units 2 hours after the loading dose was 187 (153-221) and 133 (102-165) in patient with and without morphine (P < 0.001); the difference persisted after excluding patients with vomit (P < 0.0001). High residual platelet reactivity (P2Y12 reactivity units ≥ 208) at 2 hours was found in 53% and 29% patients with and without morphine (P < 0.001) and without difference between prasugrel and ticagrelor patients. The independent predictors of high residual platelet reactivity at 2 hours were morphine use (odds ratio, 2.91 [1.71-4.97]; P < 0.0001) and age (odds ratio, 1.03 [1.01-1.05]; P = 0.010). Morphine remained associated with high residual platelet reactivity after propensity score adjustment (c-statistic, 0.68; 95% confidence interval, 0.66-0.70; P = 0.879 for Hosmer-Lemeshow test). In patients with ST-segment-elevation myocardial infarction, morphine use is associated with a delayed onset of action of the oral antiplatelet agents. This association persisted after adjusting for the propensity to receive morphine and after excluding patients with vomit. © 2014 American Heart Association, Inc.

Neuromodulatory effects of the dorsal hippocampal endocannabinoid system in dextromethorphan/morphine-induced amnesia.

PubMed

Ghasemzadeh, Zahra; Rezayof, Ameneh

2017-01-05

Dextromethorphan which is an active ingredient in many cough medicines has been previously shown to potentiate amnesic effect of morphine in rats. However, the effect of dextromethorphan, that is also a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, in combination with morphine on hippocampus-based long term memory has not been well characterized. The aim of the present study was to assess the possible role of endocannabinoid system of the dorsal hippocampus in dextromethorphan /morphine-induced amnesia. Our results showed that intraperitoneal (i.p.) injection of morphine (5mg/kg) or dextromethorphan (5-15mg/kg) before testing the passive avoidance learning induced amnesia. Combination of ineffective doses of dextromethorphan (7.5mg/kg, i.p.) and morphine (2mg/kg, i.p.) also produced amnesia, suggesting the enhancing effects of the drugs. To assess the effect of the activation or inhibition of the dorsal hippocampal cannabinoid CB 1 receptors on this amnesia, ACPA or AM251 as selective receptor agonists or antagonists were respectively injected into the CA1 regions before systemic injection of dextromethorphan and morphine. Interestingly, intra-CA1 microinjection of ACPA (0.5-1ng/rat) improved the amnesic effect of dextromethorphan /morphine combination. The microinjection of AM251 into the CA1 region enhanced the response of the combination of dextromethorphan /morphine in inducing amnesia. Moreover, Intra-CA1 microinjection of AM251 inhibited the improving effect of ACPA on dextromethorphan /morphine-induced amnesia. It is important to note that intra-CA1 microinjection of the same doses of the agonist or antagonist by itself had no effects on memory formation. Thus, it can be concluded that the dorsal hippocampal endocannabinoid system, via CB 1 receptor-dependent mechanism, may be involved in morphine/dextromethorphan -induced amnesia. Copyright © 2016 Elsevier B.V. All rights reserved.

Increased glutamate synaptic transmission in the nucleus raphe magnus neurons from morphine-tolerant rats.

PubMed

Bie, Bihua; Pan, Zhizhong Z

2005-02-09

Currently, opioid-based drugs are the most effective pain relievers that are widely used in the treatment of pain. However, the analgesic efficacy of opioids is significantly limited by the development of tolerance after repeated opioid administration. Glutamate receptors have been reported to critically participate in the development and maintenance of opioid tolerance, but the underlying mechanisms remain unclear. Using whole-cell voltage-clamp recordings in brainstem slices, the present study investigated chronic morphine-induced adaptations in glutamatergic synaptic transmission in neurons of the nucleus raphe magnus (NRM), a key supraspinal relay for pain modulation and opioid analgesia. Chronic morphine significantly increased glutamate synaptic transmission exclusively in one class of NRM cells that contains mu-opioid receptors in a morphine-tolerant state. The adenylyl cyclase activator forskolin and the cAMP analog 8-bromo-cAMP mimicked the chronic morphine effect in control neurons and their potency in enhancing the glutamate synaptic current was significantly increased in neurons from morphine-tolerant rats. MDL12330a, an adenylyl cyclase inhibitor, and H89, a protein kinase A (PKA) inhibitor, reversed the increase in glutamate synaptic transmission induced by chronic morphine. In addition, PMA, a phorbol ester activator of protein kinase C (PKC), also showed an increased potency in enhancing the glutamate synaptic current in these morphine-tolerant cells. The PKC inhibitor GF109203X attenuated the chronic morphine effect. Taken together, these results suggest that chronic morphine increases presynaptic glutamate release in mu receptor-containing NRM neurons in a morphine-tolerant state, and that the increased glutamate synaptic transmission appears to involve an upregulation of both the cAMP/PKA pathway and the PKC pathway. This glutamate-mediated activation of these NRM neurons that are thought to facilitate spinal pain transmission may contribute to the reduced opioid analgesia during opioid tolerance.

Morphine and Codeine in Oral Fluid after Controlled Poppy Seed Administration

PubMed Central

Concheiro, Marta; Newmeyer, Matthew N.; da Costa, Jose Luiz; Flegel, Ron; Gorelick, David A.; Huestis, Marilyn A.

2014-01-01

Opiates are an important drug class in drug testing programs. Ingestion of poppy seeds containing morphine and codeine can yield positive opiate tests and mislead result interpretation in forensic and clinical settings. Multiple publications evaluated urine opiate concentrations following poppy seed ingestion, but only 2 addressed oral fluid (OF) results; neither provided the ingested morphine and codeine dosage. We administered two 45g raw poppy seed doses, each containing 15.7mg morphine and 3.1mg codeine, 8h apart to 17 healthy adults. All OF specimens were screened by on-site OF immunoassay Draeger DrugTest 5000, and confirmed with OF collected with Oral-Eze® device and quantified by liquid chromatography tandem mass spectrometry (1μg/L morphine and codeine limits of quantification). Specimens (n=459) were collected before and up to 32h after the first dose. All specimens screened positive 0.5h after dosing and remained positive for 0.5-13h at Draeger 20μg/L morphine cutoff. Maximum OF morphine and codeine concentrations (Cmax) were 177 and 32.6μg/L, with times to Cmax (Tmax) of 0.5-1h and 0.5-2.5h post-dose, respectively. Windows of detection after the second dose extended at least 24h for morphine and to 18h for codeine. After both doses, the last morphine positive OF result was 1h with 40μg/L 2004 proposed US Substance Abuse and Mental Health Services Administration cutoff, and 0.5h with 95μg/L cutoff, recently recommended by the Driving Under the Influence of Drugs and Medicines project. Positive OF morphine results are possible 0.5-1h after ingestion of 15.7mg of morphine in raw poppy seeds, depending upon the cutoff employed. PMID:25345619

Facilitated extinction of morphine conditioned place preference with Tat-GluA2(3Y) interference peptide.

PubMed

Dias, C; Wang, Y T; Phillips, A G

2012-08-01

Neuroplasticity including long-term depression (LTD) has been implicated in both learning processes and addiction. LTD can be blocked by intravenous administration of the interference peptide Tat-GluA2(3Y) that prevents regulated endocytosis of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor. In this study, Tat-GluA2(3Y) was used to assess the role of LTD in the induction, expression, extinction and reinstatement of morphine-induced conditioned place preference (CPP). CPP was established in rats by pairing morphine (5 mg/kg, i.p.) or saline with a specific environmental context using a balanced protocol. Tat-GluA2(3Y) (0; 1.5; 2.25 nmol/g; i.v.), scrambled peptide (Tat-GluA2(Sc)), or vehicle was administered during the acquisition phase or prior to the test for CPP. Tat-GluA2(3Y) had no effect on the induction or initial expression of morphine-induced CPP. Rats that received Tat-GluA2(3Y) or Tat-GluA2(Sc) during acquisition were subsequently tested for 11 consecutive days in order to extinguish morphine CPP. CPP was then reinstated by an injection of morphine (5 mg/kg, i.p.). Co-administration of morphine and Tat-GluA2(3Y) during acquisition greatly facilitated extinction of CPP without affecting morphine-induced reinstatement of CPP. Using an intermittent retest schedule with bi-weekly tests to measure the maintenance of CPP, Tat-GluA2(3Y) during the acquisition phase had no effect on the maintenance of CPP. We propose that co-administration of Tat-GluA2(3Y) with morphine during acquisition of CPP weakens the association between morphine and contextual cues leading to rapid extinction of morphine CPP with repeated daily testing. Copyright © 2012 Elsevier B.V. All rights reserved.

Morphine-induced apoptosis in the ventral tegmental area and hippocampus after the development but not extinction of reward-related behaviors in rats.

PubMed

Razavi, Yasaman; Alamdary, Shabnam Zeighamy; Katebi, Seyedeh-Najmeh; Khodagholi, Fariba; Haghparast, Abbas

2014-03-01

Some data suggest that morphine induces apoptosis in neurons, while other evidences show that morphine could have protective effects against cell death. In this study, we suggested that there is a parallel role of morphine in reward circuitry and apoptosis processing. Therefore, we investigated the effect of morphine on modifications of apoptotic factors in the ventral tegmental area (VTA) and hippocampus (HPC) which are involved in the reward circuitry after the acquisition and extinction periods of conditioned place preference (CPP). In behavioral experiments, different doses of morphine (0.5, 5, and 10 mg/kg) and saline were examined in the CPP paradigm. Conditioning score and locomotor activity were recorded by Ethovision software after acquisition on the post-conditioning day, and days 4 and 8 of extinction periods. In order to investigate the molecular mechanisms in each group, we then dissected the brains and measured the expression of apoptotic factors in the VTA and HPC by western blotting analysis. All of the morphine-treated groups showed an increase of apoptotic factors in these regions during acquisition but not in extinction period. In the HPC, morphine significantly increased the ratio of Bax/Bcl-2, caspases-3, and PARP by the lowest dose (0.5 mg/kg), but, in the VTA, a considerable increase was seen in the dose of 5 mg/kg; promotion of apoptotic factors in the HPC and VTA insinuates that morphine can affect the molecular mechanisms that interfere with apoptosis through different receptors. Our findings suggest that a specific opioid receptor involves in modification of apoptotic factors expression in these areas. It seems that the reduction of cell death in response to high dose of morphine in the VTA and HPC may be due to activation of low affinity opioid receptors which are involved in neuroprotective features of morphine.

Morphine-induced conditioned place preference in rhesus monkeys: Resistance to inactivation of insula and extinction.

PubMed

Wu, XuJun; Zhao, Ning; Bai, Fan; Li, ChuanYu; Liu, CiRong; Wei, JingKuan; Zong, Wei; Yang, LiXin; Ryabinin, Andrey E; Ma, YuanYe; Wang, JianHong

2016-05-01

Drug addicts experience strong craving episodes in response to drug-associated cues. Attenuating these responses using pharmacological or behavioral approaches could aid recovery from addiction. Cue-induced drug seeking can be modeled using the conditioned place preference procedure (CPP). Our previous work showed that conditioned place preference (CPP) can be induced by administration of increasing doses of morphine in rhesus monkeys. Here, we investigated whether expression of morphine-induced CPP can be attenuated by inhibiting activity of insular cortex or by repeated unreinforced exposures to the CPP test. The insula has been demonstrated to be involved in addiction to several drugs of abuse. To test its role in morphine CPP, bilateral cannulae were implanted into the insula in seven adult monkeys. The CPP was established using a biased apparatus by intramuscular injections of morphine at increasing doses (1.5, 3.0 and 4.5mg/kg) for each monkey. After the monkeys established morphine CPP, their insulae were reversibly inactivated by bilateral microinjection with 5% lidocaine (40μl) prior to the post-conditioning test (expression) of CPP using a within-subject design. The microinjections of lidocaine failed to affect CPP expression when compared to saline injections. We subsequently investigated morphine-associated memory during six episodes of CPP tests performed in these monkeys over the following 75.0±0.2months. While the preference score showed a declining trend with repeated testing, morphine-induced CPP was maintained even on the last test performed at 75months post-conditioning. This observation indicated strong resistance of morphine-induced memories to extinction in rhesus monkeys. Although these data do not confirm involvement of insula in morphine-induced CPP, our observation that drug-associated memories can be maintained over six drug-free years following initial experience with morphine has important implications for treatment of drug addiction using extinction therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

The effect of tramadol plus paracetamol on consumption of morphine after coronary artery bypass grafting.

PubMed

Altun, Dilek; Çınar, Özlem; Özker, Emre; Türköz, Ayda

2017-02-01

To compare the effects of oral tramadol+paracetamol combination on morphine consumption following coronary artery bypass grafting (CABG) in the patient-controlled analgesia (PCA) protocol. A prospective, double-blind, randomized, clinical study. Single-institution, tertiary hospital. Fifty cardiac surgical patients undergoing primary CABG surgery. After surgery, the patients were allocated to 1 of 2 groups. Both groups received morphine according to the PCA protocol after arrival to the coronary intensive care unit (bolus 1 mg, lockout time 15 minutes). In addition to morphine administration 2 hours before operation and postoperative 2nd, 6th, 12th, 18th, 24th, 30th, 36th, 42th, and 48th hours, group T received tramadol+paracetamol (Zaldiar; 325 mg paracetamol, 37.5 mg tramadol) and group P received placebo. Sedation levels were measured with the Ramsay Sedation Scale, whereas pain was assessed with the Pain Intensity Score during mechanical ventilation and with the Numeric Rating Scale after extubation. If the Numeric Rating Scale score was ≥3 and Pain Intensity Score was ≥3, 0.05 mg/kg morphine was administered additionally. Preoperative patient characteristics, risk assessment, and intraoperative data were similar between the groups. Cumulative morphine consumption, number of PCA demand, and boluses were higher in group P (P<.01). The amount of total morphine (in mg) used as a rescue analgesia was also higher in group P (5.06±1.0), compared with group T (2.37±0.52; P<.001). The patients who received rescue doses of morphine were 8 (32%) in group T and 18 (72%) in group P (P<.001). Duration of mechanical ventilation in group P was longer than group T (P<.01). Tramadol+paracetamol combination along with PCA morphine improves analgesia and reduces morphine requirement up to 50% after CABG, compared with morphine PCA alone. Copyright © 2016 Elsevier Inc. All rights reserved.

Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration.

PubMed Central

Quiding, H; Olsson, G L; Boreus, L O; Bondesson, U

1992-01-01

1. Codeine was administered rectally to thirteen infants and young children undergoing elective surgery. Nine infants (6-10 months old) received a 4 mg suppository and four children (3-4 years old) an 8 mg suppository. Codeine and its metabolite morphine were measured in plasma by GC/MS. 2. The mean concentrations of codeine at 3, 4 and 5 h after administration were 240, 163 and 123 nmol l-1 in the younger and 309, 251 and 169 nmol l-1 in the older patients. The corresponding concentrations of morphine were 8.3, 7.4 and 4.5 nmol l-1 and 6.8, 5.5 and 2.8 nmol l-1 respectively. One patient in each age group had no detectable amounts of morphine. 3. In the four children, the rectal dose was repeated 6-hourly for four doses. The plasma concentrations of codeine and morphine following the fifth dose were similar to those after the first dose. The mean AUC(0,5 h) of morphine was 1.6% that of codeine. 4. In the infants the mean plasma half-lives of codeine and morphine were 2.6 and 2.5 h. The two infants with the lowest body weights had the longest half-lives. 5. The mean morphine/codeine concentration ratio was 4.3% in the infants and 1.6% in the children, suggesting impaired glucuronidation of morphine in the former group. The hourly concentration ratios were almost identical following the first and fifth dose in the children. 6. We conclude that at the age of 6 months infants are capable of O-demethylating codeine to morphine. PMID:1540490

Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats.

PubMed

Mattioli, Theresa-Alexandra M; Milne, Brian; Cahill, Catherine M

2010-04-16

The development of analgesic tolerance following chronic morphine administration can be a significant clinical problem. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Many studies have also demonstrated that ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive tolerance and clinical studies demonstrate that it has opioid sparing effects. In this study we demonstrate that ultra-low dose naltrexone attenuates glial activation, which may contribute to its effects on attenuating tolerance. Spinal cord sections from rats administered chronic morphine showed significantly increased immuno-labelling of astrocytes and microglia compared to saline controls, consistent with activation. 3-D images of astrocytes from animals administered chronic morphine had significantly larger volumes compared to saline controls. Co-injection of ultra-low dose naltrexone attenuated this increase in volume, but the mean volume differed from saline-treated and naltrexone-treated controls. Astrocyte and microglial immuno-labelling was attenuated in rats co-administered ultra-low dose naltrexone compared to morphine-treated rats and did not differ from controls. Glial activation, as characterized by immunohistochemical labelling and cell size, was positively correlated with the extent of tolerance developed. Morphine-induced glial activation was not due to cell proliferation as there was no difference observed in the total number of glial cells following chronic morphine treatment compared to controls. Furthermore, using 5-bromo-2-deoxyuridine, no increase in spinal cord cell proliferation was observed following chronic morphine administration. Taken together, we demonstrate a positive correlation between the prevention of analgesic tolerance and the inhibition of spinal gliosis by treatment with ultra-low dose naltrexone. This research provides further validation for using ultra-low dose opioid receptor antagonists in the treatment of various pain syndromes.

Electrolytic lesion of the nucleus raphe magnus reduced the antinociceptive effects of bilateral morphine microinjected into the nucleus cuneiformis in rats.

PubMed

Haghparast, Abbas; Ordikhani-Seyedlar, Mehdi; Ziaei, Maryam

2008-06-27

Several lines of investigation show that the rostral ventromedial medulla is a critical relay for midbrain regions, including the nucleus cuneiformis (CnF), which control nociception at the spinal cord. There is some evidence that local stimulation or morphine administration into the CnF produces the effective analgesia through the nucleus raphe magnus (NRM). The present study tries to determine the effect of morphine-induced analgesia following microinjection into the CnF in the absence of NRM. Seven days after the cannulae implantation, morphine was microinjected bilaterally into the CnF at the doses of 0.25, 1, 2.5, 5, 7.5 and 10 microg/0.3 microl saline per side. The morphine-induced antinociceptive effect measured by tail-flick test at 30, 60, 90 and 120 min after microinjection. The results showed that bilateral microinjection of morphine into the CnF dose-dependently causes increase in tail-flick latency (TFL). The 50% effective dose of morphine was determined and microinjected into the CnF (2.5 microg/0.3 microl saline per side) in rats after NRM electrolytic lesion (1 mA, 30 s). Lesion of the NRM significantly decreased TFLs, 30 (P<0.01) and 60 (P<0.05) but not 90-120 min after morphine microinjection into the CnF, compared with sham-lesion group. We concluded that morphine induces the analgesic effects through the opioid receptors in the CnF. It is also appeared that morphine-induced antinociception decreases following the NRM lesion but it seems that there are some other descending pain modulatory pathways that activate in the absence of NRM.

Recovery from Mu-opioid Receptor Desensitization following Chronic Treatment with Morphine and Methadone

PubMed Central

Quillinan, Nidia; Lau, Elaine; Virk, Michael; von Zastrow, Mark; Williams, John T

2011-01-01

Chronic treatment with morphine results in a decrease in mu-opioid receptor sensitivity, an increase in acute desensitization and a reduction in the recovery from acute desensitization in locus coeruleus neurons. With acute administration, morphine is unlike many other opioid agonists in that it does not mediate robust acute desensitization or induce receptor trafficking. This study compares mu-opioid receptor desensitization and trafficking in brain slices taken from rats treated for 6–7 days with a range of doses of morphine (60, 30, 15 mg/kg/day) and methadone (60, 30, 5 mg/kg/day) applied by subcutaneous implantation of osmotic mini pumps. Mice were treated with 45 mg/kg/day. In morphine treated animals, recovery from acute [Met]5enkephalin-induced desensitization and receptor recycling was diminished. In contrast, recovery and recycling were unchanged in slices from methadone treated animals. Remarkably the reduced recovery from desensitization and receptor recycling found in slices from morphine treated animals were not observed in animals lacking β-arrestin2. Further, pharmacological inhibition of GRK2, while not affecting the ability of [Met]5enkephalin to induce desensitization, acutely reversed the delay in recovery from desensitization produced by chronic morphine treatment. These results characterize a previously unidentified function of the GRK/arrestin system in mediating opioid regulation in response to chronic morphine administration. They also suggest that the GRK/arrestin system, rather then serving as a primary mediator of acute desensitization, controls recovery from desensitization by regulating receptor reinsertion to the plasma membrane after chronic treatment with morphine. The sustained GRK/arrestin dependent desensitization is another way in which morphine and methadone are distinguished. PMID:21430144

Baclofen prevents the elevated plus maze behavior and BDNF expression during naloxone precipitated morphine withdrawal in male and female mice.

PubMed

Pedrón, Valeria T; Varani, André P; Balerio, Graciela N

2016-05-01

In previous studies we have shown that baclofen, a selective GABAB receptor agonist, prevents the somatic expression and reestablishes the dopamine and μ-opioid receptors levels, modified during naloxone-precipitated morphine withdrawal syndrome in male and female mice. There are no previous reports regarding sex differences in the elevated plus maze (EPM) and the expression of BDNF in morphine-withdrawn mice. The present study analyses the behavioral and biochemical variations during morphine withdrawal in mice of both sexes, and whether these variations are prevented with baclofen. Swiss-Webster albino prepubertal mice received morphine (2 mg/kg, i.p.) twice daily, for 9 consecutive days. On the 10th day, one group of morphine-treated mice received naloxone (opioid receptor antagonist; 6 mg/kg, i.p.) 1 h after the last dose of morphine to precipitate withdrawal. A second group received baclofen (2 mg/kg, i.p.) before naloxone administration. The EPM behavior was measured during 15 min after naloxone injection. The expression of BDNF-positive cells was determined by immunohistochemistry. Withdrawn male mice showed a higher percentage of time spent and number of entries to the open arms compared to withdrawn female mice. Baclofen prevented this behavior in both sexes. BDNF expression decreased in the AcbC, BNST, CeC, and CA3 of the hippocampus while increased in the BLA of morphine withdrawn male. Baclofen pretreatment prevented the BDNF expression observed in morphine withdrawn male mice in all the brain areas studied except in the CeC. Baclofen prevention of the EPM behavior associated to morphine withdrawal could be partially related to changes in BDNF expression. © 2016 Wiley Periodicals, Inc.

Morphine Preconditioning Downregulates MicroRNA-134 Expression Against Oxygen-Glucose Deprivation Injuries in Cultured Neurons of Mice.

PubMed

Meng, Fanjun; Li, Yan; Chi, Wenying; Li, Junfa

2016-07-01

Brain protection by narcotics such as morphine is clinically relevant due to the extensive use of narcotics in the perioperative period. Morphine preconditioning induces neuroprotection in neurons, but it remains uncertain whether microRNA-134 (miR-134) is involved in morphine preconditioning against oxygen-glucose deprivation-induced injuries in primary cortical neurons of mice. The present study examined this issue. After cortical neurons of mice were cultured in vitro for 6 days, the neurons were transfected by respective virus vector, such as lentiviral vector (LV)-miR-control-GFP, LV-pre-miR-134-GFP, LV-pre-miR-134-inhibitor-GFP for 24 hours; after being normally cultured for 3 days again, morphine preconditioning was performed by incubating the transfected primary neurons with morphine (3 μM) for 1 hour, and then neuronal cells were exposed to oxygen-glucose deprivation (OGD) for 1 hour and oxygen-glucose recovery for 12 hours. The neuronal cells survival rate and the amount of apoptotic neurons were determined by MTT assay or TUNEL staining at designated time; and the expression levels of miR-134 were detected using real-time reverse transcription polymerase chain reaction at the same time. The neuronal cell survival rate was significantly higher, and the amount of apoptotic neurons was significantly decreased in neurons preconditioned with morphine before OGD than that of OGD alone. The neuroprotection induced by morphine preconditioning was partially blocked by upregulating miR-134 expression, and was enhanced by downregulating miR-134 expression. The expression of miR-134 was significantly decreased in morphine-preconditioned neurons alone without transfection. By downregulating miR-134 expression, morphine preconditioning protects primary cortical neurons of mice against injuries induced by OGD.

The role of morphine on rat neural stem cells viability, neuro-angiogenesis and neuro-steroidgenesis properties.

PubMed

Abdyazdani, Nima; Nourazarian, Alireza; Nozad Charoudeh, Hojjatollah; Kazemi, Masoumeh; Feizy, Navid; Akbarzade, Maryam; Mehdizadeh, Amir; Rezaie, Jafar; Rahbarghazi, Reza

2017-01-01

A lack of comprehensive data exists on the effect of morphine on neural stem cell neuro-steroidogenesis and neuro-angiogenesis properties. We, herein, investigated the effects of morphine (100μM), naloxone (100μM) and their combination on rat neural stem cells viability, clonogenicity and Ki-67 expression over a period of 72h. Any alterations in the total fatty acids profile under treatment protocols were elucidated by direct transesterification method. We also monitored the expression of p53, aromatase and 5-alpha reductase by real-time PCR assay. To examine angiogenic capacity, in vitro tubulogenesis and the level of VE-cadherin transcript were investigated during neural to endothelial differentiation under the experimental procedure. Cells supplemented with morphine displayed reduced survival (p<0.01) and clonogenicity (p<0.001). Flow cytometric analysis showed a decrease in Ki-67 during 72h. Naloxone potentially blunted morphine-induced all effects. The normal levels of fatty acids, including saturated and unsaturated were altered by naloxone and morphine supplements. Following 48h, the up-regulation of p53, aromatase and 5-alpha reductase genes occurred in morphine-primed cells. Using three-dimensional culture models of angiogenesis and real time PCR assay, we showed morphine impaired the tubulogenesis properties of neural stem cells (p<0.001) by the inhibition of trans-differentiation into vascular cells and led to decrease of in VE-cadherin expression. Collectively, morphine strongly impaired the healthy status of neural stem cells by inducing p53 and concurrent elevation of aromatase and 5-alpha reductase activities especially during early 48h. Also, neural stem cells-being exposed to morphine lost their potency to elicit angiogenesis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Intra-accumbal CB1 receptor blockade reduced extinction and reinstatement of morphine.

PubMed

Khaleghzadeh-Ahangar, Hossein; Haghparast, Abbas

2015-10-01

The limbic dopaminergic reward system is the main target of morphine-like drugs which begins from the ventral tegmental area (VTA) and sends its dopaminergic projections to the nucleus accumbens (NAc), amygdala, hippocampus and prefrontal cortex. Cannabinoid receptors exist in afferent neurons from these areas to the NAc and can modulate glutamate synaptic transmission in the NAc. Cannabinoids can interact with the opiate system in reward-related behaviors; nevertheless these systems' interaction in extinction duration and reinstatement has not been shown. In the present study, the effects of bilateral intra-accumbal administration of AM251, a CB1 receptor antagonist, on the duration of the extinction phase and reinstatement to morphine were investigated by conditioned place preference (CPP) paradigm. Forty eight adult male albino Wistar rats were used. Bilateral intra-accumbal administration of AM251 (15, 45 and 90μM/0.5μl DMSO per side) was performed. Subcutaneous administration of morphine (5mg/kg) in three consecutive days was used to induce CPP. The results showed that administration of the maximal dose of AM251 during the extinction period significantly reduces duration of extinction and reinstatement to morphine. Administration of the middle dose during the extinction period significantly attenuated reinstatement to morphine. A single microinjection of the middle dose just before the reinstatement phase significantly attenuated reinstatement to morphine only, while bilateral intra-accumbal administration of neither the lowest dose nor the vehicle (DMSO) had any effects. These results for the first time indicated that CB1 receptors within the NAc are involved in the maintenance of morphine rewarding properties, and morphine seeking behaviors in extinguished morphine-induced CPP rats. Copyright © 2015 Elsevier Inc. All rights reserved.

Morphine hyposensitivity in streptozotocin-diabetic rats: Reversal by dietary l-arginine treatment.

PubMed

Lotfipour, Shahrdad; Smith, Maree T

2018-01-01

Painful diabetic neuropathy (PDN) is a long-term complication of diabetes. Defining symptoms include mechanical allodynia (pain due to light pressure or touch) and morphine hyposensitivity. In our previous work using the streptozotocin (STZ)-diabetic rat model of PDN, morphine hyposensitivity developed in a temporal manner with efficacy abolished at 3 months post-STZ and maintained for 6 months post-STZ. As this time course mimicked that for the temporal development of hyposensitivity to the pain-relieving effects of the furoxan nitric oxide (NO) donor, PRG150 (3-methylfuroxan-4-carbaldehyde) in STZ-diabetic rats, we hypothesized that progressive depletion of endogenous NO bioactivity may underpin the temporal loss of morphine sensitivity in STZ-diabetic rats. Furthermore, we hypothesized that replenishment of NO bioactivity may restore morphine sensitivity in these animals. Diabetes was induced in male Dark Agouti rats by intravenous injection of STZ (85 mg/kg). Diabetes was confirmed on day 7 if blood glucose concentrations were ≥15 mmol/L. Mechanical allodynia was fully developed in the bilateral hindpaws by 3 weeks of STZ-diabetes in rats and this was maintained for the study duration. Morphine hyposensitivity developed in a temporal manner with efficacy abolished by 3 months post-STZ. Administration of dietary l-arginine (NO precursor) at 1 g/d to STZ-diabetic rats according to a 15-week prevention protocol initiated at 9 weeks post-STZ prevented abolition of morphine efficacy. When given as an 8-week intervention protocol in rats where morphine efficacy was abolished, dietary l-arginine at 1 g/d progressively rescued morphine efficacy and potency. Our findings implicate NO depletion in the development of morphine hyposensitivity in STZ-diabetic rats. © 2017 John Wiley & Sons Australia, Ltd.

Acute Noxious Stimulation Modifies Morphine Effect in Serotonergic but not Dopaminergic Midbrain Areas

PubMed Central

Bajic, Dusica; Commons, Kathryn G.

2010-01-01

It is poorly understood if and how pain may modify the effect of opioids on neural systems that contribute to reward and addictive behavior. We hypothesized that the activation of ascending dopaminergic and serotonergic nuclei by morphine is modified by the presence of noxious stimulation. Immunohistochemical double-labeling technique with Fos was used to examine if an intraplantar formalin injection, an acute noxious input, changed the effect of morphine on dopaminergic neurons of the ventral tegmental area (VTA), and serotonergic neurons of the dorsal raphe nucleus (DR). Four groups of rats were analyzed: (1) CONTROL injected with normal saline subcutaneously, (2) rats treated with FORMALIN into the hind paw 30 minutes after normal saline injection, (3) rats injected with MORPHINE sulfate subcutaneously, and (4) rats treated with formalin into the hind paw 30 minutes after morphine injection (MORPHINE/FORMALIN). Following morphine injection, there was an increase in the number of dopaminergic neurons in the VTA with Fos immunolabeling. However, noxious stimulation did not detectably change morphine's effect on Fos expression in VTA dopamine neurons. In contrast, the number of serotonergic neurons containing Fos was increased in the morphine/formalin group compared to all other groups and this effect was topographically selective for the dorsal area of the DR at mid rostro-caudal levels. Therefore, morphine's activation of the VTA, which is associated with motivated behavior and reward seeking, appears similar in the context of pain. However, activation of the ascending serotonin system, which influences mood and has the capacity to modify reward pathways, appears different. In addition, these findings reveal interactions between nociceptive signaling and opioids that contrasts with the notion that opioids simply block access of nociceptive signaling to supraspinal structures. PMID:20026253

Inhibitory effects of processed Aconiti tuber on morphine-induced conditioned place preference in rats.

PubMed

Wu, Guiyun; Huang, Wenqi; Zhang, Hui; Li, Qiaobo; Zhou, Jun; Shu, Haihua

2011-06-14

Our previous studies indicated that processed Aconiti tuber (PAT), a traditional Chinese herbal medicine, had antinociceptive effects and inhibitory effects on morphine tolerance by activation of kappa-opioid receptor (KOR). Preclinical studies also demonstrated that KOR agonists functionally attenuate addictive behaviors of morphine, such as conditioned place preference (CPP). Therefore, we hypothesize that PAT may inhibit morphine-induced CPP in rats. (1) Five groups of rats (n=8 for each group) were alternately subcutaneous (s.c.) injected with morphine 10mg/kg (one group receive normal saline as a control) and normal saline for 8 days and oral co-administrated with distilled water or PAT 0.3, 1.0, or 3.0 g/kg daily on days 2-9 during CPP training, respectively. (2) Other four groups of rats were randomly s.c. injected with nor-binaltorphimine (nor-BNI; 5mg/kg) or normal saline (as a control) 120 min before alternately s.c. with morphine and normal saline and oral co-administrated with distilled water or PAT 3.0 g/kg daily. Each rat was acquired pre-conditioning and post-conditioning CPP data and assayed dynorphin concentrations by radioimmunoassay in rat's nucleus accumbens (NAc) after CPP training. (1) PAT 1.0 or 3.0 g/kg dose-dependently decreased the morphine-induced increase of CPP scores. (2) Nor-BNI completely antagonized the inhibition of PAT on morphine-induced CPP. (3) PAT dose-dependently increased dynorphin content in rats' NAc after CPP training. (1) PAT dose-dependently inhibited morphine-induced CPP. (2) The inhibition of PAT on morphine-induced CPP was probably due to activation of KOR by increasing dynorphin release in rats' NAc. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Effects of voluntary and treadmill exercise on spontaneous withdrawal signs, cognitive deficits and alterations in apoptosis-associated proteins in morphine-dependent rats.

PubMed

Mokhtari-Zaer, Amin; Ghodrati-Jaldbakhan, Shahrbanoo; Vafaei, Abbas Ali; Miladi-Gorji, Hossein; Akhavan, Maziar M; Bandegi, Ahmad Reza; Rashidy-Pour, Ali

2014-09-01

Chronic exposure to morphine results in cognitive deficits and alterations of apoptotic proteins in favor of cell death in the hippocampus, a brain region critically involved in learning and memory. Physical activity has been shown to have beneficial effects on brain health. In the current work, we examined the effects of voluntary and treadmill exercise on spontaneous withdrawal signs, the associated cognitive defects, and changes of apoptotic proteins in morphine-dependent rats. Morphine dependence was induced through bi-daily administrations of morphine (10mg/kg) for 10 days. Then, the rats were trained under two different exercise protocols: mild treadmill exercise or voluntary wheel exercise for 10 days. After exercise training, their spatial learning and memory and aversive memory were examined by a water maze and by an inhibitory avoidance task, respectively. The expression of the pro-apoptotic protein Bax and the anti-apoptotic protein Bcl-2 in the hippocampus were determined by immunoblotting. We found that chronic exposure to morphine impaired spatial and aversive memory and remarkably suppressed the expression of Bcl-2, but Bax expression remained constant. Both voluntary and treadmill exercise alleviated memory impairment, increased the expression of Bcl-2 protein, and only the later suppressed the expression of Bax protein in morphine-dependent animals. Moreover, both exercise protocols diminished the occurrence of spontaneous morphine withdrawal signs. Our findings showed that exercise reduces the spontaneous morphine-withdrawal signs, blocks the associated impairment of cognitive performance, and overcomes morphine-induced alterations in apoptotic proteins in favor of cell death. Thus, exercise may be a useful therapeutic strategy for cognitive and behavioral deficits in addict individuals. Copyright © 2014 Elsevier B.V. All rights reserved.

The effect of morphine on the biosynthesis of catecholamines in the rat brain.

PubMed

Malini, M; Kwan, T K; Perumal, R

1994-02-01

In vivo studies involved monitoring the effect of morphine administration on catecholamine biosynthesis by the brain while in vitro studies involved studying the effect of morphine on the uptake of tritiated tyrosine by synaptosomes and its subsequent incorporation into the catecholamines. The extremely low levels of these endogenous compounds required the use of High Performance Liquid Chromatography with electrochemical detection. Intra-peritoneal injection of morphine at a dosage of 10 mg/kg did not produce appreciable changes in the catecholamine levels but a dosage of 30 mg/kg morphine was found to elevate dihydroxy phenylacetic acid content. At a dosage of 60 mg/kg, dopamine levels were elevated while noradrenaline was depleted. Morphine, at a concentration of 1 x 10(-5)M increases the incorporation of tritiated tyrosine into dopamine and dihydroxy phenylacetic acid in synaptosomal preparations.

Drug-seeking behavior in an invertebrate system: evidence of morphine-induced reward, extinction and reinstatement in crayfish

PubMed Central

Nathaniel, Thomas I.; Panksepp, Jules; Huber, Robert

2009-01-01

Several lines of evidence suggest that exploring the neurochemical basis of reward in invertebrate species may provide clues for the fundamental behavioral and neurobiology underpinnings of drug addiction. How the presence of drug-sensitive reward relates to a decrease in drug-seeking behavior and reinstatement of drug seeking behavior in invertebrate systems is not known. The present study of a conditioned place preference (CPP) paradigm in crayfish (Orconectes rusticus) explores morphine-induced reward, extinction and reinstatement. Repeated intra-circulatory infusions of 2.5μg/g, 5.0μg/g and 10.0μg/g doses of morphine over 5 days serve as a reward when paired with a distinct visual or tactile environment. Morphine-induced CPP was extinguished after repeated saline injections for 5 days in the previously morphine-paired compartment. After the previously established CPP had been eliminated during the extinction phase, morphine-experienced crayfish were challenged with 2.5 μg/g, 5.0 μg/g and 10.0 μg/g respectively. The priming injections of morphine reinstated CPP in all training doses, suggesting that morphine-induced CPP is unrelenting, and that with time, it can be reinstated by morphine following extinction in an invertebrate model just like in mammals. Together with other recent studies, this work demonstrates the advantage of using crayfish as an invertebrate animal model to investigate the basic biological processes that underline exposure to mammalian drugs of abuse. PMID:18822319

Comparison of Intravenous Morphine Versus Paracetamol in Sciatica: A Randomized Placebo Controlled Trial.

PubMed

Serinken, Mustafa; Eken, Cenker; Gungor, Faruk; Emet, Mucahit; Al, Behcet

2016-06-01

The objective was to compare intravenous morphine and intravenous acetaminophen (paracetamol) for pain treatment in patients presenting to the emergency department with sciatica. Patients, between the ages of 21 and 65 years, suffering from pain in the sciatic nerve distribution and a positive straight leg-raise test composed the study population. Study patients were assigned to one of three intravenous interventions: morphine (0.1 mg/kg), acetaminophen (1 g), or placebo. Physicians, nurses, and patients were blinded to the study drug. Changes in pain intensity were measured at 15 and 30 minutes using a visual analog scale. Rescue drug (fentanyl) use and adverse effects were also recorded. Three-hundred patients were randomized. The median change in pain intensity between treatment arms at 30 minutes were as follows: morphine versus acetaminophen 25 mm (95% confidence interval [CI] = 20 to 29 mm), morphine versus placebo 41 mm (95% CI = 37 to 45 mm), and acetaminophen versus placebo 16 mm (95% CI = 12 to 20 mm). Eighty percent of the patients in the placebo group (95% CI = 63.0% to 99%), 18% of the patients in the acetaminophen group (95% CI = 10.7% to 28.5%), and 6% of those in the morphine group (95% CI = 2.0% to 13.2%) required a rescue drug. Adverse effects were similar between the morphine and acetaminophen groups. Morphine and acetaminophen are both effective for treating sciatica at 30 minutes. However, morphine is superior to acetaminophen. © 2016 by the Society for Academic Emergency Medicine.

Stress-induced analgesia and morphine responses are changed in catechol-O-methyltransferase-deficient male mice.

PubMed

Kambur, Oleg; Männistö, Pekka T; Viljakka, Kaarin; Reenilä, Ilkka; Lemberg, Kim; Kontinen, Vesa K; Karayiorgou, Maria; Gogos, Joseph A; Kalso, Eija

2008-10-01

Catechol-O-methyltransferase (COMT) polymorphisms modulate pain and opioid analgesia in human beings. It is not clear how the effects of COMT are mediated and only few relevant animal studies have been performed. Here, we used old male Comt gene knock-out mice as an animal model to study the effects of COMT deficiency on nociception that was assessed by the hot plate and tail flick tests. Stress-induced analgesia was achieved by forced swim. Morphine antinociception was measured after 10 mg/kg of morphine subcutaneously. Morphine tolerance was produced with subcutaneous morphine pellets and withdrawal provoked with subcutaneous naloxone. In the hot plate test, morphine-induced antinociception was significantly greater in the COMT knock-out mice, compared to the wild-type mice. This may be due to increased availability of opioid receptors as suggested by previous human studies. In the tail flick test, opioid-mediated stress-induced analgesia was absent and morphine-induced analgesia was decreased in COMT knock-out mice. In the hot plate test, stress-induced analgesia developed to all mice regardless of the COMT genotype. There were no differences between the genotypes in the baseline nociceptive thresholds, morphine tolerance and withdrawal. Our findings show, for the first time, the importance of COMT activity in stress- and morphine-induced analgesia in mice. COMT activity seems to take part in the modulation of nociception not only in the brain, as suggested earlier, but also at the spinal/peripheral level.

Intrathecal Morphine Attenuates Recovery of Function after a Spinal Cord Injury

PubMed Central

Moreno, Georgina; Woller, Sarah; Puga, Denise; Hoy, Kevin; Balden, Robyn; Grau, James W.

2009-01-01

Abstract Prior work has shown that a high dose (20 mg/kg) of systemic morphine, required to produce significant analgesia in the acute phase of a contusion injury, undermines the long-term health of treated subjects and increases lesion size. Moreover, a single dose of systemic morphine in the early stage of injury (24 h post-injury) led to symptoms of neuropathic pain 3 weeks later, in the chronic phase. The present study examines the locus of the effects using intrathecal morphine administration. Subjects were treated with one of three doses (0, 30, or 90 μg) of intrathecal morphine 24 h after a moderate contusion injury. The 90-μg dose produced significant analgesia when subjects were exposed to noxious stimuli (thermal and incremented shock) below the level of injury. Yet, despite analgesic efficacy, intrathecal morphine significantly attenuated the recovery of locomotor function and increased lesion size rostral to the injury site. A single dose of 30 or 90 μg of intrathecal morphine also decreased weight gain, and more than doubled the incidence of mortality and autophagia when compared to vehicle-treated controls. Morphine is one of the most effective pharmacological agents for the treatment of neuropathic pain and, therefore, is indispensable for the spinally injured. Treatment can, however, adversely affect the recovery process. A morphine-induced attenuation of recovery may result from increases in immune cell activation and, subsequently, pro-inflammatory cytokine concentrations in the contused spinal cord. PMID:19388818

Effects of Morphine on Behavioral Task Performance in SIV-Infected Rhesus Macaques.

PubMed

Marcario, Joanne K; Pendyala, Gurudutt; Riazi, Mariam; Fleming, Kandace; Marquis, Janet; Callen, Shannon; Lisco, Steven J; Fowler, Stephen C; Cheney, Paul D; Buch, Shilpa J

2016-06-01

The abuse of opiates such as morphine in synergy with HIV infection not only exacerbates neuropathogenesis but significantly impacts behavioral attributes in HIV infected subjects. Thus, the goal of the current study was to characterize behavioral perturbations in rhesus macaques subjected to chronic morphine and SIV infection. Specifically, we assessed three behavioral tasks: motor skill (MS), forelimb force (FFT) and progressive ratio (PR) tasks. After collecting baseline control data (44 weeks) and data during the morphine-only dependency period (26 weeks), a subset of animals were productively infected with neurovirulent strains of SIVmac (R71/E17) for an additional 33 weeks. A general pattern in the results is that behavioral decline occurred with high CSF viral loads but not necessarily with high plasma viral loads. Compared to saline controls, all treated animals showed significant decreases in performance on all three behavioral tasks during the morphine-only dependency period. During the post infection period, only the morphine plus SIV group showed a significant further decline and this only occurred for the MS task. Taken together, these data demonstrate a clear effect of morphine to produce behavioral deficits and also suggest that morphine can act synergistically with SIV/HIV to exacerbate behavioral deficits.

Effects of morphine on behavioral task performance in SIV-infected Rhesus macaques

PubMed Central

Marcario, Joanne K; Pendyala, Gurudutt; Riazi, Mariam; Fleming, Kandace; Marquis, Janet; Callen, Shannon; Lisco, Steven J; Fowler, Stephen C.; Cheney, Paul D; Buch, Shilpa J

2016-01-01

The abuse of opiates such as morphine in synergy with HIV infection not only exacerbates neuropathogenesis but significantly impacts behavioral attributes in HIV infected subjects. Thus, the goal of the current study was to characterize behavioral perturbations in rhesus macaques subjected to chronic morphine and SIV infection. Specifically, we assessed three behavioral tasks: motor skill (MS), forelimb force (FFT) and progressive ratio (PR) tasks. After collecting baseline control data (44 weeks) and data during the morphine-only dependency period (26 weeks), a subset of animals were productively infected with neurovirulent strains of SIVmac (R71/E17) for an additional 33 weeks. A general pattern in the results is that behavioral decline occurred with high CSF viral loads but not necessarily with high plasma viral loads. Compared to saline controls, all treated animals showed significant decreases in performance on all three behavioral tasks during the morphine-only dependency period. During the post infection period, only the morphine plus SIV group showed a significant further decline and this only occurred for the MS task. Taken together, these data demonstrate a clear effect of morphine to produce behavioral deficits and also suggest that morphine can act synergistically with SIV/HIV to exacerbate behavioral deficits. PMID:27039332

Morphine and galectin-1 modulate HIV-1 infection of human monocytes-derived macrophages

PubMed Central

Reynolds, Jessica L.; Law, Wing Cheung; Mahajan, Supriya D.; Aalinkeel, Ravikumar; Nair, Bindukumar; Sykes, Donald E.; Mammen, Manoj J.; Yong, Ken-Tye; Hui, Rui; Prasad, Paras N.; Schwartz, Stanley A.

2012-01-01

Morphine is a widely abused, addictive drug that modulates immune function. Macrophages are a primary reservoir of HIV-1; therefore, they not only play a role in the development of this disease but also impact the overall course of disease progression. Galectin-1 is a member of a family of β-galactoside-binding lectins that are soluble adhesion molecules and that mediate direct cell-pathogen interactions during HIV-1 viral adhesion. Since the drug abuse epidemic and the HIV-1 epidemic are closely interrelated we propose that increased expression of galectin-1 induced by morphine may modulate HIV-1 infection of human monocytes-derived macrophages (MDM). Here, we show that galectin-1 gene and protein expression are potentiated by incubation with morphine. Confirming previous studies, morphine alone or galectin-1 alone enhance HIV-1 infection of MDM. Concomitant incubation with exogenous galectin-1 and morphine potentiated HIV-1 infection of MDM. We utilized a nanotechnology approach that uses gold nanorod-galectin-1 siRNA complexes (nanoplexes) to inhibit gene expression for galectin-1. We found that nanoplexes silenced gene expression for galectin-1 and the nanoplexes reversed the effects of morphine on galectin-1 expression. Furthermore, the effects of morphine on HIV-1 infection were reduced in the presence of the nanoplex. PMID:22430735

The development of analgesic, pro- and anti-convulsant opiate effects in the rat.

PubMed

Van Praag, H; Falcon, M; Guendelman, D; Frenk, H

1993-01-01

Evidence indicates that the neonate is capable, if not perceiving nociception, then at least reacting to nociceptive stimuli. These responses can be inhibited by opiates such as morphine. The analgesic potency of morphine in rat pups increases with maturation, due to (a) the proliferation of opiate receptors and (b), the maturation of supraspinal descending inhibition which becomes functional at 3 weeks post-natally. Tolerance to repeated injections of morphine in pups is less pronounced than in adults since it is masked by several processes, it has been demonstrated to occur within the first two weeks of life. Toxic effects of morphine in the neonate, as can be demonstrated both in behavior and EEG, differ from those in adults. Thus, convulsions induced by morphine which have been reported to occur in adults, were absent in pups. Excitatory effects of morphine in behavior develop in 3 different stages. During the first week morphine caused behavioral activation which is not mediated by specific opiate receptors. In the second week morphine produces EEG spikes in a dose-dependent fashion, but at this age these spikes were not reversible by opiate antagonists. Opiate specific EEG spikes and other opiate specific excitatory effects start to predominate during the third week of life.

Neonatal morphine in extremely and very preterm neonates: its effect on the developing brain - a review.

PubMed

Schuurmans, Juliette; Benders, Manon; Lemmers, Petra; van Bel, Frank

2015-01-01

Preterm infants requiring intensive care experience a large number of stressful and painful procedures. Management of stress and pain is therefore an important issue. This review provides an overview of the research on the use of morphine and its neurodevelopmental effects on this vulnerable group of neonates. A structural literature search of both experimental and clinical data has been done using an electronic database (PubMed), but also relevant reference lists and related articles were used. A total of 39 sources were considered relevant for this review to elucidate the effects of morphine on the developing brain. The results showed that both animal experimental and clinical data displayed conflicting results on the effects of neonatal morphine on neurodevelopmental outcome. However, in contrast to specific short-term neurological outcomes long-term neurodevelopmental outcome does not seem to be adversely affected by morphine. After a careful review of the literature, no definite conclusions concerning the effects of neonatal morphine on the long-term neurodevelopmental outcome in extremely premature neonates can be drawn. More prospectively designed trials should be conducted using reliable and validated pain assessment scores to evaluate effects of morphine on long-term neurodevelopmental outcome to demonstrate a beneficial or adverse effect of morphine in preterm infants.

Development of a nanogold-based immunochromatographic assay for detection of morphine in urine using the Amor-HK16 monoclonal antibody.

PubMed

Dehghannezhad, Ardeshir; Paknejad, Maliheh; Rasaee, Mohammad Javad; Omidfar, Kobra; Seyyed Ebrahimi, Shadi Sadat; Ghahremani, Hossein

2012-12-01

A simple, rapid competitive immunochromatography (ICG) strip test was developed to detect morphine in urine samples using a monoclonal antibody produced in-house and conjugated to gold nanoparticles. Hybridoma cells were cultured and the Amor-HK16 monoclonal antibody against morphine was obtained from the supernatant after purification by salting out and passing through a Protein G-Agarose affinity column. Morphine was obtained from morphine sulfate and a C6-hemisuccinate derivative of morphine was prepared, conjugated to bovine serum albumin, and immobilized to a nitrocellulose membrane as the test line. Goat anti-mouse antibody was used as a binder in the control line in the detection zone of the strip. Colloidal gold particles of diameter approximately 20 nm were prepared and conjugated to the monoclonal antibody. The detection limit of the test strip was found to be 2000 ng/mL of morphine in urine samples. Reliability was determined by performing the ICG test on 103 urine samples and comparing the results with those obtained by thin-layer chromatography. The sensitivity of the test was 100%, and the analysis time for the assay was approximately 5 min. The new ICG method was adequately sensitive and accurate for the rapid screening of morphine in urine.

The Influence of Polyethylene Glycol Solution on the Dissolution Rate of Sustained Release Morphine.

PubMed

Hodgman, Michael; Holland, Michael G; Englich, Ulrich; Wojcik, Susan M; Grant, William D; Leitner, Erich

2016-12-01

Whole bowel irrigation (WBI) is a management option for overdose of medications poorly adsorbed to activated charcoal, with modified release properties, or for body packers. Polyethylene glycol (PEG) is a mixture of ethylene oxide polymers of varying molecular weight. PEG with an average molecular weight of 3350 g/mol is used for WBI. PEG electrolyte lavage solution has been shown in vitro to hasten the dissolution of acetaminophen. The impact of PEG on the pharmacokinetics of extended release pharmaceuticals is unknown. Lower average molecular weight PEG mixtures are used as solvents and excipients. We sought to investigate the impact of PEG on the release of morphine from several extended release morphine formulations. An in vitro gastric model was developed. To test the validity of our model, we first investigated the previously described interaction of ethanol and Avinza®. Once demonstrated, we then investigated the effect of PEG with several extended release morphine formulations. In the validation portion of our study, we confirmed an ethanol Avinza® interaction. Subsequently, we did not observe accelerated release of morphine from Avinza® or generic extended release morphine in the presence of PEG. The use of PEG for gastric decontamination following ingestion of these extended release morphine formulations is unlikely to accelerate morphine release and aggravate intoxication.

Morphine biosynthesis in opium poppy involves two cell types: sieve elements and laticifers.

PubMed

Onoyovwe, Akpevwe; Hagel, Jillian M; Chen, Xue; Khan, Morgan F; Schriemer, David C; Facchini, Peter J

2013-10-01

Immunofluorescence labeling and shotgun proteomics were used to establish the cell type-specific localization of morphine biosynthesis in opium poppy (Papaver somniferum). Polyclonal antibodies for each of six enzymes involved in converting (R)-reticuline to morphine detected corresponding antigens in sieve elements of the phloem, as described previously for all upstream enzymes transforming (S)-norcoclaurine to (S)-reticuline. Validated shotgun proteomics performed on whole-stem and latex total protein extracts generated 2031 and 830 distinct protein families, respectively. Proteins corresponding to nine morphine biosynthetic enzymes were represented in the whole stem, whereas only four of the final five pathway enzymes were detected in the latex. Salutaridine synthase was detected in the whole stem, but not in the latex subproteome. The final three enzymes converting thebaine to morphine were among the most abundant active latex proteins despite a limited occurrence in laticifers suggested by immunofluorescence labeling. Multiple charge isoforms of two key O-demethylases in the latex were revealed by two-dimensional immunoblot analysis. Salutaridine biosynthesis appears to occur only in sieve elements, whereas conversion of thebaine to morphine is predominant in adjacent laticifers, which contain morphine-rich latex. Complementary use of immunofluorescence labeling and shotgun proteomics has substantially resolved the cellular localization of morphine biosynthesis in opium poppy.

Effects of Obesity and Leptin Deficiency on Morphine Pharmacokinetics in a Mouse Model.

PubMed

Dalesio, Nicholas M; Hendrix, Craig W; McMichael, Douglas Hale; Thompson, Carol B; Lee, Carlton K K; Pho, Huy; Arias, Rafael S; Lynn, Rachael Rzasa; Galinkin, Jeffrey; Yaster, Myron; Brown, Robert H; Schwartz, Alan R

2016-12-01

Obesity causes multiorgan dysfunction, specifically metabolic abnormalities in the liver. Obese patients are opioid-sensitive and have high rates of respiratory complications after surgery. Obesity also has been shown to cause resistance to leptin, an adipose-derived hormone that is key in regulating hunger, metabolism, and respiratory stimulation. We hypothesized that obesity and leptin deficiency impair opioid pharmacokinetics (PK) independently of one another. Morphine PK were characterized in C57BL/6J wild-type (WT), diet-induced obese (DIO), and leptin-deficient (ob/ob) mice, and in ob/ob mice given leptin-replacement (LR) therapy. WT mice received several dosing regimens of morphine. Obese mice (30 g) received one 80 mg/kg bolus of morphine. Blood was collected at fixed times after morphine injection for quantification of plasma morphine and morphine 3-glucuronide (M3G) levels. PK parameters used to evaluate morphine metabolism included area-under the curve (AUC150), maximal morphine concentration (CMAX), and M3G-to-morphine ratio, and drug elimination was determined by clearance (Cl/F), volume of distribution, and half-life (T1/2). PK parameters were compared between mouse groups by the use of 1-way analysis of variance, with P values less than .05 considered significant. DIO compared with WT mice had significantly decreased morphine metabolism with lower M3G-to-morphine ratio (mean difference [MD]: -4.9; 95% confidence interval [CI]: -8.8 to -0.9) as well as a decreased Cl/F (MD: -4.0; 95% CI: -8.9 to -0.03) Ob/ob compared with WT mice had a large increase in morphine exposure with a greater AUC150 (MD: 980.4; 95% CI: 630.1-1330.6), CMAX (MD: 6.8; 95% CI: 2.7-10.9), and longer T1/2 (MD: 23.1; 95% CI: 10.5-35.6), as well as a decreased Cl/F (MD: -7.0; 95% CI: -11.6 to -2.7). Several PK parameters were significantly greater in ob/ob compared with DIO mice, including AUC150 (MD: 636.4; 95% CI: 207.4-1065.4), CMAX (MD: 5.3; 95% CI: 3.2-10.3), and T1/2 (MD: 18.3; 95% CI: 2.8-33.7). When leptin was replaced in ob/ob mice, PK parameters began to approach DIO and WT levels. LR compared with ob/ob mice had significant decreases in AUC150 (MD: -779.9; 95% CI: -1229.8 to -330), CMAX (MD: -6.1; 95% CI: -11.4 to -0.9), and T1/2 (MD: -19; 95% CI: -35.1 to -2.8). Metabolism increased with LR, with LR mice having a greater M3G-to-morphine ratio compared with DIO (MD: 5.3; 95% CI: 0.3-10.4). Systemic effects associated with obesity decrease morphine metabolism and excretion. A previous study from our laboratory demonstrated that obesity and leptin deficiency decrease the sensitivity of central respiratory control centers to carbon dioxide. Obesity and leptin deficiency substantially decreased morphine metabolism and clearance, and replacing leptin attenuated the PK changes associated with leptin deficiency, suggesting leptin has a direct role in morphine metabolism.

Effect of morphine-induced antinociception is altered by AF64A-induced lesions on cholinergic neurons in rat nucleus raphe magnus.

PubMed

Abe, Kenji; Ishida, Kota; Kato, Masatoshi; Shigenaga, Toshiro; Taguchi, Kyoji; Miyatake, Tadashi

2002-11-01

To examine the role of cholinergic neurons in the nucleus raphe magnus (NRM) in noxious heat stimulation and in the effects of morphine-induced antinociception by rats. After the cholinergic neuron selective toxin, AF64A, was microinjected into the NRM, we examined changes in the antinociceptive threshold and effects of morphine (5 mg/kg, ip) using the hot-plate (HP) and tail-flick (TF) tests. Systemic administration of morphine inhibited HP and TF responses in control rats. Microinjection of AF64A (2 nmol/site) into the NRM significantly decreased the threshold of HP response after 14 d, whereas the TF response was not affected. Morphine-induced antinociception was significantly attenuated in rats administered AF64A. Extracellular acetylcholine was attenuated after 14 d to below detectable levels in rats given AF64A. Naloxone (1 microg/site) microinjected into control rat NRM also antagonized the antinociceptive effect of systemic morphine. These findings suggest that cholinergic neuron activation in the NRM modulates the antinociceptive effect of morphine simultaneously with the opiate system.

Picrotoxin-induced seizures modified by morphine and opiate antagonists.

PubMed

Thomas, J; Nores, W L; Kenigs, V; Olson, G A; Olson, R D

1993-07-01

The effects of naloxone, Tyr-MIF-1, and MIF-1 on morphine-mediated changes in susceptibility to picrotoxin-induced seizures were studied. Rats were pretreated with naloxone, MIF-1, Tyr-MIF-1, or saline. At 15-min intervals, they received a second pretreatment of morphine or saline and then were tested for seizures following a convulsant dose of picrotoxin. Several parameters of specific categories of seizures were scored. Morphine increased the number of focal seizure episodes, duration of postseizure akinesis, and incidence of generalized clonic seizures. Naloxone tended to block the morphine-mediated changes in susceptibility. Tyr-MIF-1 had effects similar to naloxone on duration of postseizure immobility but tended to potentiate the effects of morphine on focal seizure episodes. The effects of morphine and the opiate antagonists on focal seizure episodes and postseizure duration suggest the general involvement of several types of opiate receptors in these picrotoxin-induced behaviors. However, the observation of antagonistic effects for Tyr-MIF-1 on immobility but agonistic effects for focal seizures suggests that the type of effect exerted by opiate agents may depend upon other neuronal variables.

Comparison of tizanidine and morphine with regard to tolerance-developing ability to antinociceptive action.

PubMed

Nabeshima, T; Yamada, S; Sugimoto, A; Matsuno, K; Kameyama, T

1986-10-01

The antinociceptive, tolerance-developing and anti-withdrawal activities of tizanidine [5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzo-thiadiazole] were investigated by comparing its effects with those of morphine and clonidine in tail-flick-, hot plate-, acetic acid-induced writhing-, and naloxone-precipitated withdrawal jumping-tests. The antinociceptive action of tizanidine was not altered by naloxone, while that of morphine was antagonized. Tolerance to the tizanidine-induced antinociceptive action and to motor incoordination was developed by successive administration of tizanidine. In the tizanidine-tolerant mice, the antinociceptive action of morphine was significantly decreased, but not sleeping time induced by pentobarbital. The action of tizanidine was not modified in the morphine-tolerant mice. Tizanidine failed to induce morphine-withdrawal jumping and to inhibit naloxone-precipitated withdrawal jumping in the morphine-dependent mice. Cross tolerance to the antinociceptive action induced by tizanidine and clonidine was developed. These results suggest that alpha 2-adrenoreceptors may be involved in the action mechanism of tizanidine, but not opioid receptors. Functional tolerance to tizanidine action may be developed by successive administration of tizanidine.

Excitatory and inhibitory effects of opiates in the rat vas deferens: a dual mechanism of opiate action.

PubMed

Jacquet, Y F

1980-10-03

Both natural (-)-morphine and its unnatural enantiomer (+)-morphine exert an excitatory action on electrically stimulated contractions of rat vas deferens. Preexposure to (-)-morphine results in cross-tolerance to the inhibitory action of beta-endorphin. (-)-Naloxone and its stereoisomer (+)-naloxone also exert an excitatory action, but only (-)-naloxone bocks the inhibtory action of beta-endorphin. Thus morphine exerts a dual action on a peripheral organ: one an inhibitory action mediated by the stereospecific endorphin receptor that is blocked stereospecifically by naloxone, the other an excitatory action mediated by a nonstereospecific receptor that is not blocked by naloxone. The opiate abstinence syndrome is seen as due to the unmasking of the excitatory action of opiates when its concomitant inhibitory influence is removed by selective blockade by naloxone or weakened by selective tolerance. The view that the rat vas deferens is devoid of morphine receptors is now seen as arising from a reverse example of morphine's dual action: the masking of the inhibitory action of morphine by its concomitant and more potent excitatory action.

Acute Morphine Administration Reduces Cell-Mediated Immunity and Induces Reactivation of Latent Herpes Simplex Virus Type 1 in BALB/c Mice

PubMed Central

Mojadadi, Shafi; Jamali, Abbas; Khansarinejad, Behzad; Soleimanjahi, Hoorieh; Bamdad, Taravat

2009-01-01

Acute morphine administration is known to alter the course of herpes simplex virus infection. In this study, the effect of acute morphine administration on the reactivation of latent herpes was investigated in a mouse model. Because of the important role of cytolytic T lymphocyte (CTL) activity in the inhibition of herpes simplex virus type 1 (HSV-1) reactivation, the effect of acute morphine administration on CTL responses was also evaluated. Furthermore, lymphocyte proliferation and IFN-γ production were evaluated for their roles in the induction of the CTL response. The findings showed that acute morphine administration significantly reduced CTL responses, lymphocyte proliferation, and IFN-γ production. Furthermore, acute morphine administration has been shown to reactivate latent HSV-1. Previous studies have shown that cellular immune responses have important roles in the inhibition of HSV reactivation. These findings suggest that suppression of a portion of the cellular immune response after acute morphine administration may constitute one part of the mechanism that induces HSV reactivation. PMID:19403060

Activity of adenylyl cyclase and protein kinase A contributes to morphine-induced spinal apoptosis.

PubMed

Lim, Grewo; Wang, Shuxing; Lim, Jeong-Ae; Mao, Jianren

2005-12-02

Our previous study has shown that chronic morphine exposure induces neuronal apoptosis within the spinal cord dorsal horn; however, the mechanisms of morphine-induced apoptosis remain unclear. Here we examined whether adenylyl cyclase (AC) and protein kinase A (PKA) would play a role in this process. Intrathecal morphine regimen (10 microg, twice daily x 7 days) that resulted in antinociceptive tolerance induced spinal apoptosis as revealed by in situ terminal deoxynucleotidyl transferase (TdT)-UTP-biotin nick end labeling (TUNEL). The TUNEL-positive cells were detected primarily in the superficial laminae of the spinal cord dorsal horn, which was associated with an increase in the expression of activated caspase-3 and mitogen-activated protein kinase (MAPK) within the same spinal region. Co-administration of morphine with a broad AC inhibitor (ddA), a PKA inhibitor (H89), or a MAPK inhibitor (PD98059) substantially reduced the number of TUNEL-positive cells, as compared with the morphine alone group. The results indicate that the spinal AC and PKA pathway through intracellular MAPK may be contributory to the cellular mechanisms of morphine-induced apoptosis.

Plasma-Mediated Release of Morphine from Synthesized Prodrugs

DTIC Science & Technology

2013-01-01

UPLC )9 (Waters Inc.) was utilized for measurements of morphine, PDA and PDB. UPLC has the capability to perform rapid (< 10 min) and reproducible...for UPLC versus ~30-50 µL for HPLC. The term “morphine” refers to the free morphine alkaloid base (Malinkrodt, etc.) unless otherwise stated...Baseline UPLC profiles were obtained for phosphate buffered saline (PBS), morphine and PDA in esterase de-activated plasma. Plasma was precipitated by the

Elucidation of markers for monitoring morphine and its analogs in urine adulterated with pyridinium chlorochromate.

PubMed

Luong, Susan; Kuzhiumparambil, Unnikrishnan; Fu, Shanlin

2015-09-17

Currently, procedures that identify the drugs 'destroyed' in adulterated urine specimens are very limited. This study aimed to determine the effect of pyridinium chlorochromate (PCC) on routine opiate assays and identify reaction products formed. Results/methodology: Opiate-positive urines adulterated with PCC (20 and 100 mM) were analyzed using CEDIA ® immunoassay and GC-MS. Urine and water samples spiked with 6-monoacetylmorphine, morphine and its glucuronides (10 µg/ml) and PCC (0.02-100 mM) were monitored with LC-MS, and the products characterized. PCC significantly decreased the abundance of morphine, codeine and IS. Adulterated water and urine samples containing 6-monoacetylmorphine, morphine and morphine-3-glucuronide yielded morphinone-3-glucuronide, 7,14-dihydroxy-6-monoacetylmorphine, 7,8-diketo-6-monoacetylmorphine and 7,8-diketo-morphine (tentative assignment). Reaction pathways may be different in the two matrices.

Immunomodulatory effect of morphine: therapeutic implications.

PubMed

Dinda, Amit; Gitman, Michael; Singhal, Pravin C

2005-07-01

The immunosuppressive as well as modulatory effects of morphine have been known in clinical medicine for > 100 years. Recent developments in molecular immunology, including experiments in mu (mu) opioid receptor knockout mice has led to a better understanding of central and peripheral mechanisms involved in this process. Though there is a large volume of literature documenting adverse effects of immunosupression following the use of morphine, several reports confirm its potential usefulness as an immunomodulator. In vitro and in vivo animal experiments have demonstrated wide-spectrum effects of morphine, including anti-inflammatory, antifibrotic, antitumour, cardioprotective and renoprotective. Immunomodulation is an important field in modern medicine with rapid advancement in recent years. Though a final statement regarding the clinical relevance of morphine-induced immunomodulation cannot be made at this juncture, nevertheless, it is worthwhile to review current developments. It may encourage further clinical studies to elucidate the influence of morphine treatment on immune regulation in different specialties of medicine.

Brain cholinergic involvement during the rapid development of tolerance to morphine

NASA Technical Reports Server (NTRS)

Wahba, Z. Z.; Oriaku, E. T.; Soliman, S. F. A.

1987-01-01

The effect of repeated administration of morphine on the activities of the cholinergic enzymes, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), in specific brain regions were studied in rats treated with 10 mg/kg morphine for one or two days. Repeated administration of morphine was associated with a decline in the degree of analgesia produced and with a significant increase of AChE activity of the medulla oblongata. A single injection of morphine resulted in a significant decline in ChAT activity in the hypothalamus, cerebellum, and medulla oblongata regions. After two consecutive injections, no decline in ChAT was observed in these regions, while in the cerebral cortex the second administration elicited a significant decline. The results suggest that the development of tolerance to morphine may be mediated through changes in ChAT activity and lend support to the involvement of the central cholinergic system in narcotic tolerance.

Inhibitory effects of ginseng total saponin on up-regulation of cAMP pathway induced by repeated administration of morphine.

PubMed

Seo, Jeong-Ju; Lee, Jae-Woong; Lee, Wan-Kyu; Hong, Jin-Tae; Lee, Chong-Kil; Lee, Myung-Koo; Oh, Ki-Wan

2008-02-01

We have reported that ginseng total saponin (GTS) inhibited the development of physical and psychological dependence on morphine. However, the possible molecular mechanisms of GTS are unclear. Therefore, this study was undertaken to understand the possible molecular mechanism of GTS on the inhibitory effects of morphine-induced dependence. It has been reported that the up-regulated cAMP pathway in the LC of the mouse brain after repeated administration of morphine contributes to the feature of withdrawals. GTS inhibited up-regulation of cAMP pathway in the LC after repeated administration of morphine in this experiment. GTS inhibited cAMP levels and protein expression of protein kinase A (PKA). In addition, GTS inhibited the increase of cAMP response element binding protein (CREB) phosphorylation. Therefore, we conclude that the inhibitory effects of GTS on morphine-induced dependence might be mediated by the inhibition of cAMP pathway.

Detection of Methamphetamine and Morphine in Urine and Saliva Using Excitation-Emission Matrix Fluorescence and a Second-Order Calibration Algorithm

NASA Astrophysics Data System (ADS)

Xu, B. Y.; Ye, Y.; Liao, L. C.

2016-07-01

A new method was developed to determine the methamphetamine and morphine concentrations in urine and saliva based on excitation-emission matrix fluorescence coupled to a second-order calibration algorithm. In the case of single-drug abuse, the results showed that the average recoveries of methamphetamine and morphine were 95.3 and 96.7% in urine samples, respectively, and 98.1 and 106.2% in saliva samples, respectively. The relative errors were all below 5%. The simultaneous determination of methamphetamine and morphine in urine using two second-order algorithms was also investigated. Satisfactory results were obtained with a self-weighted alternating trilinear decomposition algorithm. The root-mean-square errors of the predictions were 0.540 and 0.0382 μg/mL for methamphetamine and morphine, respectively. The limits of detection of the proposed methods were very low and sufficient for studying methamphetamine and morphine in urine.

Morphine-Induced Preconditioning: Involvement of Protein Kinase A and Mitochondrial Permeability Transition Pore

PubMed Central

Dorsch, Marianne; Behmenburg, Friederike; Raible, Miriam; Blase, Dominic; Grievink, Hilbert; Hollmann, Markus W.; Heinen, André; Huhn, Ragnar

2016-01-01

Background Morphine induces myocardial preconditioning (M-PC) via activation of mitochondrial large conductance Ca2+-sensitive potassium (mKCa) channels. An upstream regulator of mKCa channels is protein kinase A (PKA). Furthermore, mKCa channel activation regulates mitochondrial bioenergetics and thereby prevents opening of the mitochondrial permeability transition pore (mPTP). Here, we investigated in the rat heart in vivo whether 1) M-PC is mediated by activation of PKA, and 2) pharmacological opening of the mPTP abolishes the cardioprotective effect of M-PC and 3) M-PC is critically dependent on STAT3 activation, which is located upstream of mPTP within the signalling pathway. Methods Male Wistar rats were randomised to six groups (each n = 6). All animals underwent 25 minutes of regional myocardial ischemia and 120 minutes of reperfusion. Control animals (Con) were not further treated. Morphine preconditioning was initiated by intravenous administration of 0.3 mg/kg morphine (M-PC). The PKA blocker H-89 (10 μg/kg) was investigated with and without morphine (H-89+M-PC, H-89). We determined the effect of mPTP opening with atractyloside (5 mg/kg) with and without morphine (Atr+M-PC, Atr). Furthermore, the effect of morphine on PKA activity was tested in isolated adult rat cardiomyocytes. In further experiments in isolated hearts we tested the protective properties of morphine in the presence of STAT3 inhibition, and whether pharmacological prevention of the mPTP-opening by cyclosporine A (CsA) is cardioprotective in the presence of STAT3 inhibition. Results Morphine reduced infarct size from 64±5% to 39±9% (P<0.05 vs. Con). H-89 completely blocked preconditioning by morphine (64±9%; P<0.05 vs. M-PC), but H-89 itself had not effect on infarct size (61±10%; P>0.05 vs. Con). Also, atractyloside abolished infarct size reduction of morphine completely (65±9%; P<0.05 vs. M-PC) but had no influence on infarct size itself (64±5%; P>0.05 vs. Con). In isolated hearts STAT3 inhibitor Stattic completely abolished morphine-induced preconditioning. Administration of Stattic and mPTP inhibitor cyclosporine A reduced infarct size to 31±6% (Stat+CsA, P<0.05 vs. Con). Cyclosporine A alone reduced infarct size to 26±7% (CsA P<0.05 vs. Con). In cardiomyocytes, PKA activity was increased by morphine. Conclusion Our data suggest that morphine-induced cardioprotection is mediated by STAT3-activation and inhibition of mPTP, with STA3 located upstream of mPTP. There is some evidence that protein kinase A is involved within the signalling pathway. PMID:26968004

The effect of propofol on intrathecal morphine-induced pruritus and its mechanism.

PubMed

Liu, Xiulan; Zhang, Jing; Zhao, Hongyan; Mei, Hongxia; Lian, Qingquan; Shangguan, Wangning

2014-02-01

Previous studies have shown that a low dose of propofol IV bolus had a beneficial effect on intrathecal morphine-induced pruritus in humans. However, its exact mechanism has not been fully understood. In this study, we hypothesized that propofol relieved intrathecal morphine-induced pruritus in rats by upregulating the expression of cannabinoid-1 (CB[1]) receptors in anterior cingulate cortex (ACC). Twenty-four Sprague-Dawley rats were divided into a control group and 20, 40, 80 μg/kg morphine groups to create an intrathecal morphine-induced scratching model. The effects of propofol on intrathecal 40 μg/kg morphine-induced scratching responses were then evaluated. Sixty rats were randomly assigned to control, normal saline, intralipid, and propofol groups, with pruritus behavior observation or killed 8 minutes after venous injection of normal saline, intralipid, or propofol, and brain tissues were then collected for assay. Immunohistochemistry was then performed to identify the expression of CB (1) receptor in ACC, and the concentration of CB(1) receptor in ACC was determined by Western blot analysis. Compared with the control group, rats in the 20, 40, 80 μg/kg morphine groups had higher mean scratching response rates after intrathecal morphine injection (P =0.020, 0.005, and 0.002, respectively). There was a statistical difference between 20 and 40 μg/kg morphine groups at 10 to 15 and 15 to 20 timepoints after intrathecal morphine injection (P = 0.049 and 0.017, respectively). Propofol almost abolished the scratching response that was induced by 40 μg/kg intrathecal morphine injection (F[2, 15] = 46.87, P < 0.001; F[22, 165] = 2.37, P = 0.001). Compared with the intralipid and normal saline groups, the scratching behavior was significantly attenuated in the propofol group (P < 0.001). Compared with control, normal saline, and intralipid groups, the protein expression of CB(1) receptor in ACC (Western blot) in the propofol group increased (0.86 ± 0.21, 0.94 ± 0.18, 0.86 ± 0.13, and 1.34 ± 0.32, respectively, P < 0.001). There was no significant difference among control, normal saline, and intralipid groups. Compared with the control, normal saline, and intralipid groups, the average number of neurons of CB(1) receptor in the ACC area were higher in the propofol group (21.0 ± 1.4, 19.3 ± 1.8, 24.8 ± 7.7, and 37.2 ± 3.3, respectively, P < 0.001). Morphine elicits dose-independent scratching responses after intrathecal injection in rats. Morphine 40 μg/kg intrathecal injection-induced scratching responses can be prevented by propofol. Increased protein expression of CB(1) receptors in ACC may contribute to the reversal of intrathecal morphine-induced scratching.

Low-dose morphine elicits ventilatory excitant and depressant responses in conscious rats: Role of peripheral μ-opioid receptors.

PubMed

Henderson, Fraser; May, Walter J; Gruber, Ryan B; Young, Alex P; Palmer, Lisa A; Gaston, Benjamin; Lewis, Stephen J

2013-08-01

The systemic administration of morphine affects ventilation via a mixture of central and peripheral actions. The aims of this study were to characterize the ventilatory responses elicited by a low dose of morphine in conscious rats; to determine whether tolerance develops to these responses; and to determine the potential roles of peripheral μ-opioid receptors (μ-ORs) in these responses. Ventilatory parameters were monitored via unrestrained whole-body plethysmography. Conscious male Sprague-Dawley rats received an intravenous injection of vehicle or the peripherally-restricted μ-OR antagonist, naloxone methiodide (NLXmi), and then three successive injections of morphine (1 mg/kg) given 30 min apart. The first injection of morphine in vehicle-treated rats elicited an array of ventilatory excitant (i.e., increases in frequency of breathing, minute volume, respiratory drive, peak inspiratory and expiratory flows, accompanied by decreases in inspiratory time and end inspiratory pause) and inhibitory (i.e., a decrease in tidal volume and an increase in expiratory time) responses. Subsequent injections of morphine elicited progressively and substantially smaller responses. The pattern of ventilatory responses elicited by the first injection of morphine was substantially affected by pretreatment with NLXmi whereas NLXmi minimally affected the development of tolerance to these responses. Low-dose morphine elicits an array of ventilatory excitant and depressant effects in conscious rats that are subject to the development of tolerance. Many of these initial actions of morphine appear to involve activation of peripheral μ-ORs whereas the development of tolerance to these responses does not.

The feasibility of physiologically based pharmacokinetic modeling in forensic medicine illustrated by the example of morphine.

PubMed

Schaefer, Nadine; Moj, Daniel; Lehr, Thorsten; Schmidt, Peter H; Ramsthaler, Frank

2018-03-01

In forensic medicine, expert opinion is often required concerning dose and time of intake of a substance, especially in the context of fatal intoxications. In the present case, a 98-year-old man died 4 days after admission to a hospital due to a femur neck fracture following a domestic fall in his retirement home. As he had obtained high morphine doses in the context of palliative therapy and a confusion of his supplemental magnesium tablets with a diuretic by the care retirement home was suspected by the relatives, a comprehensive postmortem examination was performed. Forensic toxicological GC- and LC-MS analyses revealed, besides propofol, ketamine, and a metamizole metabolite in blood and urine, toxic blood morphine concentrations of approximately 3 mg/l in femoral and 5 mg/l in heart blood as well as 2, 7, and 10 mg/kg morphine in brain, liver, and lung, respectively. A physiologically based pharmacokinetic (PBPK) model was developed and applied to examine whether the morphine concentrations were (i) in agreement with the morphine doses documented in the clinical records or (ii) due to an excessive morphine administration. PBPK model simulations argue against an overdosing of morphine. The immediate cause of death was respiratory and cardiovascular failure due to pneumonia following a fall, femur neck fracture, and immobilization accompanied by a high and probably toxic concentration of morphine, attributable to the administration under palliative care conditions. The presented case indicates that PBPK modeling can be a useful tool in forensic medicine, especially in question of a possible drug overdosing.

Modest increase in risk of acute coronary syndrome associated with morphine use in cancer patients: a population-based nested case-control study.

PubMed

Lee, Cynthia Wei-Sheng; Muo, Chih-Hsin; Liang, Ji-An; Sung, Fung-Chang; Kao, Chia-Hung

2014-06-01

Morphine is widely used for pain management in cancer patients. Use of heroin, a morphine derivative, is a risk factor for acute coronary syndrome (ACS). This study investigates the risk of ACS associated with morphine use by comparing the incidence of ACS in cancer patients treated with and without morphine. This is a population-based nested case-control study using the Longitudinal Health Insurance Database 2000 in Taiwan. In total, 31,384 patients on the database were diagnosed with cancer without prior history of ACS during 1998-2010. In this cohort, 499 patients subsequently developed ACS and 30,885 patients did not. The 499 patients were designated as the ACS group; controls were selected from the remaining 30,885 patients and matched 3:1 to each case for age, sex, year of cancer diagnosis, and index year. Logistic regression was used to estimate the odds ratios and 95% confidence intervals, and the multivariable model was applied to control for age, sex, and Charlson comorbidity score. Cancer patients who received morphine had a 32% higher risk of developing ACS than non-morphine users. This increase in risk was significant when evaluating the overall cancer patients, but non-significant when evaluating any specific cancer type. The risk of ACS increased significantly with increasing morphine dosage (to ≥65 mg/y). Morphine treatment is associated with a modest increase in risk of ACS in patients with malignancy, but this association displays low significance in specific cancer types. Copyright © 2014 Elsevier Ltd. All rights reserved.

Simultaneous determination of morphine, codeine and 6-acetyl morphine in human urine and blood samples using direct aqueous derivatisation: validation and application to real cases.

PubMed

Chericoni, S; Stefanelli, F; Iannella, V; Giusiani, M

2014-02-15

Opiates play a relevant role in forensic toxicology and their assay in urine or blood is usually performed for example in workplace drug-testing or toxicological investigation of drug impaired driving. The present work describes two new methods for detecting morphine, codeine and 6-monoacethyl morphine in human urine or blood using a single step derivatisation in aqueous phase. Propyl chloroformate is used as the dramatizing agent followed by liquid-liquid extraction and gas-chromatography-mass spectroscopy to detect the derivatives. The methods have been validated both for hydrolysed and unhydrolysed urine. For hydrolysed urine, the LOD and LOQ were 2.5ng/ml and 8.5ng/ml for codeine, and 5.2ng/ml and 15.1ng/ml for morphine, respectively. For unhydrolysed urine, the LOD and LOQ were 3.0ng/ml and 10.1ng/ml for codeine, 2.7ng/ml and 8.1ng/ml for morphine, 0.8ng/ml and 1.5ng/ml for 6-monoacetyl morphine, respectively. In blood, the LOD and LOQ were 0.44ng/ml and 1.46ng/ml for codeine, 0.29ng/ml and 0.98ng/ml for morphine, 0.15ng/ml and 0.51ng/ml for 6-monoacetyl morphine, respectively. The validated methods have been applied to 50 urine samples and 40 blood samples (both positive and negative) and they can be used in routine analyses. Copyright © 2013 Elsevier B.V. All rights reserved.

Differential development of antinociceptive tolerance to morphine and fentanyl is not linked to efficacy in the ventrolateral periaqueductal gray of the rat

PubMed Central

Bobeck, Erin N.; Haseman, Rachel A.; Hong, Dana; Ingram, Susan L.; Morgan, Michael M.

2012-01-01

Systemic administration of morphine typically produces greater tolerance than higher efficacy mu-opioid receptor (MOPr) agonists, such as fentanyl. The objective of the present study was to test this relationship by measuring antinociceptive efficacy and tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray (vlPAG). MOPr agonist efficacy was evaluated by microinjecting the irreversible opioid receptor antagonist β-funaltrexamine hydrochloride (β-FNA) into the vlPAG prior to a dose-response analysis of morphine and fentanyl antinociception. In contrast to systemic administration of morphine and fentanyl, microinjection of these drugs into the vlPAG had similar efficacy as measured by similar reductions in maximal antinociception following β-FNA administration. Analysis of tolerance revealed a rightward shift in the dose-response curve to a single pretreatment with morphine, but not fentanyl. Moreover, the magnitude of tolerance to morphine was comparable following one, four, or eight pretreatments. Tolerance to fentanyl also was evident following four or eight microinjections. These data are surprising in that antinociceptive efficacy appears to vary depending on the site of administration. Moreover, the similar efficacy following microinjection of morphine and fentanyl into the vlPAG was associated with comparable tolerance, with the one exception of no tolerance to acute administration of fentanyl. Perspective These data reveal that antinociceptive tolerance following vlPAG administration of opioids develops rapidly, is evident with both morphine and fentanyl, and the magnitude is relatively consistent regardless of the number of pretreatments. PMID:22766006

Opioid modulation of reflex versus operant responses following stress in the rat.

PubMed

King, C D; Devine, D P; Vierck, C J; Mauderli, A; Yezierski, R P

2007-06-15

In pre-clinical models intended to evaluate nociceptive processing, acute stress suppresses reflex responses to thermal stimulation, an effect previously described as stress-induced "analgesia." Suggestions that endogenous opioids mediate this effect are based on demonstrations that stress-induced hyporeflexia is enhanced by high dose morphine (>5 mg/kg) and is reversed by naloxone. However, reflexes and pain sensations can be modulated differentially. Therefore, in the present study direct comparisons were made of opioid agonist and antagonist actions, independently and in combination with acute restraint stress in Long Evans rats, on reflex lick-guard (L/G) and operant escape responses to nociceptive thermal stimulation (44.5 degrees C). A high dose of morphine (>8 mg/kg) was required to reduce reflex responding, but a moderate dose of morphine (1 mg/kg) significantly reduced escape responding. The same moderate dose (and also 5 mg/kg) of morphine significantly enhanced reflex responding. Naloxone (3 mg/kg) significantly enhanced escape responding but did not affect L/G responding. Restraint stress significantly suppressed L/G reflexes (hyporeflexia) but enhanced escape responses (hyperalgesia). Stress-induced hyperalgesia was significantly reduced by morphine and enhanced by naloxone. In contrast, stress-induced hyporeflexia was blocked by both naloxone and 1 mg/kg of morphine. Thus, stress-induced hyperalgesia was opposed by endogenous opioid release and by administration of morphine. Stress-induced hyporeflexia was dependent upon endogenous opioid release but was counteracted by a moderate dose of morphine. These data demonstrate a differential modulation of reflex and operant outcome measures by stress and by separate or combined opioid antagonism or administration of morphine.

Olive (Olea europaea L.) leaf extract elicits antinociceptive activity, potentiates morphine analgesia and suppresses morphine hyperalgesia in rats.

PubMed

Esmaeili-Mahani, Saeed; Rezaeezadeh-Roukerd, Maryam; Esmaeilpour, Khadije; Abbasnejad, Mehdi; Rasoulian, Bahram; Sheibani, Vahid; Kaeidi, Ayat; Hajializadeh, Zahra

2010-10-28

Olive (Olea europaea) leaves are used as anti-rheumatic, anti-inflammatory, antinociceptive, antipyretic, vasodilatory, hypotensive, antidiuretic and hypoglycemic agents in traditional medicine. Recently, it has been shown that olive leaf extract (OLE) has calcium channel blocker property; however, its influences on nociceptive threshold and morphine effects have not yet been clarified. All experiments were carried out on male Wistar rats. The tail-flick, hot-plate and formalin tests were used to assess the effect of OLE on nociceptive threshold. To determine the effect of OLE on analgesic and hyperalgesic effects of morphine, OLE (6, 12 and 25 mg/kg i.p.) that had no significant nociceptive effect, was injected concomitant with morphine (5 mg/kg and 1 μg/kg i.p., respectively). The tail-flick test was used to assess the effect of OLE on anti- and pro-nociceptive effects of morphine. The data showed that OLE (50-200 mg/kg i.p.) could produce dose-dependent analgesic effect on tail-flick and hot-plate tests. Administration of 200 mg/kg OLE (i.p.) caused significant decrease in pain responses in the first and the second phases of formalin test. In addition, OLE could potentiate the antinociceptive effect of 5 mg/kg morphine and block low-dose morphine-induced hyperalgesia. Our results indicate that olive leaf extract has analgesic property in several models of pain and useful influence on morphine analgesia in rats. Therefore, it can be used for the treatment and/or management of painful conditions. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Role of nitric oxide in additive anticonvulsant effects of agmatine and morphine.

PubMed

Payandemehr, Borna; Rahimian, Reza; Bahremand, Arash; Ebrahimi, Ali; Saadat, Seyedehpariya; Moghaddas, Peiman; Fadakar, Kaveh; Derakhshanian, Hoda; Dehpour, Ahmad Reza

2013-06-13

The anticonvulsant effects of agmatine, an endogenous polyamine and a metabolite of l-arginine, have been shown in various experimental seizure models. Agmatine also potentiates the anti-seizure activity of morphine. The present study aimed to investigate a possible involvement of nitric oxide (NO) pathway in the protection by agmatine and morphine co-administration against pentylenetetrazole (PTZ) -induced seizure in male mice. To this end, the thresholds for the clonic seizures induced by the intravenous administration of PTZ, a GABA antagonist, were assessed. Intraperitoneal administration of morphine at lower dose (1mg/kg) increased the seizure threshold. Also intraperitoneal administration of agmatine (5 and 10mg/kg) increased the seizure threshold significantly. Combination of subeffective doses of morphine and agmatine led to potent anticonvulsant effects. Non-effective doses of morphine (0.1 and 0.5mg/kg) were able to induce anticonvulsant effects in mice pretreated with agmatine (3mg/kg). Concomitant administration of either the non-selective nitric oxide synthase (NOS) inhibitor L-NAME (1, 5mg/kg, i.p.) or the selective NOS inhibitor 7-NI (15, 30mg/kg, i.p.), with an ineffective combination of morphine (0.1mg/kg) plus agmatine (1mg/kg) produced significant anticonvulsant impacts. Moreover, the NO precursor, l-arginine (30, 60mg/kg, i.p.), inhibited the anticonvulsant action of agmatine (3mg/kg) plus morphine (0.5mg/kg) co-administration. Our results indicate that pretreatment of animals with agmatine enhances the anticonvulsant effects of morphine via a mechanism which may involve the NO pathway. Copyright © 2013 Elsevier Inc. All rights reserved.

The Impact of Morphine After a Spinal Cord Injury

PubMed Central

Hook, Michelle A.; Liu, Grace T.; Washburn, Stephanie N.; Ferguson, Adam R.; Bopp, Anne C.; Huie, John R.; Grau, James W.

2007-01-01

Nociceptive stimulation, at an intensity that elicits pain-related behavior, attenuates recovery of locomotor and bladder functions, and increases tissue loss after a contusion injury. These data imply that nociceptive input (e.g., from tissue damage) can enhance the loss of function after injury, and that potential clinical treatments, such pretreatment with an analgesic, may protect the damaged system from further secondary injury. The current study examined this hypothesis and showed that a potential treatment (morphine) did not have a protective effect. In fact, morphine appeared to exacerbate the effects of nociceptive stimulation. Experiment 1 showed that after spinal cord injury 20 mg/kg of systemic morphine was necessary to induce strong antinociception and block behavioral reactivity to shock treatment, a dose that was much higher than that needed for sham controls. In Experiment 2, contused rats were given one of three doses of morphine (Vehicle, 10, 20 mg/kg) prior to exposure to uncontrollable electrical stimulation or restraint alone. Despite decreasing nociceptive reactivity, morphine did not attenuate the long-term consequences of shock. Rats treated with morphine and shock had higher mortality rates, and displayed allodynic responses to innocuous sensory stimuli three weeks later. Independent of shock, morphine per se undermined recovery of sensory function. Rats treated with morphine alone also had significantly larger lesions than those treated with saline. These results suggest that nociceptive stimulation affects recovery despite a blockade of pain-elicited behavior. The results are clinically important because they suggest that opiate treatment may adversely affect the recovery of function after injury. PMID:17383022

Neurobiological Effects of Morphine after Spinal Cord Injury

PubMed Central

Woller, Sarah A.; Bancroft, Eric; Aceves, Miriam; Funk, Mary Katherine; Hartman, John; Garraway, Sandra M.

2017-01-01

Abstract Opioids and non-steroidal anti-inflammatory drugs are used commonly to manage pain in the early phase of spinal cord injury (SCI). Despite its analgesic efficacy, however, our studies suggest that intrathecal morphine undermines locomotor recovery and increases lesion size in a rodent model of SCI. Similarly, intravenous (IV) morphine attenuates locomotor recovery. The current study explores whether IV morphine also increases lesion size after a spinal contusion (T12) injury and quantifies the cell types that are affected by early opioid administration. Using an experimenter-administered escalating dose of IV morphine across the first seven days post-injury, we quantified the expression of neuron, astrocyte, and microglial markers at the injury site. SCI decreased NeuN expression relative to shams. In subjects with SCI treated with IV morphine, virtually no NeuN+ cells remained across the rostral-caudal extent of the lesion. Further, whereas SCI per se increased the expression of astrocyte and microglial markers (glial fibrillary acidic protein and OX-42, respectively), morphine treatment decreased the expression of these markers. These cellular changes were accompanied by attenuation of locomotor recovery (Basso, Beattie, Bresnahan scores), decreased weight gain, and the development of opioid-induced hyperalgesia (increased tactile reactivity) in morphine-treated subjects. These data suggest that morphine use is contraindicated in the acute phase of a spinal injury. Faced with a lifetime of intractable pain, however, simply removing any effective analgesic for the management of SCI pain is not an ideal option. Instead, these data underscore the critical need for further understanding of the molecular pathways engaged by conventional medications within the pathophysiological context of an injury. PMID:27762659

Analgesic activity of ZC88, a novel N-type voltage-dependent calcium channel blocker, and its modulation of morphine analgesia, tolerance and dependence.

PubMed

Meng, Ge; Wu, Ning; Zhang, Cheng; Su, Rui-Bin; Lu, Xin-Qiang; Liu, Yin; Yun, Liu-Hong; Zheng, Jian-Quan; Li, Jin

2008-05-31

ZC88 is a novel non-peptide N-type voltage-sensitive calcium channel blocker synthesized by our institute. In the present study, the oral analgesic activity of ZC88 in animal models of acute and neuropathic pain, and functional interactions between ZC88 and morphine in terms of analgesia, tolerance and dependence were investigated. In mice acetic acid writhing tests, ZC88 (10-80 mg/kg) administered by oral route showed significant antinociceptive effects in a dose-dependent manner. The ED50 values of ZC88 were 14.5 and 14.3 mg/kg in male and female mice, respectively. In sciatic nerve chronic constriction injury rats, mechanical allodynia was ameliorated by oral administration of ZC88 at doses of 14, 28 and 56 mg/kg, suggesting ZC88 relieved allodynic response of neuropathic pain. When concurrently administered with morphine, ZC88 (20-80 mg/kg) dose-dependently potentiated morphine analgesia and attenuated morphine analgesic tolerance in hot-plate tests. ZC88 also prevented chronic exposure to morphine-induced physical dependence and withdrawal, but not morphine-induced psychological dependence in conditioned place preference model. These results suggested that ZC88, a new non-peptide N-type calcium channel blocker, had notable oral analgesia and anti-allodynia for acute and neuropathic pain. ZC88 might be used in pain relief by either application alone or in combination with opioids because it enhanced morphine analgesia while prevented morphine-induced tolerance and physical dependence.

Changes in adaptability following perinatal morphine exposure in juvenile and adult rats.

PubMed

Klausz, Barbara; Pintér, Ottó; Sobor, Melinda; Gyarmati, Zsuzsa; Fürst, Zsuzsanna; Tímár, Júlia; Zelena, Dóra

2011-03-05

The problem of drug abuse among pregnant women causes a major concern. The aim of the present study was to examine the adaptive consequences of long term maternal morphine exposure in offspring at different postnatal ages, and to see the possibility of compensation, as well. Pregnant rats were treated daily with morphine from the day of mating (on the first two days 5mg/kgs.c. than 10mg/kg) until weaning. Male offspring of dams treated with physiological saline served as control. Behavior in the elevated plus maze (EPM; anxiety) and forced swimming test (FST; depression) as well as adrenocorticotropin and corticosterone hormone levels were measured at postpartum days 23-25 and at adult age. There was only a tendency of spending less time in the open arms of the EPM in morphine treated rats at both ages, thus, the supposed anxiogenic impact of perinatal exposure with morphine needs more focused examination. In response to 5min FST morphine exposed animals spent considerable longer time with floating and shorter time with climbing at both ages which is an expressing sign of depression-like behavior. Perinatal morphine exposure induced a hypoactivity of the stress axis (adrenocorticotropin and corticosterone elevations) to strong stimulus (FST). Our results show that perinatal morphine exposure induces long term depression-like changes. At the same time the reactivity to the stress is failed. These findings on rodents presume that the progenies of morphine users could have lifelong problems in adaptive capability and might be prone to develop psychiatric disorders. Copyright © 2010 Elsevier B.V. All rights reserved.

Polymorphism of μ-Opioid Receptor Gene (OPRM1:c.118A>G) Might Not Protect against or Enhance Morphine-Induced Nausea or Vomiting

PubMed Central

Chen, Li-Kuei; Chen, Shiou-Sheng; Huang, Chi-Hsiang; Yang, Hong-Jyh; Lin, Chen-Jung; Chien, Kuo-Liong; Fan, Shou-Zen

2013-01-01

A cohort, double blind, and randomized study was conducted to investigate the effect of a single nucleotide polymorphism of the μ-opioid receptor at nucleotide position 118 (OPRM1:c.118A>G) on the association with the most common side effects (nausea or vomiting) induced by intravenous patient control analgesia (IVPCA) with morphine, including incidence and severity analysis. A total of 129 Taiwanese women undergoing gynecology surgery received IVPCA with pure morphine for postoperative pain relief. Blood samples were collected and sequenced with high resolution melting analysis to detect three different genotypes of OPRM1 (AA, AG, and GG). All candidates 24 h postoperatively will be interviewed to record the clinical phenotype with subjective complaints and objective observations. The genotyping after laboratory analysis showed that 56 women (43.4%) were AA, 57 (44.2%) were AG, and 16 (12.4%) were GG. The distribution of genotype did not violate Hardy-Weinberg equilibrium test. There was no significant difference neither between the severity and incidence of IVPCA morphine-induced side effects and genotype nor between the association between morphine consumption versus genotype. However, there was significant difference of the relation between morphine consumption and the severity and incidence of IVPCA morphine-induced nausea and vomiting. The genetic analysis for the severity and incidence of IVPCA morphine-induced nausea or vomiting showed no association between phenotype and genotype. It might imply that OPRM1:c.118A>G does not protect against IVPCA morphine-induced nausea or vomiting. PMID:23431434

Opioid needs of patients with advanced cancer and the morphine dose-limiting law in Egypt.

PubMed

Alsirafy, Samy A; El-Mesidi, Salah M; El-Sherief, Wesam A; Galal, Khaled M; Abou-Elela, Enas N; Aklan, Nahla A

2011-01-01

Morphine is the drug of choice for moderate to severe cancer pain management. The Egyptian Narcotics Control Law limits the amount of morphine prescribed in a single prescription to a maximum of 420 mg for tablets and 60 mg for ampoules. The usual practice in Egypt is to provide that limited amount of morphine on a weekly basis. The aim of this study is to estimate the extent to which Egyptian patients may be undertreated because of this law. We reviewed the medical records of advanced cancer patients referred to the first palliative care unit in Egypt over a seven-month period. Cancer pain was managed following the WHO guidelines. After modifying the internal institutional policy, patients received adequate amounts of the available opioids without any violations of the law. From 117 eligible advanced cancer patients, 58 (50%) patients required strong opioids, 32 (27%) required weak opioids, and 27 (23%) required no regular opioids. The mean last prescribed opioid dose for those who required strong opioids was 194 mg of oral morphine equivalent/24 h (± 180). For this group of patients, a single weekly prescription would supply enough oral morphine for only 26% of them. In the case of parenteral morphine, none of these patients would receive an adequate supply. In view of the current morphine dose-limiting law and practices in Egypt, the majority of patients suffering severe cancer pain would not have access to adequate morphine doses. That dose-limiting law and other restrictive regulations represent an obstacle to cancer pain control in Egypt and should be revised urgently.

Involvement of substance P and central opioid receptors in morphine modulation of the CHS response.

PubMed

Nelson, C J; Lysle, D T

2001-04-02

Morphine administration prior to challenge with the antigen 2,4-dinitro-fluorobenzene increases the contact hypersensitivity (CHS) response in rats. The present study extended these findings by showing that central, but not systemic, administration of N-methylnaltrexone antagonized the morphine-induced enhancement of the CHS response. The importance of the neuroimmune mediator substance P was shown via the attenuation of the morphine-induced enhancement following both systemic and topical administration of the NK-1 antagonist WIN51,708. Taken together, the findings of the present study provide new data showing that central opioid receptors and peripheral substance P are involved in the morphine-induced enhancement of the CHS response.

Role of medial prefrontal cortex Narp in the extinction of morphine conditioned place preference.

PubMed

Blouin, Ashley M; Han, Sungho; Pearce, Anne M; Cheng, Kailun; Lee, Jongah J; Johnson, Alexander W; Wang, Chuansong; During, Matthew J; Holland, Peter C; Shaham, Yavin; Baraban, Jay M; Reti, Irving M

2013-01-15

Narp knockout (KO) mice demonstrate an impaired extinction of morphine conditioned place preference (CPP). Because the medial prefrontal cortex (mPFC) has been implicated in extinction learning, we tested whether Narp cells in this region play a role in the extinction of morphine CPP. We found that intracranial injections of adenoassociated virus (AAV) expressing wild-type (WT) Narp into the mPFC of Narp KO mice rescued the extinction and the injection of AAV expressing a dominant negative form of Narp (NarpN) into the mPFC of WT mice impaired the extinction of morphine CPP. These findings suggest that Narp in the mPFC mediates the extinction of morphine CPP.

Effects of morphine on circadian rhythms of motor activity and body temperature in pig-tailed macaques.

PubMed

Weed, Michael R; Hienz, Robert D

2006-07-01

Previous studies of the effects of opiates on motor activity and body temperature in nonhuman primates have been limited in scope and typically only conducted with restrained animals. The present study used radio-telemetry devices to continuously measure activity and temperature in unrestrained pig-tailed macaques for 24 h following morphine administration. Two dose-response functions (0.56 to 5.6 mg/kg, i.m.) were determined, one with morphine administered at 9 a.m. and one with morphine administrated at 3 p.m. Under both the 9 a.m. or 3 p.m. administration schedules, body temperature and activity were increased acutely. Activity was also reduced the following morning after morphine administered at either time. In other regards, morphine's effects on both temperature and activity differed between 9 a.m. and 3 p.m. injection, including periods of decreased activity immediately after the acute increases after 9 a.m. but not 3 p.m. administration. Surprisingly, motor activity also increased 9-12 h post-injection following morphine administered at 9 a.m., but not at 3 p.m. These results clearly show an interaction between timing of morphine administration and effects on temperature and activity. These results also underscore the fact that single injections of drugs may have multiple and delayed effects on circadian rhythms in macaques.

Effect of morphine and methadone acute treatment on immunological activity in mice: pharmacokinetic and pharmacodynamic correlates.

PubMed

Pacifici, R; Patrini, G; Venier, I; Parolaro, D; Zuccaro, P; Gori, E

1994-06-01

This report describes the 24-hr time course of the immunomodulatory effects of an acute s.c. injection of morphine in C57BL6 mice, and correlates these effects with the drug's analgesic properties and serum levels. Acute morphine treatment had a biphasic effect on various immune parameters: there was an increase in in vitro phagocytosis and the killing of Candida Albican cells by peritoneal polymorphonuclear leukocytes 20 and 40 min after the injection of morphine, 20 mg/kg, when analgesia and serum morphine concentrations were at their peak. Interestingly, 24 hr after morphine administration (when antinociception and morphine blood levels were no longer detectable) these parameters underwent a marked reduction. Similarly, macrophage-mediated inhibition of tumor cells proliferation was first stimulated (at 20 and 40 min) and then depressed (at 24 hr). Splenic natural killer cell cytotoxicity, determined by standard 51Cr release from YAC-1 target cells, also was evaluated. No differences in natural killer activity was observed at any of the monitored time points. In addition, we evaluated the immunomodulatory effects of an acute injection of methadone (a synthetic narcotic compound) at a dose inducing the same degree of analgesia as morphine. None of the tested immunoparameters were affected by the administration of methadone, which indicates the different drug-sensitivity of immunological correlates in vivo.

Lubiprostone Reverses the Inhibitory Action of Morphine on Mucosal Secretion in Human Small Intestine

PubMed Central

Sun, Xiaohong; Wang, Xiyu; Wang, Guo-Du; Xia, Yun; Liu, Sumei; Qu, Meihua; Needleman, Bradley J.; Mikami, Dean J.; Melvin, W. Scott; Bohn, Laura M.; Ueno, Ryuji; Wood, Jackie D.

2016-01-01

Background and Aims Treatments with morphine or opioid agonists cause constipation. Lubiprostone is approved for treatment of adult idiopathic constipation and constipation-predominant IBS in adult women. We tested whether lubiprostone can reverse morphine-suppression of mucosal secretion in human intestine and explored the mechanism of action. Methods Fresh segments of jejunum discarded during Roux-En-Y gastric bypass surgeries were used. Changes in short-circuit current (ΔIsc) were recorded in Ussing flux chambers as a marker for electrogenic chloride secretion during pharmacological interactions between morphine, prostaglandin receptor antagonists, chloride channel blockers and lubiprostone. Results Morphine suppressed basal Isc. Lubiprostone reversed morphine suppression of basal Isc. Lubiprostone, applied to the mucosa in concentrations ranging from 3 nM to 30 μM, evoked increases in Isc in concentration-dependent manner when applied to the mucosal side of muscle-stripped preparations. Blockade of enteric nerves did not change stimulation of Isc by lubiprostone. Removal of chloride or application of bumetanide or NPPB suppressed or abolished responses to lubiprostone. Antagonists acting at CFTR channels and prostaglandin EP4 receptors, but not at E1, EP1-3 receptors, partially suppressed stimulation of Isc by lubiprostone. Conclusions Antisecretory action of morphine results from suppression of excitability of secretomotor neurons in the enteric nervous system. Lubiprostone, which does not affect enteric neurons directly, bypasses the action of morphine by directly opening mucosal chloride channels. PMID:21181441

Lubiprostone reverses the inhibitory action of morphine on mucosal secretion in human small intestine.

PubMed

Sun, Xiaohong; Wang, Xiyu; Wang, Guo-Du; Xia, Yun; Liu, Sumei; Qu, Meihua; Needleman, Bradley J; Mikami, Dean J; Melvin, W Scott; Bohn, Laura M; Ueno, Ryuji; Wood, Jackie D

2011-02-01

Treatments with morphine or opioid agonists cause constipation. Lubiprostone is approved for treatment of adult idiopathic constipation and constipation-predominant IBS in adult women. We tested whether lubiprostone can reverse morphine-suppression of mucosal secretion in human intestine and explored the mechanism of action. Fresh segments of jejunum discarded during Roux-En-Y gastric bypass surgeries were used. Changes in short-circuit current (ΔIsc) were recorded in Ussing flux chambers as a marker for electrogenic chloride secretion during pharmacological interactions between morphine, prostaglandin receptor antagonists, chloride channel blockers and lubiprostone. Morphine suppressed basal Isc. Lubiprostone reversed morphine suppression of basal Isc. Lubiprostone, applied to the mucosa in concentrations ranging from 3 nM to 30 μM, evoked increases in Isc in concentration-dependent manner when applied to the mucosal side of muscle-stripped preparations. Blockade of enteric nerves did not change stimulation of Isc by lubiprostone. Removal of chloride or application of bumetanide or NPPB suppressed or abolished responses to lubiprostone. Antagonists acting at CFTR channels and prostaglandin EP(4) receptors, but not at E(1), EP(1-3) receptors, partially suppressed stimulation of Isc by lubiprostone. Antisecretory action of morphine results from suppression of excitability of secretomotor neurons in the enteric nervous system. Lubiprostone, which does not affect enteric neurons directly, bypasses the action of morphine by directly opening mucosal chloride channels.

Dopamine D4 Receptor Counteracts Morphine-Induced Changes in μ Opioid Receptor Signaling in the Striosomes of the Rat Caudate Putamen

PubMed Central

Suárez-Boomgaard, Diana; Gago, Belén; Valderrama-Carvajal, Alejandra; Roales-Buján, Ruth; Van Craenenbroeck, Kathleen; Duchou, Jolien; Borroto-Escuela, Dasiel O.; Medina-Luque, José; de la Calle, Adelaida; Fuxe, Kjell; Rivera, Alicia

2014-01-01

The mu opioid receptor (MOR) is critical in mediating morphine analgesia. However, prolonged exposure to morphine induces adaptive changes in this receptor leading to the development of tolerance and addiction. In the present work we have studied whether the continuous administration of morphine induces changes in MOR protein levels, its pharmacological profile, and MOR-mediated G-protein activation in the striosomal compartment of the rat CPu, by using immunohistochemistry and receptor and DAMGO-stimulated [35S]GTPγS autoradiography. MOR immunoreactivity, agonist binding density and its coupling to G proteins are up-regulated in the striosomes by continuous morphine treatment in the absence of changes in enkephalin and dynorphin mRNA levels. In addition, co-treatment of morphine with the dopamine D4 receptor (D4R) agonist PD168,077 fully counteracts these adaptive changes in MOR, in spite of the fact that continuous PD168,077 treatment increases the [3H]DAMGO Bmax values to the same degree as seen after continuous morphine treatment. Thus, in spite of the fact that both receptors can be coupled to Gi/0 protein, the present results give support for the existence of antagonistic functional D4R-MOR receptor-receptor interactions in the adaptive changes occurring in MOR of striosomes on continuous administration of morphine. PMID:24451133

OPRM1 c.118A>G Polymorphism and Duration of Morphine Treatment Associated with Morphine Doses and Quality-of-Life in Palliative Cancer Pain Settings

PubMed Central

Hajj, Aline; Halepian, Lucine; Osta, Nada El; Chahine, Georges; Kattan, Joseph; Rabbaa Khabbaz, Lydia

2017-01-01

Despite increased attention on assessment and management, pain remains the most persistent symptom in patients with cancer, in particular in end-of-life settings, with detrimental impact on their quality-of-life (QOL). We conducted this study to evaluate the added value of determining some genetic and non-genetic factors to optimize cancer pain treatment. Eighty-nine patients were included in the study for the evaluation of palliative cancer pain management. The regression analysis showed that age, OPRM1 single nucleotide polymorphism (SNP), as well as the duration of morphine treatment were significantly associated with morphine doses at 24 h (given by infusion pump; p = 0.043, 0.029, and <0.001, respectively). The mean doses of morphine decreased with age but increased with the duration of morphine treatment. In addition, patients with AG genotype c.118A>G OPRM1 needed a higher dose of morphine than AA patients. Moreover, metastases, OPRM1 SNP, age, and gender were significantly associated with the QOL in our population. In particular, AA patients for OPRM1 SNP had significantly lower cognitive function than AG patients, a result not previously reported in the literature. These findings could help increase the effectiveness of morphine treatment and enhance the QOL of patients in regards to personalized medicine. PMID:28346387

Endogenous Cholinergic Neurotransmission Contributes to Behavioral Sensitization to Morphine

PubMed Central

Bajic, Dusica; Soiza-Reilly, Mariano; Spalding, Allegra L.; Berde, Charles B.; Commons, Kathryn G.

2015-01-01

Neuroplasticity in the mesolimbic dopaminergic system is critical for behavioral adaptations associated with opioid reward and addiction. These processes may be influenced by cholinergic transmission arising from the laterodorsal tegmental nucleus (LDTg), a main source of acetylcholine to mesolimbic dopaminergic neurons. To examine this possibility we asked if chronic systemic morphine administration affects expression of genes in ventral and ventrolateral periaqueductal gray at the level of the LDTg using rtPCR. Specifically, we examined gene expression changes in the area of interest using Neurotransmitters and Receptors PCR array between chronic morphine and saline control groups. Analysis suggested that chronic morphine administration led to changes in expression of genes associated, in part, with cholinergic neurotransmission. Furthermore, using a quantitative immunofluorescent technique, we found that chronic morphine treatment produced a significant increase in immunolabeling of the cholinergic marker (vesicular acetylcholine transporter) in neurons of the LDTg. Finally, systemic administration of the nonselective and noncompetitive neuronal nicotinic antagonist mecamylamine (0.5 or 2 mg/kg) dose-dependently blocked the expression, and to a lesser extent the development, of locomotor sensitization. The same treatment had no effect on acute morphine antinociception, antinociceptive tolerance or dependence to chronic morphine. Taken together, the results suggest that endogenous nicotinic cholinergic neurotransmission selectively contributes to behavioral sensitization to morphine and this process may, in part, involve cholinergic neurons within the LDTg. PMID:25647082

Comparison of Electroacupuncture and Morphine-Mediated Analgesic Patterns in a Plantar Incision-Induced Pain Model

PubMed Central

Tsai, Shih-Ying; Chen, Kuen-Bao; Hsu, Sheng-Feng; Chen, Julia Yi-Ru

2014-01-01

Electroacupuncture (EA) is a complementary therapy to improve morphine analgesia for postoperative pain, but underlying mechanism is not well-known. Herein, we investigated EA-induced analgesic effect in a plantar incision (PI) model in male Sprague-Dawley rats. PI was performed at the left hind paw. EA of 4 Hz and high intensity or sham needling was conducted at right ST36 prior to PI and repeated for another 2 days. Behavioral responses to mechanical and thermal stimuli, spinal phospho-ERK, and Fos expression were all analyzed. In additional groups, naloxone and morphine were administered to elucidate involvement of opioid receptors and for comparison with EA. EA pretreatment significantly reduced post-PI tactile allodynia for over 1 day; repeated treatments maintained analgesic effect. Intraperitoneal naloxone could reverse EA analgesia. Low-dose subcutaneous morphine (1 mg/kg) had stronger inhibitory effect on PI-induced allodynia than EA for 1 h. However, analgesic tolerance appeared after repeated morphine injections. Both EA and morphine could equally inhibit PI-induced p-ERK and Fos inductions. We conclude that though EA and morphine attenuate postincision pain through opioid receptor activations, daily EA treatments result in analgesic accumulation whereas daily morphine injections develop analgesic tolerance. Discrepant pathways and mechanisms underlying two analgesic means may account for the results. PMID:25530786

Morphine drives internal ribosome entry site-mediated hnRNP K translation in neurons through opioid receptor-dependent signaling

PubMed Central

Lee, Pin-Tse; Chao, Po-Kuan; Ou, Li-Chin; Chuang, Jian-Ying; Lin, Yen-Chang; Chen, Shu-Chun; Chang, Hsiao-Fu; Law, Ping-Yee; Loh, Horace H.; Chao, Yu-Sheng; Su, Tsung-Ping; Yeh, Shiu-Hwa

2014-01-01

Heterogeneous nuclear ribonucleoprotein K (hnRNP K) binds to the promoter region of mu-opioid receptor (MOR) to regulate its transcriptional activity. How hnRNP K contributes to the analgesic effects of morphine, however, is largely unknown. We provide evidence that morphine increases hnRNP K protein expression via MOR activation in rat primary cortical neurons and HEK-293 cells expressing MORs, without increasing mRNA levels. Using the bicistronic reporter assay, we examined whether morphine-mediated accumulation of hnRNP K resulted from translational control. We identified potential internal ribosome entry site elements located in the 5′ untranslated regions of hnRNP K transcripts that were regulated by morphine. This finding suggests that internal translation contributes to the morphine-induced accumulation of hnRNP K protein in regions of the central nervous system correlated with nociceptive and antinociceptive modulatory systems in mice. Finally, we found that down-regulation of hnRNP K mediated by siRNA attenuated morphine-induced hyperpolarization of membrane potential in AtT20 cells. Silencing hnRNP K expression in the spinal cord increased nociceptive sensitivity in wild-type mice, but not in MOR-knockout mice. Thus, our findings identify the role of translational control of hnRNP K in morphine-induced analgesia through activation of MOR. PMID:25361975

Venlafaxine prevents morphine antinociceptive tolerance: The role of neuroinflammation and the l-arginine-nitric oxide pathway.

PubMed

Mansouri, Mohammad Taghi; Naghizadeh, Bahareh; Ghorbanzadeh, Behnam; Alboghobeish, Soheila; Amirgholami, Neda; Houshmand, Gholamreza; Cauli, Omar

2018-05-01

Opioid-induced neuroinflammation and the nitric oxide (NO) signal-transduction pathway are involved in the development of opioid analgesic tolerance. The antidepressant venlafaxine (VLF) modulates NO in nervous tissues, and so we investigated its effect on induced tolerance to morphine, neuroinflammation, and oxidative stress in mice. Tolerance to the analgesic effects of morphine were induced by injecting mice with morphine (50 mg/kg) once a day for three consecutive days; the effect of co-administration of VLF (5 or 40 mg/kg) with morphine was similarly tested in a separate group. To determine if the NO precursor l-arginine hydrochloride (l-arg) or NO are involved in the effects rendered by VLF, animals were pre-treated with l-arg (200 mg/kg), or the NO synthesis inhibitors N(ω)-nitro-l-arginine methyl ester (L-NAME; 30 mg/kg) or aminoguanidine hydrochloride (AG; 100 mg/kg), along with VLF (40 mg/kg) for three days before receiving morphine for another three days. Nociception was assessed with a hot-plate test on the fourth day, and the concentration of tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), interleukin-6 (IL-6), interleukin-10, brain-derived neurotrophic factor, NO, and oxidative stress factors such as total thiol, malondialdehyde content, and glutathione peroxidase (GPx) activity in the brain was also determined. Co-administration of VLF with morphine attenuated morphine-induced analgesic tolerance and prevented the upregulation of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), NO, and malondialdehyde in brains of mice with induced morphine tolerance; chronic VLF administration inhibited this decrease in brain-derived neurotrophic factor, total thiol, and GPx levels. Moreover, repeated administration of l-arg before receipt of VLF antagonized the effects induced by VLF, while L-NAME and AG potentiated these effects. VLF attenuates morphine-induced analgesic tolerance, at least partly because of its anti-inflammatory and antioxidative properties. VLF also appears to suppress the development of morphine-induced analgesic tolerance through an l-arg-NO-mediated mechanism. Copyright © 2018 Elsevier Inc. All rights reserved.

The toxicology of heroin-related death: estimating survival times.

PubMed

Darke, Shane; Duflou, Johan

2016-09-01

The feasibility of intervention in heroin overdose is of clinical importance. The presence of 6-monoacetyl morphine (6MAM) in the blood is suggestive of survival times of less than 20-30 minutes following heroin administration. The study aimed to determine the proportions of cases in which 6MAM was present, and compare concentrations of secondary metabolites and circumstances of death by 6MAM status. Analysis of cases of heroin-related death presenting to the Department of Forensic Medicine Sydney, 1 January 2013-12 December 2014. Sydney, Australia. A total of 145 cases. The mean age was 40.5 years and 81% were male. Concentrations of 6MAM, free morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Circumstances of death included bronchopneumonia, apparent sudden collapse, location and other central nervous system (CNS) depressants. 6MAM was detected in 43% [confidence interval (CI) = 35-51%] of cases. The median free morphine concentration of 6MAM-positive cases was more than twice that of cases without 6MAM (0.26 versus 0.12 mg/l). 6MAM-positive cases also had lower concentrations of the other major heroin metabolites: M3G (0.05 versus 0.29 mg/l), M6G (0.02 versus 0.05 mg/l) with correspondingly lower M3G/morphine (0.54 versus 2.71) and M6G/morphine (0.05 versus 0.50) ratios. Significant independent correlates of 6MAM were a higher free morphine concentration [odds ratio (OR) = 1.7], a lower M6G/free morphine ratio (OR = 0.5) and signs of apparent collapse (OR = 6.7). In heroin-related deaths in Sydney, Australia during 2013 and 2014, 6- monoacetyl morphine was present in the blood in less than half of cases, suggesting that a minority of cases had survival times after overdose of less than 20-30 minutes. The toxicology of heroin metabolites and the circumstances of death were consistent with 6- monoacetyl morphine as a proxy for a more rapid death. © 2016 Society for the Study of Addiction.

Flurbiprofen improves dysfunction of T-lymphocyte subsets and natural killer cells in cancer patients receiving post-operative morphine analgesia.

PubMed

Shen, Jin-Chun; Sun, He-Liang; Zhang, Ming-Qiang; Liu, Xiao-Yu; Wang, Zhong- Yun; Yang, Jian-Jun

2014-08-01

Acute pain can lead to immune dysfunction, which can be partly ameliorated by successful pain management. Opioids, which are widely used for analgesia, can result in the deterioration of immune function. This study aimed to investigate the influence of morphine with or without flurbiprofen as post-operative analgesics on the immune systems of patients undergoing gastric cancer surgery. 60 patients undergoing gastric cancer surgery were equally randomized into two groups. They received post-operative patient-controlled intravenous (IV) analgesia using morphine either with or without flurbiprofen. Visual analogue scale (VAS) scores, Bruggemann comfort scale (BCS) scores, morphine consumption, time of first flatus, incidence of nausea/vomiting, and T-lymphocyte subsets (CD3⁺, CD4⁺, and CD8⁺) and natural killer cells (CD3⁻CD16⁺CD56⁺) were evaluated. No significant difference was observed in the VAS scores, BCS scores, and nausea/vomiting incidence between groups. Less morphine was consumed and the time of first flatus was earlier in patients receiving morphine with flurbiprofen than morphine alone. The expression of CD3⁺, CD4⁺, CD4⁺/CD8⁺, and CD3⁻CD16⁺CD56⁺ decreased at 2 hours after incision and, except for CD3⁻CD16⁺CD56⁺, returned to baseline at 120 hours after surgery. Moreover, the expression of CD3⁻CD16⁺CD56⁺ at 2 hours after incision and the expression of CD3⁺, CD4⁺, CD4⁺/CD8⁺, and CD3⁻CD16⁺CD56⁺ at 24 hours after surgery were higher in patients receiving morphine with flurbiprofen than morphine alone. The combination of morphine and flurbiprofen ameliorates the immune depression in Tlymphocyte subsets and natural killer cells and provides a similar analgesic efficacy to morphine alone in patients undergoing gastric cancer surgery.

Evaluation of Analgesia, Tolerance, and the Mechanism of Action of Morphine-6-O-Sulfate Across Multiple Pain Modalities in Sprague-Dawley Rats.

PubMed

Yadlapalli, Jai Shankar K; Dogra, Navdeep; Walbaum, Anqi W; Wessinger, William D; Prather, Paul L; Crooks, Peter A; Dobretsov, Maxim

2017-09-01

Morphine-6-O-sulfate (M6S) is a mixed μ/δ-opioid receptor (OR) agonist and potential alternative to morphine for treatment of chronic multimodal pain. To provide more support for this hypothesis, the antinociceptive effects of M6S and morphine were compared in tests that access a range of pain modalities, including hot plate threshold (HPT), pinprick sensitivity threshold (PST) and paw pressure threshold tests. Acutely, M6S was 2- to 3-fold more potent than morphine in HPT and PST tests, specifically, derived from best-fit analysis of dose-response relationships of morphine/M6S half-effective dose (ED50) ratios (lower, upper 95% confidence interval [CI]) were 2.8 (2.0-5.8) in HPT and 2.2 (2.1, 2.4) in PST tests. No differences in analgesic drug potencies were detected in the PPT test (morphine/M6S ED50 ratio 1.2 (95% CI, 0.8-1.4). After 7 to 9 days of chronic treatment, tolerance developed to the antinociceptive effects of morphine, but not to M6S, in all 3 pain tests. Morphine-tolerant rats were not crosstolerant to M6S. The antinociceptive effects of M6S were not sensitive to κ-OR antagonists. However, the δ-OR antagonist, naltrindole, blocked M6S-induced antinociception by 55% ± 4% (95% CI, 39-75) in the HPT test, 94% ± 4% (95% CI, 84-105) in the PST test, and 5% ± 17% (95% CI, -47 to 59) or 51% ± 14% (95% CI, 14-84; 6 rats per each group) in the paw pressure threshold test when examined acutely or after 7 days of chronic treatment, respectively. Activity via δ-ORs thus appears to be an important determinant of M6S action. M6S also exhibited favorable antinociceptive and tolerance profiles compared with morphine in 3 different antinociceptive assays, indicating that M6S may serve as a useful alternative for rotation in morphine-tolerant subjects.

Effect and Safety of Morphine Use in Acute Anterior ST-Segment Elevation Myocardial Infarction.

PubMed

Bonin, Mickael; Mewton, Nathan; Roubille, Francois; Morel, Olivier; Cayla, Guillaume; Angoulvant, Denis; Elbaz, Meyer; Claeys, Marc J; Garcia-Dorado, David; Giraud, Céline; Rioufol, Gilles; Jossan, Claire; Ovize, Michel; Guerin, Patrice

2018-02-10

Morphine is commonly used to treat chest pain during myocardial infarction, but its effect on cardiovascular outcome has never been directly evaluated. The aim of this study was to examine the effect and safety of morphine in patients with acute anterior ST-segment elevation myocardial infarction followed up for 1 year. We used the database of the CIRCUS (Does Cyclosporine Improve Outcome in ST Elevation Myocardial Infarction Patients) trial, which included 969 patients with anterior ST-segment elevation myocardial infarction, admitted for primary percutaneous coronary intervention. Two groups were defined according to use of morphine preceding coronary angiography. The composite primary outcome was the combined incidence of major adverse cardiovascular events, including cardiovascular death, heart failure, cardiogenic shock, myocardial infarction, unstable angina, and stroke during 1 year. A total of 554 (57.1%) patients received morphine at first medical contact. Both groups, with and without morphine treatment, were comparable with respect to demographic and periprocedural characteristics. There was no significant difference in major adverse cardiovascular events between patients who received morphine compared with those who did not (26.2% versus 22.0%, respectively; P =0.15). The all-cause mortality was 5.3% in the morphine group versus 5.8% in the no-morphine group ( P =0.89). There was no difference between groups in infarct size as assessed by the creatine kinase peak after primary percutaneous coronary intervention (4023±118 versus 3903±149 IU/L; P =0.52). In anterior ST-segment elevation myocardial infarction patients treated by primary percutaneous coronary intervention, morphine was used in half of patients during initial management and was not associated with a significant increase in major adverse cardiovascular events at 1 year. © 2018 The Authors and Hospices Civils de Lyon. Published on behalf of the American Heart Association, Inc., by Wiley.

A Single-Dose Intra-Articular Morphine plus Bupivacaine versus Morphine Alone following Knee Arthroscopy: A Systematic Review and Meta-Analysis

PubMed Central

Wang, Yi-lun; Li, Yu-sheng; Wei, Jie; Li, Hui; Yang, Tuo; Yang, Tu-bao; Lei, Guang-hua

2015-01-01

Objectives The purpose of this study was to compare the efficacy and safety of a single-dose intra-articular morphine plus bupivacaine versus morphine alone in patients undergoing arthroscopic knee surgery. Methods Randomized controlled trials comparing a combination of morphine and bupivacaine with morphine alone injected intra-articularly in the management of pain after knee arthrocopic surgery were retrieved (up to August 10, 2014) from MEDLINE, the Cochrane Library and Embase databases. The weighted mean difference (WMD), relative risk (RR) and their corresponding 95% confidence intervals (CIs) were calculated using RevMan statistical software. Results Thirteen randomized controlled trials were included. Statistically significant differences were observed with regard to the VAS values during the immediate period (0-2h) (WMD -1.16; 95% CI -2.01 to -0.31; p = 0.007) and the time to first request for rescue analgesia (WMD = 2.05; 95% CI 0.19 to 3.92; p = 0.03). However, there was no significant difference in the VAS pain score during the early period (2-6h) (WMD -0.36; 95% CI -1.13 to 0.41; p = 0.35), the late period (6-48h) (WMD 0.11; 95% CI -0.40 to 0.63; p = 0.67), and the number of patients requiring supplementary analgesia (RR = 0.78; 95% CI 0.57 to 1.05; p = 0.10). In addition, systematic review showed that intra-articular morphine plus bupivacaine would not increase the incidence of adverse effects compared with morphine alone. Conclusion The present study suggested that the administration of single-dose intra-articular morphine plus bupivacaine provided better pain relief during the immediate period (0-2h), and lengthened the time interval before the first request for analgesic rescue without increasing the short-term side effects when compared with morphine alone. Level of Evidence Level I, meta-analysis of Level I studies. PMID:26474401

Activation of serotonin 5-HT2C receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in morphine-dependent mice

PubMed Central

Zhang, Gongliang; Wu, Xian; Zhang, Yong-Mei; Liu, Huan; Jiang, Qin; Pang, Gang; Tao, Xinrong; Dong, Liuyi; Stackman, Robert W.

2015-01-01

Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and social problem with devastating consequences. Repeated exposure to the opioid, for example morphine, can induce profound, long-lasting behavioral sensitization and physical dependence, which are thought to reflect neuroplasticity in neural circuitry. Central serotonin (5-HT) neurotransmission participates in the development of dependence on and the expression of withdrawal from morphine. Serotonin 5-HT2C receptor (5-HT2CR) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT2CR agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT2CR activation on the behavioral sensitization and naloxone-precipitated withdrawal symptoms were examined in mice underwent repeated exposure to morphine. Male mice received morphine (10 mg/kg, s.c.) to develop behavioral sensitization. Lorcaserin, a 5-HT2CR agonist, prevented the induction and expression, but not the development, of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. Pretreatment of lorcaserin, or the positive control clonidine (an alpha 2-adrenoceptor agonist), ameliorated the naloxone-precipitated withdrawal symptoms. SB 242084, a selective 5-HT2CR antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT2CR protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT2CR can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5-HT2CR may represent a new avenue for the treatment of opioid addiction. PMID:26432939

Cost effectiveness analysis of intravenous ketorolac and morphine for treating pain after limb injury: double blind randomised controlled trial

PubMed Central

Rainer, Timothy H; Jacobs, Philip; Ng, Y C; Cheung, N K; Tam, Michael; Lam, Peggo K W; Wong, Robert; Cocks, Robert A

2000-01-01

Objectives To investigate the cost effectiveness of intravenous ketorolac compared with intravenous morphine in relieving pain after blunt limb injury in an accident and emergency department. Design Double blind, randomised, controlled study and cost consequences analysis. Setting Emergency department of a university hospital in the New Territories of Hong Kong. Participants 148 adult patients with painful isolated limb injuries (limb injuries without other injuries). Main outcome measures Primary outcome measure was a cost consequences analysis comparing the use of ketorolac with morphine; secondary outcome measures were pain relief at rest and with limb movement, adverse events, patients' satisfaction, and time spent in the emergency department. Results No difference was found in the median time taken to achieve pain relief at rest between the group receiving ketorolac and the group receiving morphine, but with movement the median reduction in pain score in the ketorolac group was 1.09 per hour (95% confidence interval 1.05 to 2.02) compared with 0.87 (0.84 to 1.06) in the morphine group (P=0.003). The odds of experiencing adverse events was 144.2 (41.5 to 501.6) times more likely with morphine than with ketorolac. The median time from the initial delivery of analgesia to the participant leaving the department was 20 (4.0 to 39.0) minutes shorter in the ketorolac group than in the morphine group (P=0.02). The mean cost per person was $HK44 (£4; $5.6) in the ketorolac group and $HK229 in the morphine group (P<0.0001). The median score for patients' satisfaction was 6.0 for ketorolac and 5.0 for morphine (P<0.0001). Conclusion Intravenous ketorolac is a more cost effective analgesic than intravenous morphine in the management of isolated limb injury in an emergency department in Hong Kong, and its use may be considered as the dominant strategy. PMID:11082083

Intravenous and Intratracheal Thyrotropin Releasing Hormone and Its Analog Taltirelin Reverse Opioid-Induced Respiratory Depression in Isoflurane Anesthetized Rats.

PubMed

Boghosian, James D; Luethy, Anita; Cotten, Joseph F

2018-07-01

Thyrotropin releasing hormone (TRH) is a tripeptide hormone and a neurotransmitter widely expressed in the central nervous system that regulates thyroid function and maintains physiologic homeostasis. Following injection in rodents, TRH has multiple effects including increased blood pressure and breathing. We tested the hypothesis that TRH and its long-acting analog, taltirelin, will reverse morphine-induced respiratory depression in anesthetized rats following intravenous or intratracheal (IT) administration. TRH (1 mg/kg plus 5 mg/kg/h, i.v.) and talitrelin (1 mg/kg, i.v.), when administered to rats pretreated with morphine (5 mg/kg, i.v.), increased ventilation from 50% ± 6% to 131% ± 7% and 45% ± 6% to 168% ± 13%, respectively (percent baseline; n = 4 ± S.E.M.), primarily through increased breathing rates (from 76% ± 9% to 260% ± 14% and 66% ± 8% to 318% ± 37%, respectively). By arterial blood gas analysis, morphine caused a hypoxemic respiratory acidosis with decreased oxygen and increased carbon dioxide pressures. TRH decreased morphine effects on arterial carbon dioxide pressure, but failed to impact oxygenation; taltirelin reversed morphine effects on both arterial carbon dioxide and oxygen. Both TRH and talirelin increased mean arterial blood pressure in morphine-treated rats (from 68% ± 5% to 126% ± 12% and 64% ± 7% to 116% ± 8%, respectively; n = 3 to 4). TRH, when initiated prior to morphine (15 mg/kg, i.v.), prevented morphine-induced changes in ventilation; and TRH (2 mg/kg, i.v.) rescued all four rats treated with a lethal dose of morphine (5 mg/kg/min, until apnea). Similar to intravenous administration, both TRH (5 mg/kg, IT) and taltirelin (2 mg/kg, IT) reversed morphine effects on ventilation. TRH or taltirelin may have clinical utility as an intravenous or inhaled agent to antagonize opioid-induced cardiorespiratory depression. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Mrz 2/579, a fast kinetic NMDA channel blocker, reduces the development of morphine tolerance in awake rats.

PubMed

Houghton, A K; Parsons, C G; Headley, P M

2001-04-01

The purpose of the present study was to investigate whether uncompetitive NMDA antagonists with fast channel blocking kinetics, which show fewer side effects in man than compounds such as ketamine, affect the development of tolerance to continuous exposure to morphine. Rats were trained on the Randall--Selitto apparatus before being implanted, under halothane anaesthesia, with primed mini-osmotic pumps (240 microl/day). Six rats were implanted with a vehicle filled pump, seven with a morphine filled pump (28.8 mg/kg/day), and eight with a pair of pumps, one containing morphine and the other Mrz 2/579, a new NMDA antagonist (40 mg/kg/day). A fourth group was implanted with a morphine filled pump followed 25 h later by a Mrz 2/579 filled pump. Paw withdrawal tests were undertaken immediately before, and at 2, 4, 6, 8, 10, 12, 24, 48 and 72 h after the first pump was implanted. Before pump implantation, withdrawal thresholds were 120+/-7 g (mean+/-SEM, n=30). Vehicle infusion had no effect on withdrawal thresholds, whereas morphine infusion increased them significantly at 2 and 4 h after pump implantation (+2 h: 208+/-14 g; P<0.001 vs. control). From 6 h the antinociception elicited by morphine declined progressively; at 10 h withdrawal thresholds were significantly lower than the 2 h post-treatment value (P<0.001). In rats treated with morphine plus Mrz 2/579, thresholds remained significantly higher between 10--72 h post-implantation than with morphine alone (P<0.05). In contrast, infusion of the same level of Mrz 2/579 once tolerance had developed did not reverse tolerance. These results indicate that fast NMDA channel blockers such as Mrz 2/579 may prove to be useful in enhancing analgesia to continuous morphine administration.

Induction of cross-tolerance between protective effect of morphine and nicotine in 6-hydroxydopamine-induce neurotoxicity in SH-SY5Y human dopaminergic neuroblastoma cells.

PubMed

Elyasi, Leila; Eftekhar-Vaghefi, Seyed Hassan; Asadi-Shekaaria, Majid; Esmaeili-Mahani, Saeed

2018-06-27

Parkinson's disease is a progressive neurodegenerative disease characterized by progressive and selective death of dopaminergic neurons. It has been reported that nicotine and morphine have protective roles during neuronal damage in Parkinson's disease. In addition, the induction of cross-tolerance between their biological effects has been shown in numerous reports. Here, we investigated the effects of nicotine and morphine on 6-OHDA-induced neurotoxicity in human neuroblastoma SH-SY5Y cell line as an in vitro model of Parkinson's disease. Cell damage was induced by 150 μM 6-OHDA and the cells viability was examined by MTT assay. Intracellular reactive oxygen species, calcium level and mitochondrial membrane potential were determined by fluorescence spectrophotometer method. Biochemical markers of apoptosis were also evaluated by immunoblotting. The data showed that morphine and nicotine prevent 6-OHDA- induced cell damage and apoptosis. However, the protective effects of nicotine were not observed in chronic morphine-pretreated cells. Morphine had no protective effects in chronic nicotine-incubated cells. A cross-tolerance between protective effects of morphine and nicotine was occurred in 6-OHDA-induced SH-SY5Y cell toxicity.

Opiate-like substances in an invertebrate, an opiate receptor on invertebrate and human immunocytes, and a role in immunosuppression.

PubMed Central

Stefano, G B; Digenis, A; Spector, S; Leung, M K; Bilfinger, T V; Makman, M H; Scharrer, B; Abumrad, N N

1993-01-01

The presence of morphine-like and codeine-like substances was demonstrated in the pedal ganglia, hemolymph, and mantle tissues of the mollusc Mytilus edulis. The pharmacological activities of the endogenous morphine-like material resemble those of authentic morphine. Both substances were found to counteract, in a dose-dependent manner, the stimulatory effect of tumor necrosis factor alpha or interleukin 1 alpha on human monocytes and Mytilus immunocytes, when added simultaneously to the incubation medium. The immunosuppressive effect of this opiate material expresses itself in a lowering of chemotactic activity, cellular velocity, and adherence. Codeine mimics the activity of authentic morphine, but only at much higher concentrations. Specific high-affinity receptor sites (mu 3) for morphine have been identified on human monocytes and Mytilus immunocytes. In Mytilus recovering from experimentally induced stress, the return of "altered" immunocytes to a more inactive state appears to be due to a significant rise in the content of morphine-like material in the pedal ganglia and hemolymph at this time. Thus, morphine may have a role in calming or terminating the state of immune alertness. PMID:8248214

Effects of CCK-8 on the reinstatement of morphine-induced CPP and expression of behavioral sensitization in rats.

PubMed

Wen, D; Zang, G; Sun, D; Yang, S; Yu, F; Li, S; Ma, C; Cong, B

2013-05-15

Cholecystokinin octapeptide (CCK-8), a neuropeptide, plays an important role in morphine dependence and several addictive behaviors. We have previously reported that CCK-8 attenuates the acquisition of morphine-induced conditioned place preference (CPP), but the possible functions of CCK-8 on drug relapse remain unclear. Here we evaluated the effects of CCK-8 on the reinstatement of extinguished morphine-induced CPP and behavioral sensitization. A single injection of 0.1 and 1μg CCK-8 (i.c.v.) significantly attenuated both drug- (morphine) and stress- (foot shock) primed reinstatement of CPP and reduced the escalated locomotor activity in reinstatement tests. Additionally, CCK-8 blocked the expression of morphine-induced behavioral sensitization. However, administration of CCK-8 (0.01, 0.1 and 1μg) alone to morphine-pretreated rats could not trigger reinstatement of CPP and had no significant effect on threshold sensitivity to foot shock. In conclusion, our study identifies a distinct inhibitory effect of CCK-8 on the reinstatement of drug-seeking behavior and provides a potential application to the medication of drug relapse. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Pharmacological action of Panax ginseng on the behavioral toxicities induced by psychotropic agents.

PubMed

Kim, Hyoung-Chun; Shin, Eun-Joo; Jang, Choon-Gon; Lee, Myung-Koo; Eun, Jae-Soon; Hong, Jin-Tae; Oh, Ki-Wan

2005-09-01

Morphine-induced analgesia has been shown to be antagonized by ginseng total saponins (GTS), which also inhibit the development of analgesic tolerance to and physical dependence on morphine. GTS is involved in both of these processes by inhibiting morphine-6-dehydrogenase, which catalyzes the synthesis of morphinone from morphine, and by increasing the level of hepatic glutathione, which participates in the toxicity response. Thus, the dual actions of ginseng are associated with the detoxification of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contractions in guinea pig ileum (mu-receptors) and mouse vas deferens (delta-receptors) are not mediated through opioid receptors, suggesting the involvement of non-opioid mechanisms. GTS also attenuates hyperactivity, reverse tolerance (behavioral sensitization), and conditioned place preference induced by psychotropic agents, such as methamphetamine, cocaine, and morphine. These effects of GTS may be attributed to complex pharmacological actions between dopamine receptors and a serotonergic/adenosine A2A/ delta-opioid receptor complex. Ginsenosides also attenuate the morphine-induced cAMP signaling pathway. Together, the results suggest that GTS may be useful in the prevention and therapy of the behavioral side effects induced by psychotropic agents.

Chronic morphine treatment reduces recovery from opioid desensitization.

PubMed

Dang, Vu C; Williams, John T

2004-09-01

Tolerance and dependence result from long-term exposure to opioids, and there is growing evidence linking acute receptor desensitization to these more long-term processes. Receptor desensitization encompasses a series of events leading to the loss of receptor function and internalization. This study examines the onset and recovery from desensitization in locus ceruleus neurons recorded in brain slices taken from animals that have been chronically treated with morphine. After chronic morphine treatment, desensitization was altered as follows. First, the rate of desensitization was increased. Second, recovery from desensitization was always incomplete, even after a brief (1-2 min) exposure to agonist. This contrasts with experiments in controls in which recovery from desensitization, after a brief exposure to agonist, was complete within 25 min. Finally, morphine-6-beta-D-glucuronide, a metabolite of morphine that was ineffective at causing desensitization in controls, induced significant desensitization in slices from morphine-treated animals. When brain slices from controls were treated with inhibitors of PKC or monensin, agents known to compromise G-protein-coupled receptor resensitization, desensitization was increased, and recovery was significantly reduced. These results indicate that receptor resensitization maintains signaling during periods of intense and sustained stimulation. After chronic morphine treatment, desensitization is potentiated, and receptor resensitization is compromised.

Stress antagonizes morphine-induced analgesia in rats

NASA Technical Reports Server (NTRS)

Vernikos, J.; Shannon, L.; Heybach, J. P.

1981-01-01

Exposure to restraint stress resulted in antagonism of the analgesic effect of administered morphine in adult male rats. This antagonism of morphine-induced analgesia by restraint stress was not affected by adrenalectomy one day prior to testing, suggesting that stress-induced secretion of corticosteroids is not critical to this antagonism. In addition, parenteral administration of exogenous adrenocorticotropin (ACTH) mimicked the effect of stress in antagonizing morphine's analgesic efficacy. The hypothesis that ACTH is an endogenous opiate antagonist involved in modulating pain sensitivity is supported.

Sublingual and oral morphine administration. Review and new findings.

PubMed

Robison, J M; Wilkie, D J; Campbell, B

1995-12-01

Clinical reports rave about the efficacy of sublingual morphine, but most research data suggest that sublingual morphine lacks the necessary physical characteristics to be absorbed through sublingual tissues. This article clarifies these assertions by reviewing the clinical literature that supports sublingual administration, the theories relevant to sublingual morphine administration, and the pharmacokinetic research that supports or negates the benefit of this route. Recommendations for clinical nursing practice are provided to guide decision-making in care of patients with cancer pain.

Opiate receptor binding properties of morphine-, dihydromorphine-, and codeine 6-O-sulfate ester congeners.

PubMed

Crooks, Peter A; Kottayil, Santosh G; Al-Ghananeem, Abeer M; Byrn, Stephen R; Butterfield, D Allan

2006-08-15

A series of 3-O-acyl-6-O-sulfate esters of morphine, dihydromorphine, N-methylmorphinium iodide, codeine, and dihydrocodeine were prepared and evaluated for their ability to bind to mu-, delta-, kappa(1)-, kappa(2)-, and kappa(3)-opiate receptors. Several compounds exhibited good affinity for the mu-opiate receptor. Morphine-3-O-propionyl-6-O-sulfate had four times greater affinity than morphine at the mu-opiate receptor and was the most selective compound at this receptor subtype.

Impact of morphine on the expression of insulin receptor and protein levels of insulin/IGFs in rat neural stem cells.

PubMed

Salarinasab, Sadegh; Nourazarian, AliReza; Nikanfar, Masoud; Abdyazdani, Nima; Kazemi, Masoumeh; Feizy, Navid; Rahbarghazi, Reza

2017-11-01

Alzheimer's disease is correlated with neuronal degeneration and loss of neuronal precursors in different parts of the brain. It has been found disturbance in the homeostasis neural stem cells (NSCs) can cause neurodegeneration. Morphine, an analgesic agent, can disrupt the dynamic and normal state of NSCs. However, more investigations are required to clearly address underlying mechanisms. The current experiment aimed to investigate the effects of morphine on the cell distribution of insulin factor and receptor and insulin-like growth factors (IGF1, IGF2) in NSCs. NSCs were isolated from rats and stemness feature confirmed by antibodies against nestin and Sox2. The cells were exposed to 100μM morphine, 50μM naloxone and combination of these two drugs for 72h. The neural cell growth, changes in levels of insulin and insulin-like growth factors secreted by NSCs as well as the insulin-receptor-gene expression were assessed by flow cytometry, ELlSA, and real-time PCR, respectively. Cell cycle assay revealed the exposure of cells to morphine for 72h increased cell apoptosis and decreased neural stem cell growth. The biosynthesis of insulin, insulin-like growth factors, and insulin receptor were reduced (p<0.05) after NSCs exposure to morphine at the concentration of 100μM for 24, 48 and 72h. Naloxone is a competitive antagonist which binds MOR where morphine (and endogenous opioids) bind, and reversed the detrimental effects of morphine. It can be concluded that morphine initiated irregularity in NSCs kinetics and activity by reducing the secretion of insulin and insulin-like growth factors and down-regulation of insulin receptor. Copyright © 2017 Elsevier B.V. All rights reserved.

Morphine and outcomes in acute decompensated heart failure: an ADHERE analysis.

PubMed

Peacock, W F; Hollander, J E; Diercks, D B; Lopatin, M; Fonarow, G; Emerman, C L

2008-04-01

Morphine is a long-standing therapy in acute decompensated heart failure (ADHF), despite few supporting data. A study was undertaken to compare the outcomes of patients who did and did not receive morphine for ADHF. The study was a retrospective analysis of the Acute Decompensated Heart Failure National Registry (ADHERE) which enrols hospitalised patients with treatment for, or a primary discharge diagnosis of, ADHF. Patients were stratified into cohorts based on whether or not they received intravenous morphine. ANOVA, Wilcoxon and chi(2) tests were used in univariate analysis, followed by multivariate analysis controlling for parameters previously associated with mortality. Analyses were repeated for ejection fraction subgroups and in patients not on mechanical ventilation. There were 147 362 hospitalisations in ADHERE at December 2004, 20 782 of whom (14.1%) received morphine and 126 580 (85.9%) did not. There were no clinically relevant differences between the groups in the initial age, heart rate, blood pressure, blood urea nitrogen, creatinine, haemoglobin, ejection fraction or atrial fibrillation. A higher prevalence of rest dyspnoea, congestion on chest radiography, rales and raised troponin occurred in the morphine group. Patients on morphine received more inotropes and vasodilators, were more likely to require mechanical ventilation (15.4% vs 2.8%), had a longer median hospitalisation (5.6 vs 4.2 days), more ICU admissions (38.7% vs 14.4%), and had greater mortality (13.0% vs 2.4%) (all p<0.001). Even after risk adjustment and exclusion of ventilated patients, morphine was an independent predictor of mortality (OR 4.84 (95% CI 4.52 to 5.18), p<0.001). Morphine is associated with increased adverse events in ADHF which includes a greater frequency of mechanical ventilation, prolonged hospitalisation, more ICU admissions and higher mortality.

Predicting the effectiveness of virtual reality relaxation on pain and anxiety when added to PCA morphine in patients having burns dressings changes.

PubMed

Konstantatos, A H; Angliss, M; Costello, V; Cleland, H; Stafrace, S

2009-06-01

Pain arising in burns sufferers is often severe and protracted. The prospect of a dressing change can heighten existing pain by impacting both physically and psychologically. In this trial we examined whether pre-procedural virtual reality guided relaxation added to patient controlled analgesia with morphine reduced pain severity during awake dressings changes in burns patients. We conducted a prospective randomized clinical trial in all patients with burns necessitating admission to a tertiary burns referral centre. Eligible patients requiring awake dressings changes were randomly allocated to single use virtual reality relaxation plus intravenous morphine patient controlled analgesia (PCA) infusion or to intravenous morphine patient controlled analgesia infusion alone. Patients rated their worst pain intensity during the dressing change using a visual analogue scale. The primary outcome measure was presence of 30% or greater difference in pain intensity ratings between the groups in estimation of worst pain during the dressing change. Of 88 eligible and consenting patients having awake dressings changes, 43 were assigned to virtual reality relaxation plus intravenous morphine PCA infusion and 43 to morphine PCA infusion alone. The group receiving virtual reality relaxation plus morphine PCA infusion reported significantly higher pain intensities during the dressing change (mean=7.3) compared with patients receiving morphine PCA alone (mean=5.3) (p=0.003) (95% CI 0.6-2.8). The addition of virtual reality guided relaxation to morphine PCA infusion in burns patients resulted in a significant increase in pain experienced during awake dressings changes. In the absence of a validated predictor for responsiveness to virtual reality relaxation such a therapy cannot be recommended for general use in burns patients having awake dressings changes.

Administration of intravenous morphine for acute pain in the emergency department inflicts an economic burden in Europe

PubMed Central

Casamayor, Montserrat; Hennebert, Marc; Brazzi, Luca; Prosen, Gregor

2018-01-01

Background Acute pain is among the leading causes of referral to the emergency department (ED) in industrialized countries. Its management mainly depends on intensity. Moderate-to-severe pain is treated with intravenous (IV) administered opioids, of which morphine is the most commonly used in the ED. We have estimated the burden of IV administration of morphine in the five key European countries (EU5) using a micro-costing approach. Scope A structured literature review was conducted to identify clinical guidelines for acute pain management in EU5 and clinical studies conducted in the ED setting. The data identified in this literature review constituted the source for all model input parameters, which were clustered as analgesic (morphine), material used for IV morphine administration, nurse workforce time and management of morphine-related adverse events and IV-related complications. Findings The cost per patient of IV morphine administration in the ED ranges between €18.31 in Spain and €28.38 in Germany. If costs associated with the management of morphine-related adverse events and IV-related complications are also considered, the total costs amount to €121.13–€132.43. The main driver of those total costs is the management of IV-related complications (phlebitis, extravasation and IV prescription errors; 73% of all costs) followed by workforce time (14%). Conclusions IV morphine provides effective pain relief in the ED, but the costs associated with the IV administration inflict an economic burden on the respective national health services in EU5. An equally rapid-onset and efficacious analgesic that does not require IV administration could reduce this burden. PMID:29675049

Importance of GluA1 Subunit-Containing AMPA Glutamate Receptors for Morphine State-Dependency

PubMed Central

Aitta-aho, Teemu; Möykkynen, Tommi P.; Panhelainen, Anne E.; Vekovischeva, Olga Yu.; Bäckström, Pia; Korpi, Esa R.

2012-01-01

In state-dependency, information retrieval is most efficient when the animal is in the same state as it was during the information acquisition. State-dependency has been implicated in a variety of learning and memory processes, but its mechanisms remain to be resolved. Here, mice deficient in AMPA-type glutamate receptor GluA1 subunits were first conditioned to morphine (10 or 20 mg/kg s.c. during eight sessions over four days) using an unbiased procedure, followed by testing for conditioned place preference at morphine states that were the same as or different from the one the mice were conditioned to. In GluA1 wildtype littermate mice the same-state morphine dose produced the greatest expression of place preference, while in the knockout mice no place preference was then detected. Both wildtype and knockout mice expressed moderate morphine-induced place preference when not at the morphine state (saline treatment at the test); in this case, place preference was weaker than that in the same-state test in wildtype mice. No correlation between place preference scores and locomotor activity during testing was found. Additionally, as compared to the controls, the knockout mice showed unchanged sensitization to morphine, morphine drug discrimination and brain regional μ-opioid receptor signal transduction at the G-protein level. However, the knockout mice failed to show increased AMPA/NMDA receptor current ratios in the ventral tegmental area dopamine neurons of midbrain slices after a single injection of morphine (10 mg/kg, s.c., sliced prepared 24 h afterwards), in contrast to the wildtype mice. The results indicate impaired drug-induced state-dependency in GluA1 knockout mice, correlating with impaired opioid-induced glutamate receptor neuroplasticity. PMID:22675452

Dextromethorphan differentially affects opioid antinociception in rats

PubMed Central

Chen, Shiou-Lan; Huang, Eagle Yi-Kung; Chow, Lok-Hi; Tao, Pao-Luh

2005-01-01

Opioid drugs such as morphine and meperidine are widely used in clinical pain management, although they can cause some adverse effects. A number of studies indicate that N-methyl-D-aspartate (NMDA) receptors may play a role in the mechanism of morphine analgesia, tolerance and dependence. Being an antitussive with NMDA antagonist properties, dextromethorphan (DM) may have some therapeutic benefits when coadministered with morphine. In the present study, we investigated the effects of DM on the antinociceptive effects of different opioids. We also investigated the possible pharmacokinetic mechanisms involved. The antinociceptive effects of the μ-opioid receptor agonists morphine (5 mg kg−1, s.c.), meperidine (25 mg kg−1, s.c.) and codeine (25 mg kg−1, s.c.), and the κ-opioid agonists nalbuphine (8 mg kg−1, s.c.) and U-50,488H (20 mg kg−1, s.c.) were studied using the tail-flick test in male Sprague–Dawley rats. Coadministration of DM (20 mg kg−1, i.p.) with these opioids was also performed and investigated. The pharmacokinetic effects of DM on morphine and codeine were examined, and the free concentration of morphine or codeine in serum was determined by HPLC. It was found that DM potentiated the antinociceptive effects of some μ-opioid agonists but not codeine or κ-opioid agonists in rats. DM potentiated morphine's antinociceptive effect, and acutely increased the serum concentration of morphine. In contrast, DM attenuated the antinociceptive effect of codeine and decreased the serum concentration of its active metabolite (morphine). The pharmacokinetic interactions between DM and opioids may partially explain the differential effects of DM on the antinociception caused by opioids. PMID:15655510

Managing Postoperative Analgesic Failure: Tramadol Versus Morphine for Refractory Pain in the Post-Operative Recovery Unit.

PubMed

Byrne, Kelly; Nolan, Aoife; Barnard, John; Tozer, Megan; Harris, David; Sleigh, Jamie

2017-02-01

This study aimed to discover whether co-analgesia with tramadol or additional morphine was more effective for patients who still had severe pain despite being given 10 mg intravenous morphine in the post-anesthesia care unit (PACU). All eligible patients were consented and recruited to the trial pre-operatively, but only a small subgroup – whose pain was not successfully controlled (pain score 6/10 or more) after receiving 10 mg of morphine in the PACU—were then randomized to enter the trial and receive, in a double blinded fashion, the analgesic study drug; which consisted of either a further 10 mg of morphine, or 100 mg of tramadol, titrated intravenously to control their pain. The groups were compared as to: the time to readiness for discharge, the patient’s pain scores over time, and the presence of side effects. There was no statistically significant difference in any of the outcomes measured. The time to readiness for discharge from PACU was 119 minutes in the morphine group and 120 minutes in the tramadol group. However in approximately half the cases who entered the trial (i.e., where pain had not been controlled with the pre-enrollment baseline 10 mg of morphine in PACU) neither a further 10 mg of morphine nor 100 mg of tramadol effectively relieved the patient’s pain. We found no difference between additional morphine and co-analgesia with tramadol in this study. Patients who don’t respond to reasonable doses of opioids in PACU are very likely to be unresponsive to further opioids, and other non-opioid analgesic techniques (such as regional anesthesia) should be considered early in this group of patients.

Decrease in serotonin concentration in raphe magnus nucleus and attenuation of morphine analgesia in two mice models of neuropathic pain.

PubMed

Sounvoravong, Sourisak; Nakashima, Mihoko N; Wada, Mitsuhiro; Nakashima, Kenichiro

2004-01-26

The alleviation of neuropathic pain cannot be satisfactorily achieved by treatment with opioids. There is much evidence to indicate that the active site of morphine for inducing effective analgesia is in the raphe magnus nucleus, where serotonin (5-HT, 5-hydroxytryptamine) acts as a primary transmitter. Therefore, we developed the hypothesis that 5-HT released in the raphe magnus nucleus could be related to the effectiveness of morphine in two mice models of neuropathic pain, diabetic (DM)-induced neuropathy and sciatic nerve ligation (SL). Two weeks after a single administration of streptozotocin, or 10 days after sciatic nerve ligation, mice were subcutaneously (s.c.) injected with morphine at 3, 5 and 10 mg/kg. The antinociceptive effect of morphine was estimated in the tail-pinch test; 5-HT content was measured after induction of neuropathic pain by microdialysis followed by high-performance liquid chromatography with electrochemical detection (HPLC-ECD). Morphine produced as insufficient antinociceptive effect in SL mice at all doses compared with that in sham-operated mice, while in DM mice, morphine given s.c. at 5 and 10 mg/kg produced antinociceptive effects compared with those in non-diabetic mice, but not at 3 mg/kg. The 5-HT content of dialysates, expressed as AUC for 75 min, in SL and DM mice was less than that in control mice. However, morphine given s.c. at 5 mg/kg did not significantly affect 5-HT levels in both mice models compared to their controls. These results suggest that the decrease in 5-HT levels in the raphe magnus nucleus may be related to attenuation of the analgesic effect of morphine caused by the abnormal pain state found in diabetes and partial peripheral nerve injury.

Role of glutamatergic receptors located in the nucleus raphe magnus on antinociceptive effect of morphine microinjected into the nucleus cuneiformis of rat.

PubMed

Haghparast, Abbas; Soltani-Hekmat, Ava; Khani, Abbas; Komaki, Alireza

2007-10-29

Neurons in the nucleus cuneiformis (CnF), located just ventrolateral to the periaqueductal gray, project to medullary nucleus raphe magnus (NRM), which is a key medullary relay for descending pain modulation and is critically involved in opioid-induced analgesia. Previous studies have shown that antinociceptive response of CnF-microinjected morphine can be modulated by the specific subtypes of glutamatergic receptors within the CnF. In this study, we evaluated the role of NMDA and kainate/AMPA receptors that are widely distributed within the NRM on morphine-induced antinociception elicited from the CnF. Hundred and five male Wistar rats weighing 250-300 g were used. Morphine (10, 20 and 40 microg) and NMDA receptor antagonist, MK-801 (10 microg) or kainate/AMPA receptor antagonist, DNQX (0.5 microg) in 0.5 microl saline were stereotaxically microinjected into the CnF and NRM, respectively. The latency of tail-flick response was measured at set intervals (2, 7, 12, 17, 22, 27 min after microinjection) by using an automated tail-flick analgesiometer. The results showed that morphine microinjection into the CnF dose-dependently causes increase in tail-flick latency (TFL). MK-801 microinjected into the NRM, just 1 min before morphine injection into the CnF, significantly attenuated antinociceptive effects of morphine. On the other hand, DNQX microinjected into the NRM, significantly increased TFL after local application of morphine into the CnF. We suggest that morphine related antinociceptive effect elicited from the CnF is mediated, in part, by NMDA receptor at the level of the NRM whereas kainite/AMPA receptor has a net inhibitory influence at the same pathway.

Effect of preemptive intra-articular morphine and ketamine on pain after arthroscopic rotator cuff repair: a prospective, double-blind, randomized controlled study.

PubMed

Khashan, M; Dolkart, O; Amar, E; Chechik, O; Sharfman, Z; Mozes, G; Maman, E; Weinbroum, A A

2016-02-01

Rotator cuff tear is a leading etiology of shoulder pain and disability. Surgical treatment is indicated in patients with persistent pain who fail a trial of non-surgical treatment. Pain reduction following rotator cuff repair, particularly within the first 24-48 h, is a major concern to both doctors and patients. This study aimed to compare the postoperative antinociceptive additive effects of pre-incisional intra-articular (IA) ketamine when combined with morphine with two times the dose of morphine or saline. In this prospective, randomized, double blind, controlled trial patients undergoing arthroscopic rotator cuff tear repair (ARCR) under general anesthesia were enrolled. Patients were randomly assigned to one of the three intervention groups. Twenty minutes prior to incision, morphine (20 mg/10 ml), ketamine (50 mg + morphine 10 mg/10 ml), or saline (0.9 % 10 ml) (n = 15/group), were administered to all patients. First 24 h postoperative analgesia consisted of intravenous patient controlled analgesia (IV-PCA) morphine and oral rescue paracetamol 1000 mg or oxycodone 5 mg. 24-h, 2-week and 3-month patient rated pain numeric rating scale (NRS) and analgesics consumption were documented. Patients' demographic and perioperative data were similar among all groups. The 24-h and the 2-week NRSs were significantly (p < 0.05) lower in both treatment groups compared to placebo, but were not significantly different between the two intervention groups. PCA-morphine and oral analgesics were consumed similarly among the groups throughout the study phases. Pre-incisional intra-articular morphine reduced pain in the first 2 weeks after arthroscopic rotator cuff repair. Further research is warranted to elucidate the optimal timing and dosing of IA ketamine and morphine for postoperative analgesic effects.

Ketamine added to morphine or hydromorphone patient-controlled analgesia for acute postoperative pain in adults: a systematic review and meta-analysis of randomized trials.

PubMed

Wang, Li; Johnston, Bradley; Kaushal, Alka; Cheng, Davy; Zhu, Fang; Martin, Janet

2016-03-01

To determine whether ketamine added to morphine or hydromorphone patient-controlled analgesia (PCA) provides clinically relevant reductions in postoperative pain, opioid requirements, and adverse events when compared with morphine or hydromorphone PCA in adults undergoing surgery. We systematically searched six databases up to June 2, 2015 for randomized controlled trials (RCTs) comparing ketamine plus morphine/hydromorphone PCA vs morphine/hydromorphone PCA for postoperative pain in adults. Thirty-six RCTs including 2,502 patients proved eligible, and 22 of these were at low risk of bias. The addition of ketamine to morphine/hydromorphone PCA decreased postoperative pain intensity at six to 72 hr when measured at rest (weighted mean difference [WMD] on a 10-cm visual analogue scale ranged from -0.4 to -1.3 cm) and during mobilization (WMD ranged from -0.4 to -0.5 cm). Adjunctive ketamine also significantly reduced cumulative morphine consumption at 24-72 hr by approximately 5-20 mg. Predefined subgroup analyses and meta-regression did not detect significant differences across subgroups, including a dose-response relationship. There was no significant difference in patient satisfaction scores at 24 and 48 hr. Nevertheless, the addition of ketamine to morphine/hydromorphone PCA significantly reduced postoperative nausea and vomiting (relative risk, 0.71; 95% confidence interval [CI], 0.60 to 0.85; absolute risk reduction, 8.9%; 95% CI, 4.6 to 12.2). Significant effects on other adverse events (e.g., hallucinations, vivid dreams) were not detected, though only a few studies reported on them. Adding ketamine to morphine/hydromorphone PCA provides a small improvement in postoperative analgesia while reducing opioid requirements. Adjunctive ketamine also reduces postoperative nausea and vomiting without a detected increase in other adverse effects; however, adverse events were probably underreported.

Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine.

PubMed

Zwicker, Jill G; Miller, Steven P; Grunau, Ruth E; Chau, Vann; Brant, Rollin; Studholme, Colin; Liu, Mengyuan; Synnes, Anne; Poskitt, Kenneth J; Stiver, Mikaela L; Tam, Emily W Y

2016-05-01

To examine the relationship between morphine exposure and growth of the cerebellum and cerebrum in very preterm neonates from early in life to term-equivalent age, as well as to examine morphine exposure and brain volumes in relation to neurodevelopmental outcomes at 18 months corrected age (CA). A prospective cohort of 136 very preterm neonates (24-32 weeks gestational age) was serially scanned with magnetic resonance imaging near birth and at term-equivalent age for volumetric measurements of the cerebellum and cerebrum. Motor outcomes were assessed with the Peabody Developmental Motor Scales, Second Edition and cognitive outcomes with the Bayley Scales of Infant and Toddler Development, Third Edition at 18 months CA. Generalized least squares models and linear regression models were used to assess relationships between morphine exposure, brain volumes, and neurodevelopmental outcomes. A 10-fold increase in morphine exposure was associated with a 5.5% decrease in cerebellar volume, after adjustment for multiple clinical confounders and total brain volume (P = .04). When infants exposed to glucocorticoids were excluded, the association of morphine was more pronounced, with an 8.1% decrease in cerebellar volume. Morphine exposure was not associated with cerebral volume (P = .30). Greater morphine exposure also predicted poorer motor (P < .001) and cognitive outcomes (P = .006) at 18 months CA, an association mediated, in part, by slower brain growth. Morphine exposure in very preterm neonates is independently associated with impaired cerebellar growth in the neonatal period and poorer neurodevelopmental outcomes in early childhood. Alternatives to better manage pain in preterm neonates that optimize brain development and functional outcomes are urgently needed. Copyright © 2016 Elsevier Inc. All rights reserved.

The use-dependent, nicotinic antagonist BTMPS reduces the adverse consequences of morphine self-administration in rats in an abstinence model of drug seeking

PubMed Central

Hall, Brandon J.; Pearson, Laura S.; Terry, Alvin V.; Buccafusco, Jerry J.

2011-01-01

In this study, the use-dependent, nicotinic receptor antagonist bis (2, 2, 6, 6-tetramethyl-4-piperidinyl) sebacate (BTMPS) was evaluated for its ability to attenuate the adverse consequences associated with morphine in rats in all three phases of an abstinence model of drug seeking: self-administration, acute withdrawal, and delayed test of drug seeking. Rats were allowed to self-administer morphine (FR1 schedule) with an active response lever, on a 24hr basis inside operant chambers, for 14 days. Each rat was subsequently evaluated for stereotypical behaviors associated with spontaneous morphine withdrawal. Rats were then placed in standard housing cages for a six week period of protracted abstinence from morphine. After this period, each rat was placed back into its respective operant chamber for a 14 day assessment of unrewarded drug seeking responses. BTMPS was administered to the animals in all three clinically relevant phases in three separate sets of experiments. BTMPS treatment during the self-administration phase resulted in up to a 34% reduction of lever responses to morphine when compared to vehicle treated control animals, as well as a 32% reduction in the dose of morphine self-administered. When given during self-administration and acute withdrawal, BTMPS treatment decreased acute withdrawal symptoms (up to 64%) of morphine use and reduced (up to 45%) drug seeking responses after six weeks of protracted withdrawal compared to control animals. BTMPS treatment after six weeks of abstinence from morphine had no effect. These results offer insight into the role of central cholinergic receptors in the onset and maintenance of drug addiction. PMID:21651919

Breathing and temperature control disrupted by morphine and stabilized by clonidine in neonatal rats.

PubMed

Kesavan, Kalpashri; Ezell, Tarrah; Bierman, Alexis; Nunes, Ana Rita; Northington, Frances J; Tankersley, Clarke G; Gauda, Estelle B

2014-09-15

Sedative-analgesics are often given to newborn infants and are known to affect many components of the autonomic nervous system. While morphine is most frequently used, α-2 adrenergic receptor agonists are being increasingly used in this population. Alpha-2 adrenergic receptors agonists also have anti-shivering properties which may make it a desirable drug to give to infants undergoing therapeutic hypothermia. The aim of this study was to systematically compare two different classes of sedative-analgesics, morphine, a μ-opioid receptor agonist, and clonidine an α-2 adrenergic receptor agonist on breathing, metabolism and core body temperature (CBT) in neonatal rodents. Breathing parameters, oxygen consumption (VO2) and carbon dioxide production (VCO2), were measured prior to, 10 and 90 min after intraperitoneal (IP) administration of morphine (2, 10 or 20 mg/kg), clonidine (40, 200 or 400 μg/kg), or saline in Sprague-Dawley rat pups at postnatal day 7 (p7) while continuously monitoring CBT. Morphine reduced the respiratory rate, VO2 and VCO2 greater than clonidine at all dosages used (p<0.05, morphine vs. clonidine, for all metabolic and respiratory parameters). Furthermore, morphine induced prolonged respiratory pauses, which were not observed in animals treated with clonidine or saline. Morphine caused hypothermia which was dose dependent, while clonidine stabilized CBT in comparison to saline treated animals (p<0.0001). In the newborn rat, morphine causes profound respiratory depression and hypothermia while clonidine causes minimal respiratory depression and stabilizes CBT. All together, we suggest that clonidine promotes autonomic stability and may be a desirable agent to use in infants being treated with therapeutic hypothermia. Copyright © 2014 Elsevier B.V. All rights reserved.

The consummatory and motivational behaviors for natural rewards following long-term withdrawal from morphine: no anhedonia but persistent maladaptive behaviors for high-value rewards.

PubMed

Li, Yingying; Zheng, Xigeng; Xu, Na; Zhang, Yue; Liu, Zhengkui; Bai, Yunjing

2017-04-01

The negative affective state, e.g., anhedonia, emerges after abstinence from abused drugs may be linked to the motivational processes of drug craving and relapse. Although anhedonia diminishes over time with drug abstinence, it is not yet rather explicit whether anhedonia exists or not following protracted withdrawal. The behavioral responses to natural rewards were examined after 2 to 3 weeks withdrawal from morphine. Male rats were pretreated with either a binge-like morphine paradigm or daily saline injection for 5 days. The consummatory and motivational behaviors for three natural rewards (sucrose solutions 4, 15, and 60%, social stimulus: male rat, and sexual stimulus: estrous female rat) were examined under varied testing conditions. The morphine-withdrawn rats significantly increased their intake of 15% sucrose solution during the 1-h consumption test and their operant responding for 15% sucrose solution under a progressive ratio (PR) schedule of reinforcement. When obtaining a reinforcer was associated with a 0.5 mA foot shock under a PR-punishment schedule, the morphine-withdrawn rats showed a higher performance for 60% sucrose solution. Meanwhile, the morphine-withdrawn rats displayed a higher motivation to sexual stimulus during the free-approach test and more approaching behaviors towards sexual stimulus in a conflict-based approach test (concurrent presence of reward and aversive stimulus). No anhedonia-like behavior but sensitized behaviors for natural rewards were found after long-term morphine withdrawal. Notably, the morphine-withdrawn rats displayed persistent motivated behaviors for high-value rewards (60% sucrose and sexual stimulus) in the conflict tests suggesting impairments in inhibitory control in morphine-treated rats.

Midazolam Plus Haloperidol as Adjuvant Analgesics to Morphine in Opium Dependent Patients: A Randomized Clinical Trial.

PubMed

Afzalimoghaddam, Mohammad; Edalatifard, Maryam; Nejati, Amir; Momeni, Mehdi; Isavi, Nader; Karimialavijeh, Ehsan

2016-01-01

Tolerance to opioids among opium-dependent patients creates obstacles for proper pain management of these patients in the emergency department (ED). The aim of the present study was to investigate the efficacy of intramuscular (IM) haloperidol plus midazolam on morphine analgesia among opium-dependent patients. Opium-dependent adults who were admitted to the ED for new-onset severe pain in the limbs or abdomen (within 24 hours of admission and a pain score of over six, using a numerical rating scale [NRS]) were recruited. Participants were randomly assigned into two groups. Group A received morphine 0.05 mg/kg intravenously (IV) and a mixture of midazolam 2.5 mg and haloperidol 2.5 mg (diluted in 5 cc of distilled water, IM); group B received morphine 0.05 mg/kg IV and distilled water 5 cc, IM. Measured outcomes were related to: 1) pain intensity; 2) total doses of morphine; 3) changes in hemodynamic status and level of consciousness of patients. NRS scores (zero to 10) before and one, three and six hours following intervention, as well as total doses of morphine, were recorded. We recruited 68 males (78.16%) and 19 females (21.83%). The mean age was 38.28±6.59 years. The pain score in group A declined more rapidly over six hours than that in group B. Moreover, as compared to group B, the amount of morphine use decreased significantly in group A. Based on the present data, adding haloperidol plus midazolam to morphine for pain management improved pain scores and lowered morphine consumption among opium-dependent patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effect of intravenous parecoxib on post-craniotomy pain.

PubMed

Williams, D L; Pemberton, E; Leslie, K

2011-09-01

Pain management in craniotomy patients is challenging, with mild-to-moderate pain intensity, moderate-to-high risk of postoperative nausea and vomiting (PONV), and potentially catastrophic consequences of analgesic-related side-effects. The aim of this study was to determine whether i.v. parecoxib administered at dural closure during craniotomy decreased total morphine consumption and morphine-related side-effects compared with placebo. One hundred adult patients presenting for supratentorial craniotomy under propofol/remifentanil anaesthesia were randomized to receive parecoxib, 40 mg i.v., or placebo in a double-blind manner. All patients received local anaesthetic scalp infiltration, regular i.v. paracetamol, nurse-administered morphine in the post-anaesthesia care unit (PACU) until verbal analogue pain scores were ≤4/10 and patient-controlled morphine thereafter. Morphine consumption, pain intensity, and analgesia-related side-effects were recorded during the first 24 h after operation. Ninety-six patients (49 control and 47 parecoxib) were included in the analyses. Fifty-nine (61%) patients received morphine in the PACU and only one patient (control) did not receive any morphine in the postoperative period. There were no significant differences between the two groups in morphine consumption [20 (range: 0-102) vs 16 (range: 1-92) mg; P=0.38], pain intensity [excellent/very good pain relief in 78% of parecoxib patients; 74% of control patients (P=0.72)] or analgesia-related side-effects (PONV in 51% of parecoxib patients; 56% of control patients; P=0.55) in the first 24 h after operation. No major morbidity was recorded. Our study demonstrated no clinical benefit to adding i.v. parecoxib to local anaesthetic scalp infiltration, i.v. paracetamol, and patient-controlled i.v. morphine after supratentorial craniotomy.

Effectiveness of prehospital morphine, fentanyl, and methoxyflurane in pediatric patients.

PubMed

Bendall, Jason C; Simpson, Paul M; Middleton, Paul M

2011-01-01

To compare the effectiveness of intravenous morphine, intranasal (IN) fentanyl, and inhaled methoxyflurane for managing moderate to severe pain in pediatric patients in the out-of-hospital setting. We conducted a retrospective comparative study of 3,312 pediatric patients aged between 5 and 15 years who had moderate to severe pain (pain score ≥ 5) and who received intravenous morphine, IN fentanyl, or inhaled methoxyflurane, either alone or in combination, between January 1, 2004, and November 30, 2006. Multivariate logistic regression was used to analyze data extracted from a clinical database containing routinely entered information from patient health care records. The primary outcome measure was effective analgesia, defined as a reduction in pain severity of ≥ 30% of initial pain score using an 11-point verbal numeric rating scale. Effective analgesia was achieved in 82.5% of cases overall. All analgesic agents were effective in the majority of patients (87.5%, 89.5%, and 78.3% for morphine, fentanyl, and methoxyflurane, respectively). There was evidence that methoxyflurane was less effective than both morphine (odds ratio [OR] 0.52; 95% confidence interval [CI] 0.36-0.74) and fentanyl (OR 0.43; 95% CI 0.29-0.62; p < 0.0001). There was no clinical or statistical evidence of difference in the effectiveness of fentanyl and morphine in this population (OR 1.22; 95% CI 0.74-2.01). There was no evidence that combination analgesia was better than either fentanyl or morphine alone. Intranasal fentanyl and intravenous morphine are equally effective analgesic agents in pediatric patients with moderate to severe acute pain in the out-of-hospital setting. Methoxyflurane is less effective in comparison with both morphine and fentanyl, but is an effective analgesic in the majority of children.

Action of Phα1β, a peptide from the venom of the spider Phoneutria nigriventer, on the analgesic and adverse effects caused by morphine in mice.

PubMed

Tonello, Raquel; Rigo, Flávia; Gewehr, Camila; Trevisan, Gabriela; Pereira, Elizete Maria Rita; Gomez, Marcus Vinicius; Ferreira, Juliano

2014-06-01

Opioids are standard therapy for the treatment of pain; however, adverse effects limit their use. Voltage-gated calcium channel blockers may be used to increase opioid analgesia, but their effect on opioid-induced side effects is little known. Thus, the goal of this study was to evaluate the action of the peptide Phα1β, a voltage-gated calcium channel blocker, on the antinociceptive and adverse effects produced by morphine in mice. A single administration of morphine (3-10 mg/kg) was able to reduce heat nociception as well as decrease gastrointestinal transit. The antinociception caused by a single injection of morphine was slightly increased by an intrathecal injection of Phα1β (30 pmol/site). Repeated treatment with morphine caused tolerance, hyperalgesia, withdrawal syndrome, and constipation, and the Phα1β (.1-30 pmol/site, intrathecal) was able to reverse these effects. Finally, the effects produced by the native form of Phα1β were fully mimicked by a recombinant version of this peptide. Taken together, these data show that Phα1β was effective in potentiating the analgesia caused by a single dose of morphine as well as in reducing tolerance and the adverse effects induced by repeated administration of morphine, indicating its potential use as an adjuvant drug in combination with opioids. This article presents preclinical evidence for a useful adjuvant drug in opioid treatment. Phα1β, a peptide calcium channel blocker, could be used not only to potentiate morphine analgesia but also to reduce the adverse effects caused by repeated administration of morphine. Copyright © 2014. Published by Elsevier Inc.

BREATHING AND TEMPERATURE CONTROL DISRUPTED BY MORPHINE AND STABILIZED BY CLONIDINE IN NEONATAL RATS

PubMed Central

Kesavan, Kalpashri; Ezell, Tarrah; Bierman, Alexis; Nunes, Ana Rita; Northington, Frances J.; Tankersley, Clarke G.; Gauda, Estelle B.

2014-01-01

Background Sedative-analgesics are often given to newborn infants and are known to affect many components of the autonomic nervous system. While morphine is most frequently used, α-2 adrenergic receptor agonists are being increasingly used in this population. Alpha-2 adrenergic receptors agonists also have anti-shivering properties which may make it a desirable drug to give to infants undergoing therapeutic hypothermia. The aim of this study was to systematically compare two different classes of sedative-analgesics, morphine, a μ-opioid receptor agonist, and clonidine an α-2 adrenergic receptor agonist on breathing, metabolism and core body temperature (CBT) in neonatal rodents. Methods Breathing parameters, oxygen consumption (VO2) and carbon dioxide production (VCO2), were measured prior to, 10 and 90 minutes after intraperitoneal (IP) administration of morphine (2, 10 or 20mg/kg), clonidine (40, 200 or 400 μg/kg), or saline in Sprague-Dawley rat pups at postnatal day 7 (p7) while continuously monitoring CBT. Results Morphine reduced the respiratory rate, VO2 and VCO2 greater than clonidine at all dosages used (p<0.05, morphine vs. clonidine, for all metabolic and respiratory parameters). Furthermore, morphine induced prolonged respiratory pauses, which were not observed in animals treated with clonidine or saline. Morphine caused hypothermia which was dose dependent, while clonidine stabilized CBT in comparison to saline treated animals (p<0.0001). Conclusion In the newborn rat, morphine causes profound respiratory depression and hypothermia while clonidine causes minimal respiratory depression and stabilizes CBT. All together, we suggest that clonidine promotes autonomic stability and may be a desirable agent to use in infants being treated with therapeutic hypothermia. PMID:25008573

Endogenous Opioid Inhibition of Chronic Low Back Pain Influences Degree of Back Pain Relief Following Morphine Administration

PubMed Central

Bruehl, Stephen; Burns, John W.; Gupta, Rajnish; Buvanendran, Asokumar; Chont, Melissa; Schuster, Erik; France, Christopher R.

2014-01-01

Background and Objectives Factors underlying differential responsiveness to opioid analgesic medications used in chronic pain management are poorly understood. We tested whether individual differences in endogenous opioid inhibition of chronic low back pain were associated with magnitude of acute reductions in back pain ratings following morphine administration. Methods In randomized, counterbalanced order over three sessions, 50 chronic low back pain patients received intravenous naloxone (8mg), morphine (0.08 mg/kg), or placebo. Back pain intensity was rated pre-drug and again after peak drug activity was achieved using the McGill Pain Questionnaire-Short Form (Sensory and Affective subscales, VAS intensity measure). Opioid blockade effect measures to index degree of endogenous opioid inhibition of back pain intensity were derived as the difference between pre-to post-drug changes in pain intensity across placebo and naloxone conditions, with similar morphine responsiveness measures derived across placebo and morphine conditions. Results Morphine significantly reduced back pain compared to placebo (MPQ-Sensory, VAS; P < .01). There were no overall effects of opioid blockade on back pain intensity. However, individual differences in opioid blockade effects were significantly associated with degree of acute morphine-related reductions in back pain on all measures, even after controlling for effects of age, sex, and chronic pain duration (P < .03). Individuals exhibiting greater endogenous opioid inhibition of chronic back pain intensity reported less acute relief of back pain with morphine. Conclusions Morphine appears to provide better acute relief of chronic back pain in individuals with lower natural opioidergic inhibition of chronic pain intensity. Possible implications for personalized medicine are discussed. PMID:24553304

Effects of corticotropin-releasing factor receptor-1 antagonists on the brain stress system responses to morphine withdrawal.

PubMed

Navarro-Zaragoza, Javier; Núñez, Cristina; Laorden, M Luisa; Milanés, M Victoria

2010-05-01

The role of stress in drug addiction is well established. The negative affective states of withdrawal most probably involve recruitment of brain stress neurocircuitry [e.g., induction of hypothalamo-pituitary-adrenocortical (HPA) axis, noradrenergic activity, and corticotropin-releasing factor (CRF) activity]. The present study investigated t$he role of CRF receptor-1 subtype (CRF1R) on the response of brain stress system to morphine withdrawal. The effects of naloxone-precipitated morphine withdrawal on noradrenaline (NA) turnover in the paraventricular nucleus (PVN), HPA axis activity, signs of withdrawal, and c-Fos expression were measured in rats pretreated with vehicle, CP-154526 [N-butyl-N-ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine], or antalarmin (selective CRF1R antagonists). Tyrosine hydroxylase-positive neurons expressing CRF1R were seen at the level of the nucleus tractus solitarius-A(2) cell group in both control and morphine-withdrawn rats. CP-154526 and antalarmin attenuated the increases in body weight loss and irritability that were seen during naloxone-induced morphine withdrawal. Pretreatment with CRF1R antagonists resulted in no significant modification of the increased NA turnover at PVN, plasma corticosterone levels, or c-Fos expression that was seen during naloxone-induced morphine withdrawal. However, blockade of CRF1R significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropin levels. These results suggest that the CRF1R subtype may be involved in the behavioral and somatic signs and in adrenocorticotropin release (partially) during morphine withdrawal. However, CRF1R activation may not contribute to the functional interaction between NA and CRF systems in mediating morphine withdrawal-activation of brain stress neurocircuitry.

Single-sweep spectral analysis of contact heat evoked potentials: a novel approach to identify altered cortical processing after morphine treatment

PubMed Central

Hansen, Tine M; Graversen, Carina; Frøkjær, Jens B; Olesen, Anne E; Valeriani, Massimiliano; Drewes, Asbjørn M

2015-01-01

Aims The cortical response to nociceptive thermal stimuli recorded as contact heat evoked potentials (CHEPs) may be altered by morphine. However, previous studies have averaged CHEPs over multiple stimuli, which are confounded by jitter between sweeps. Thus, the aim was to assess single-sweep characteristics to identify alterations induced by morphine. Methods In a crossover study 15 single-sweep CHEPs were analyzed from 62 electroencephalography electrodes in 26 healthy volunteers before and after administration of morphine or placebo. Each sweep was decomposed by a continuous wavelet transform to obtain normalized spectral indices in the delta (0.5–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–32 Hz) and gamma (32–80 Hz) bands. The average distribution over all sweeps and channels was calculated for the four recordings for each volunteer, and the two recordings before treatments were assessed for reproducibility. Baseline corrected spectral indices after morphine and placebo treatments were compared to identify alterations induced by morphine. Results Reproducibility between baseline CHEPs was demonstrated. As compared with placebo, morphine decreased the spectral indices in the delta and theta bands by 13% (P = 0.04) and 9% (P = 0.007), while the beta and gamma bands were increased by 10% (P = 0.006) and 24% (P = 0.04). Conclusion The decreases in the delta and theta band are suggested to represent a decrease in the pain specific morphology of the CHEPs, which indicates a diminished pain response after morphine administration. Hence, assessment of spectral indices in single-sweep CHEPs can be used to study cortical mechanisms induced by morphine treatment. PMID:25556985

Comparative effects of cyclo-oxygenase and nitric oxide synthase inhibition on the development and reversal of spinal opioid tolerance

PubMed Central

Powell, Kelly J; Hosokawa, Akiko; Bell, Andrew; Sutak, Maaja; Milne, Brian; Quirion, Remi; Jhamandas, Khem

1999-01-01

This study examined the effects of the COX inhibitors, ketorolac and ibuprofen, and the NOS inhibitor L-NAME for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphine. Repeated administration of intrathecal morphine (15 μg), once daily, resulted in a progressive decline of antinociceptive effect and an increase in the ED50 value in the tailflick and paw pressure tests. Co-administration of ketorolac (30 and 45 μg) or S(+) ibuprofen (10 μg) with morphine (15 μg) prevented the decline of antinociceptive effect and increase in ED50 value. Similar treatment with L-NAME (100 μg) exerted weaker effects. Administration of S(+) but not R(−) ibuprofen (10 mg kg−1) had similar effects on systemic administration of morphine (15 mg kg−1). Intrathecal or systemic administration of the COX or NOS inhibitors did not alter the baseline responses in either tests. Acute keterolac or S(+) ibuprofen also did not potentiate the acute actions of spinal or systemic morphine, but chronic intrathecal administration of these agents increased the potency of acute morphine. In animals already tolerant to intrathecal morphine, subsequent administration of ketorolac (30 μg) with morphine (15 μg) partially restored the antinociceptive effect and ED50 value of acute morphine, reflecting the reversal of tolerance. Intrathecal L-NAME (100 μg) exerted a weaker effect. These data suggest that spinal COX activity, and to a lesser extent NOS activity, contributes to the development and expression of opioid tolerance. Inhibition of COX may represent a useful approach for the prevention as well as reversal of opioid tolerance. PMID:10401553

Effects of aqueous, methanolic and chloroform extracts of rhizome and aerial parts of Valeriana officinalis L. on naloxone-induced jumping in morphine-dependent mice.

PubMed

Sharifzadeh, Mohammad; Hadjiakhoondi, Abbas; Khanavi, Mahnaz; Susanabadi, Maryam

2006-06-01

In the present study, the effects of rhizomes and aerial parts extracts of Valeriana officinalis L. on morphine dependence in mice have been investigated. Animals were treated subcutaneously with morphine (50, 50 and 75 mg/kg) three times daily (10 am, 1 pm and 4 pm) for 3 days, and a last dose of morphine (50 mg/kg) was administered on the fourth day. Withdrawal syndrome (jumping) was precipitated by naloxone (5 mg/kg) which was administered intraperitoneally 2 hours after the last dose of morphine. To study the effects of the aqueous, methanolic and chloroform extracts of both aerial parts and rhizome of the V. officinalis L. on naloxone-induced jumping in morphine-dependent animals, 10 injections of morphine (three administrations each day) for dependence and a dose of 5 mg/kg of naloxone for withdrawal induction were employed. Intraperitoneal injection of different doses (1, 5, 25 and 50 mg/kg) of aqueous, methanolic and chloroform extracts of the rhizome of V. officinalis L. 60 minutes before naloxone injection decreased the jumping response dose-dependently. Pre-treatment of animals with different doses (1, 5, 25, 50 and 100 mg/kg) of aqueous and methanolic extracts of aerial parts of V. officinalis L. 60 minutes before naloxone injection caused a significant decrease on naloxone-induced jumping. The chloroform extract of the aerial parts of V. officinalis L. did not show any significant changes on jumping response in morphine-dependent animals. It is concluded that the extracts of V. officinalis L. could affect morphine withdrawal syndrome via possible interactions with inhibitory neurotransmitters in nervous system.

Dose-response of intrathecal morphine when administered with intravenous ketorolac for post-cesarean analgesia: a two-center, prospective, randomized, blinded trial.

PubMed

Berger, J S; Gonzalez, A; Hopkins, A; Alshaeri, T; Jeon, D; Wang, S; Amdur, R L; Smiley, R

2016-12-01

The appropriate dose of intrathecal morphine for post-cesarean analgesia is unclear. With the inclusion of routine non-steroidal anti-inflammatory drugs, the required dose of morphine may be significantly less than the 200-300μg common a decade ago. We performed a two-center, prospective, randomized, blinded trial comparing three doses of intrathecal morphine, combined with routine intravenous ketorolac, in 144 healthy women undergoing elective cesarean delivery. Patients received an intrathecal injection of hyperbaric bupivacaine 12mg, fentanyl 15μg and a randomized dose of 50, 100, or 150μg morphine in a volume of 2.2mL. Patients received intravenous ketorolac 30mg before leaving the operating room and 15mg intravenously every 6h for the duration of the study (24h). All received postoperative patient-controlled intravenous morphine. The primary endpoint was total intravenous morphine administered postoperatively over 24h, analyzed using mixed model regression. There were no differences between dose groups (or institutions) in intravenous morphine use over 24h. Visual analog scale scores for pain and nausea did not differ. Pruritus was greater in the 100 and 150μg groups than the 50μg group at 6h and 12h, but there was no difference between groups in nausea or pruritus treatments. Respiratory depression or significant sedation did not occur. The dose-response relationship of intrathecal morphine for multimodal post-cesarean analgesia suggests that 50μg produces analgesia similar to that produced by either 100μg or 150μg. Copyright © 2016 Elsevier Ltd. All rights reserved.

Time Dependent Antinociceptive Effects of Morphine and Tramadol in the Hot Plate Test: Using Different Methods of Drug Administration in Female Rats

PubMed Central

Gholami, Morteza; Saboory, Ehsan; Mehraban, Sogol; Niakani, Afsaneh; Banihabib, Nafiseh; Azad, Mohamad-Reza; Fereidoni, Javid

2015-01-01

Morphine and tramadol which have analgesic effects can be administered acutely or chronically. This study tried to investigate the effect of these drugs at various times by using different methods of administration (intraperitoneal, oral, acute and chronic). Sixty adult female rats were divided into six groups. They received saline, morphine or tramadol (20 to 125 mg/Kg) daily for 15 days. A hot plate test was performed for the rats at the 1st, 8th and 15th days. After drug withdrawal, the hot plate test was repeated at the 17th, 19th, and 22nd days. There was a significant correlation between the day, drug, group, and their interaction (P<0.001). At 1st day (d1), both morphine, and tramadol caused an increase in the hot plate time comparing to the saline groups (P<0.001), while there was no correlation between drug administration methods of morphine and/or tramadol. At the 8th day (d8), morphine and tramadol led to the most powerful analgesic effect comparing to the other experimental days (P<0.001). At the 15th day (d15), their effects diminished comparing to the d8. After drug withdrawal, analgesic effect of morphine, and tramadol disappeared. It can be concluded that the analgesic effect of morphine and tramadol increases with the repeated use of them. Thereafter, it may gradually decrease and reach to a level compatible to d1. The present data also indicated that although the analgesic effect of morphine and tramadol is dose-and-time dependent, but chronic exposure to them may not lead to altered nociceptive responses later in life. PMID:25561936

Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants exposed to morphine

PubMed Central

Zwicker, Jill G; Miller, Steven P; Grunau, Ruth E; Chau, Vann; Brant, Rollin; Studholme, Colin; Liu, Mengyuan; Synnes, Anne; Poskitt, Kenneth J; Stiver, Mikaela L; Tam, Emily WY

2017-01-01

Objective To examine the relationship between morphine exposure and growth of the cerebellum and cerebrum in very preterm neonates from early in life to term-equivalent age, as well as to examine morphine exposure and brain volumes in relation to neurodevelopmental outcomes at 18 months corrected age (CA). Study design A prospective cohort of 136 very preterm neonates (24–32 weeks gestational age) was serially scanned with MRI near birth and at term-equivalent age for volumetric measurements of the cerebellum and cerebrum. Motor outcomes were assessed with the Peabody Scales of Motor Development-2 and cognitive outcomes with the Bayley-III at 18 months CA. Generalized least squares models and linear regression models were used to assess relationships between morphine exposure, brain volumes, and neurodevelopmental outcomes. Results A 10-fold increase in morphine exposure was associated with a 5.5% decrease in cerebellar volume, after adjustment for multiple clinical confounders and total brain volume (P=0.04). When infants exposed to glucocorticoids were excluded, the association of morphine was more pronounced, with an 8.2% decrease in cerebellar volume. Morphine exposure was not associated with cerebral volume (P=0.30). Greater morphine exposure also predicted poorer motor (P<0.001) and cognitive outcomes (P=0.006) at 18 months CA, an association mediated, in part, by slower brain growth. Conclusions Morphine exposure in very preterm neonates is independently associated with impaired cerebellar growth in the neonatal period and poorer neurodevelopmental outcomes in early childhood. Alternatives to better manage pain in preterm neonates that optimize brain development and functional outcomes are urgently needed. PMID:26763312

Determination of morphine and codeine in urine using poly(dimethylsiloxane) microchip electrophoresis with electrochemical detection.

PubMed

Zhang, Qian-Li; Xu, Jing-Juan; Li, Xiang-Yun; Lian, Hong-Zhen; Chen, Hong-Yuan

2007-01-04

In this paper, a poly(dimethylsiloxane) (PDMS) microchip with electrochemical (EC) detection was developed for rapid separation and detection of morphine and codeine. It was found that morphine and codeine were well separated within 140 s in phosphate buffer solution (PBS) (pH 6.6, 40 mM)-beta-cyclodextrin (beta-CD) (20 mM)-acetonitrile (30%, v/v). The detection limit was 0.2 microM for morphine and 1 microM for codeine. The protocol was successfully applied to monitoring the amount of morphine and codeine in human urine. Compared with the conventional methods, the presented method had many advantages such as lower instrument cost, less reagent consumption and shorter analysis time.

Dispositional study of opioids in mice pretreated with sympathomimetic agents.

PubMed

Dambisya, Y M; Chan, K; Wong, C L

1992-08-01

Brain and plasma levels of morphine and codeine were determined by an assay method involving solid-phase extraction and ion-pair reversed phase HPLC. Detection was by a variable wavelength UV-detector (for codeine) and an amperometric electro-chemical detector (for morphine) coupled in series. Ephedrine or phenylpropanolamine pretreatment did not interfere with the plasma disposition of morphine, evidenced by overlapping plasma concentration-time profiles. Brain opioid levels were equally unaffected by sympathomimetic pretreatment. The relative ratios of brain to plasma concentrations at the time corresponding to the respective peak anti-nociceptive activity for morphine and codeine revealed no significant differences. It is concluded that single doses of ephedrine and phenylpropanolamine do not affect the disposition of morphine and codeine in mice.

Pre-conditioned place preference treatment of chloral hydrate interrupts the rewarding effect of morphine.

PubMed

Sun, YongMei; Zong, Wei; Zhou, MuRu; Ma, YuanYe; Wang, JianHong

2015-08-01

The medical use of morphine as a pain killer is hindered by its side effects including dependence and further addiction. As the prototypical μ receptor agonist, morphine's rewarding effect can be measured by conditioned place preference (CPP) paradigms in animals. Chloral hydrate is a clinical sedative. Using a morphine CPP paradigm that mainly contains somatosensory cues, we found that pre-CPP treatment in rats using chloral hydrate for 6 consecutive days could disrupt the establishment of CPP in a U shape. Chloral hydrate had no effect on the body weight of rats. Our results indicate that prior treatment with chloral hydrate can interrupt the rewarding effect of morphine. Copyright © 2015 Elsevier Inc. All rights reserved.

Does adding low doses of oral naltrexone to morphine alter the subsequent opioid requirements and side effects in trauma patients?

PubMed

Farahmand, Shervin; Ahmadi, Omid; Dehpour, Ahmadreza; Khashayar, Patricia

2012-01-01

The present study aims to assess the influence of ultra-low doses of opioid antagonists on the analgesic properties of opioids and their side effects. In the present randomized, double-blind controlled trial, the influence of the combination of ultra-low-dose naltrexone and morphine on the total opioid requirement and the frequency of the subsequent side effects was compared with that of morphine alone (added with placebo) in patients with trauma in the upper or lower extremities. Although the morphine and naltrexone group required 0.04 mg more opioids during the study period, there was no significant difference between the opioid requirements of the 2 groups. Nausea was less frequently reported in patients receiving morphine and naltrexone. The combination of ultra-low-dose naltrexone and morphine in extremity trauma does not affect the opioid requirements; it, however, lowers the risk of nausea. Copyright © 2012 Elsevier Inc. All rights reserved.

Electromechanical coupling in rat basilar artery in response to morphine.

PubMed

Waters, A; Harder, D R

1983-12-01

Force development, intracellular membrane potential (Em), and voltage vs. current curves were measured in rat basilar artery to help elucidate the mechanism of action of morphine sulfate and a synthetic narcotic, meperidine hydrochloride, on this preparation. Morphine sulfate caused a dose-dependent contraction of these vessels, which was reversible with naloxone. Electrical studies show that morphine may act upon this vascular smooth muscle preparation by decreasing potassium conductance (gk). This hypothesis is supported by the findings that morphine sulfate depolarized these cells and increased the input resistance (rin) determined by the application of rectangular hyperpolarizing and depolarizing current pulses through the microelectrode during impalement and recording of the associated voltage changes (delta V). Meperidine hydrochloride had significantly less effect on this preparation than morphine sulfate. Further studies show that the vehicular medium used for the commercially available preparation of naloxone (viz. the methyl and propyl esters of p-hydroxybenzoic acid in a ratio of 9:1) is, in vitro, a vasodilator of cerebral vascular smooth muscle.

Inhibitory effect of harmane on morphine-dependent Guinea pig ileum.

PubMed

Aricioglu, Feyza; Utkan, Tijen

2003-12-01

Studies on the occurrence and properties of b-carbolines structurally related to harmala alkaloids have gained attention since it was hypothesized that some of these compounds play a role in processes of substance abuse and dependence. This study investigates the effects of harmane on naloxone-precipitated withdrawal syndrome in morphine-dependent guinea pig ileum. Segments of ilea from starved male guinea pigs were obtained and fixed at a resting tension of 1 g in an organ bath containing 10(-6) M morphine in Tyrode solution at 37 degrees C, which was bubbled with 95% O(2) and 5% CO(2). Tissues were incubated in 10(-6) M morphine containing Tyrode solution for 4 hours before harmane was added. Naloxone and harmane had no effect on naive ilea. Naloxone (10(-6) M) contracted morphine-dependent ilea. Harmane significantly inhibited the contractile response to naloxone in a dose-dependent manner (10(-7) M = 24%; 10(-6) M = 49.3%; 10(-5) = 70%). These results suggest that harmane may have beneficial effects on morphine withdrawal syndrome.

Effect of Bacopasides on acquisition and expression of morphine tolerance.

PubMed

Rauf, Khalid; Subhan, Fazal; Abbas, Muzaffar; Badshah, Amir; Ullah, Ihsan; Ullah, Sami

2011-07-15

Opioids are extensively used for the management of both chronic malignant and non malignant pains. One major serious limitation associated with chronic use of opioids is the development of tolerance to its analgesic effect. The effect of Bacopa monnieri, a renowned ayurvedic medicine for acquisition and expression of morphine tolerance in mice, was investigated. Bacopa monnieri, n-Butanol fraction was analyzed on High performance liquid chromatography (HPLC), for Bacopaside A major components i.e. Bacoside A(3), Bacopaside ll and Bacosaponin C. Antinociceptive effect of n-Butanol extract of Bacopa monnieri (n Bt-ext BM) (5, 10 and 15 mg/kg) was assessed on hot plate. Effect of different doses of n Bt-ext BM on morphine antinociception was also assessed. n Bt-ext BM was also screened for development of tolerance to antinociceptive effect of Bacopa monnieri by administering 15 mg/kg n Bt-ext BM for seven days. Tolerance to morphine analgesia was induced in mice by administering intraperitoneally (I.P.) 20 mg/kg morphine twice daily for five days. Acute and Chronic administration of 5, 10 and 15 mg/kg n Bt-ext BM significantly reduced both expression and development of tolerance to morphine analgesia in mice. Additionally, Bacopa monnieri was found to enhance antinociceptive effect of morphine in intolerant animals. However, no tolerance to Bacopa monnieri antinociceptive effect was observed in seven days treatment schedule. These findings indicate effectiveness of Bacopa monnieri for management of morphine tolerance. Copyright © 2011 Elsevier GmbH. All rights reserved.

Agmatine inhibits chronic morphine exposure-induced impairment of hippocampal neural progenitor proliferation in adult rats.

PubMed

Liu, Ying; Lu, Guan-Yi; Chen, Wen-Qiang; Li, Yun-Feng; Wu, Ning; Li, Jin

2018-01-05

Our previous studies have shown that agmatine inhibited opioid dependence, yet the neural mechanism remains unclear. Growing evidence showed that opioids decrease neurogenesis in the adult hippocampal subgranular zone by inhibiting neural progenitor proliferation. However, whether agmatine affects chronic opioid exposure-induced impairment to hippocampal neural progenitor cell proliferation remains unknown. In the present study, we investigated the role of agmatine in hippocampal neural progenitors in morphine dependence rats. We found that chronic administration of morphine for 12 days induced morphine dependence in rats. This treatment not only decreased the proliferation of hippocampal neural progenitors in the granule cell layer, but also decreased the levels of hippocampal cAMP, pCREB and BDNF. However, these alterations can be restored to normal levels by co-treatment of agmatine (10mg/kg, s.c.). In vitro treatment with agmatine (10µM) for two days significantly increased proliferation of the cultured hippocampal neural progenitors. Concurrent treatment of agmatine (10µM) with morphine (10 or 50µM) reversed the supression of morphine-induced neural progenitor proliferation. In conclusion, we found that agmatine abolished chronic morphine-induced decrease in proliferation of hippocampal progenitors in vivo and in vitro, which may be due to the increase in cAMP-CREB-BDNF signaling. The enhancement of agmatine to proliferation of hippocampal progenitors may be one of the important mechanisms involved in the inhibition of morphine dependence by agmatine. Copyright © 2017. Published by Elsevier B.V.

Combined action of MK-801 and ceftriaxone impairs the acquisition and reinstatement of morphine-induced conditioned place preference, and delays morphine extinction in rats.

PubMed

Fan, Yaodong; Niu, Haichen; Rizak, Joshua D; Li, Ling; Wang, Guimei; Xu, Liqi; Ren, He; Lei, Hao; Yu, Hualin

2012-10-01

It is well established that glutamate and its receptors, particularly the N-methyl-D-aspartate receptor (NMDAR), play a significant role in addiction and that the inhibition of glutamatergic hyperfunction reduces addictive behaviors in experimental animals. Specifically, NMDAR antagonists such as MK-801, and an inducer of the expression of glutamate transporter subtype-1 (GLT-1) (ceftriaxone) are known to inhibit addictive behavior. The purpose of this study was to determine whether the combined action of a low dose of MK-801 and a low dose of ceftriaxone provides better inhibition of the acquisition, extinction, and reinstatement of morphine-induced conditioned place preference (CPP) than either compound alone. A morphine-paired CPP experiment was used to study the effects of low doses of MK-801, ceftriaxone and a combination of both on reward-related memory (acquisition, extinction, and reinstatement of morphine preference) in rats. A low dose of neither MK-801 (0.05 mg/kg, i.p.) nor ceftriaxone (25 mg/kg, i.p.) alone effectively impaired CPP behaviors. However, when applied in combination, they reduced the acquisition of morphine-induced CPP and completely prevented morphine reinstatement. Their combination also notably impaired the extinction of morphine-induced CPP. The combined action of a low dose of an NMDAR antagonist (MK-801) and GLT-1 activation by ceftriaxone effectively changed different phases of CPP behavior.

An enriched environment reduces the stress level and locomotor activity induced by acute morphine treatment and by saline after chronic morphine treatment in mice.

PubMed

Xu, Jia; Sun, Jinling; Xue, Zhaoxia; Li, Xinwang

2014-06-18

This study investigated the relationships among an enriched environment, stress levels, and drug addiction. Mice were divided randomly into four treatment groups (n=12 each): enriched environment without restraint stress (EN), standard environment without restraint stress (SN), enriched environment with restraint stress (ES), and standard environment with restraint stress (SS). Mice were reared in the respective environment for 45 days. Then, the ES and SS groups were subjected to restraint stress daily (2 h/day) for 14 days, whereas the EN and SN groups were not subjected to restraint stress during this stage. The stress levels of all mice were tested in the elevated plus maze immediately after exposure to restraint stress. After the 2-week stress testing period, mice were administered acute or chronic morphine (5 mg/kg) treatment for 7 days. Then, after a 7-day withdrawal period, the mice were injected with saline (1 ml/kg) or morphine (5 mg/kg) daily for 2 days to observe locomotor activity. The results indicated that the enriched environment reduced the stress and locomotor activity induced by acute morphine administration or saline after chronic morphine treatment. However, the enriched environment did not significantly inhibit locomotor activity induced by morphine challenge. In addition, the stress level did not mediate the effect of the enriched environment on drug-induced locomotor activity after acute or chronic morphine treatment.

Low-Dose Cannabinoid Type 2 Receptor Agonist Attenuates Tolerance to Repeated Morphine Administration via Regulating μ-Opioid Receptor Expression in Walker 256 Tumor-Bearing Rats.

PubMed

Zhang, Mingyue; Wang, Kun; Ma, Min; Tian, Songyu; Wei, Na; Wang, Guonian

2016-04-01

Morphine is widely used in patients with moderate and severe cancer pain, whereas the development of drug tolerance remains a major problem associated with opioid use. Previous studies have shown that cannabinoid type 2 (CB2) receptor agonists induce morphine analgesia, attenuate morphine tolerance in normal and neuropathic pain animals, induce transcription of the μ-opioid receptor (MOR) gene in Jurkat T cells, and increase morphine analgesia in cancer pain animals. However, no studies of the effects of CB2 receptor agonists on morphine tolerance in cancer pain have been performed. Therefore, we investigated the effect of repeated intrathecal (IT) injection of the low-dose CB2 receptor agonist AM1241 on the development of morphine tolerance in walker 256 tumor-bearing rats. We also tested the influence of the CB2 receptor agonist AM1241 on MOR protein and messenger ribonucleic acid (mRNA) expression in the rat spinal cord and dorsal root ganglia (DRG). Walker 256 cells were implanted into the plantar region of each rat's right hindpaw. Tumor-bearing rats received IT injection of the CB2 receptor agonist AM1241 or antagonist AM630 with or without morphine subcutaneously twice daily for 8 days. Rats receiving drug vehicle only served as the control group. Mechanical paw withdrawal threshold and thermal paw withdrawal latency were assessed by a von Frey test and hot plate test 30 minutes after drug administration every day. MOR protein and mRNA expression in the spinal cord and DRG were detected after the last day (day 8) of drug administration via Western blot and real-time reverse transcription polymerase chain reaction. The data were analyzed via analysis of variance followed by Student t test with Bonferroni correction for multiple comparisons. Repeated morphine treatments reduced the mechanical withdrawal threshold and thermal latency. Coadministration of a nonanalgetic dose of the CB2 receptor agonist AM1241 with morphine significantly inhibited the development of morphine tolerance and increased the MOR protein expression in the spinal cord and DRG and mRNA expression in the spinal cord in tumor-bearing rats. Our findings indicate that IT injection of a nonanalgetic dose of a CB2 receptor agonist increased the analgesia effect and alleviated tolerance to morphine in tumor-bearing rats, potentially by regulating MOR expression in the spinal cord and DRG. This receptor may be a new target for prevention of the development of opioid tolerance in cancer pain.

Recent Advances in the Synthesis of Morphine and Related Alkaloids

NASA Astrophysics Data System (ADS)

Chida, Noritaka

Morphine, an alkaloid isolated from the opium poppy, has been widely used as an analgesic, and has been a fascinating synthetic target of organic chemists. After the first total synthesis reported in 1952, a number of synthetic studies toward morphine have been reported, and findings obtained in such studies have greatly contributed to the progress of synthetic organic chemistry as well as medicinal chemistry. This review provides an overview of recent studies toward the total synthesis of morphine and related alkaloids. Work reported in the literature since 2004 will be reviewed.

Improvement of Morphine-Mediated Analgesia by Inhibition of β-Arrestin 2 Expression in Mice Periaqueductal Gray Matter

PubMed Central

Li, Yuting; Liu, Xing; Liu, Chang; Kang, Jiuhong; Yang, Jingyu; Pei, Gang; Wu, Chunfu

2009-01-01

Morphine is a well-known μ-opioid receptor (MOR) agonist and an efficient analgesic, but its long-term use inevitably leads to drug addiction and tolerance. Here, we show that specific inhibition of β-arrestin2 with its siRNA lentivirus microinjected in mice periaqueductal gray matter (PAG) significantly improved both acute and chronic morphine analgesia and delayed the tolerance in the hotplate test. The specific effect of β-arrestin2 was proven by overexpression or knockdown of its homology β-arrestin1 in PAG, which showed no significant effects on morphine analgesia. These findings suggest that specific siRNA targeting β-arrestin2 may constitute a new approach to morphine therapy and other MOR agonist-mediated analgesia and tolerance. PMID:19399231

Intracerebroventricular morphine for refractory cancer pain: transitioning to the home setting.

PubMed

Adolph, Michael D; Stretanski, Michael F; McGregor, John M; Rawn, Bonnie L; Ross, Patrick M; Benedetti, Costantino

2010-08-01

Refractory cancer pain may be effectively controlled by titrating intracerebroventricular (ICV) preservative-free opioid. In this case report, a continuous infusion of ICV morphine permitted our patient with lung cancer and painful spinal metastases to be discharged to home hospice with family. The approach exploits the high potency of morphine injected into cerebrospinal fluid (CSF). Sterile, injectable, preservative-free morphine is directly infused into CSF through a subcutaneous Ommaya reservoir placed under the scalp by a neurosurgeon, with an attached catheter passed through a burr hole in the skull with its tip in a cerebral ventricle. Although investigators have described home care of patients receiving intraspinal analgesics, no report describes the process of transitioning the patient receiving continuous ICV morphine infusion to the home setting.

Seizures induced by carbachol, morphine, and leucine-enkephalin: a comparison.

PubMed

Snead, O C

1983-04-01

The electrical, behavioral, and pharmacological properties of seizures induced by morphine, leucine-enkephalin, and the muscarinic cholinergic agonist carbachol were examined and compared. Low-dose carbachol given intracerebroventricularly (ICV) produced seizures similar electrically to those produced by ICV morphine and leucine-enkephalin, although there was some difference in site of subcortical origin of onset. Carbachol and morphine were similar in that they had the same anticonvulsant profile, produced similar behavioral changes, caused generalized absence seizures in low doses and generalized convulsive seizures in high doses, and were capable of chemical kindling. However, opiate-induced seizures were not overcome by cholinergic antagonists, nor were carbachol seizures blocked by opiate antagonists. These data suggest that there may be a common noncholinergic, nonopiatergic system involved in mediating carbachol- and morphine-induced seizures but not enkephalin seizures.

The effect of nimodipine on memory impairment during spontaneous morphine withdrawal in mice: Corticosterone interaction.

PubMed

Vaseghi, Golnaz; Rabbani, Mohammed; Hajhashemi, Valiollah

2012-11-15

Effects of the nimodipine, L-type calcium channel antagonist, has been studied on memory loss caused by spontaneous morphine withdrawal in mice. Mice were made dependent by increasing doses of morphine over three days. Memory was evaluated using object recognition task, which is based on tendency of rodents to exploration of new objects. The test was comprised of three sections: 15 min habitation, 12 min first trial and 5 min test trial. Recognition index was evaluated 4h after the last dose of morphine. Nimodipine was administrated either in chronic form (1, 5 and 10mg/kg) with daily doses of morphine or it was given as a single injection (5 and 10mg/kg) on the last day. Nimodipine in both treatment forms prevented the memory impairment following spontaneous morphine withdrawal. Corticosterone concentration was increased in brain and blood of mice during abstinence phase and pretreatment with nimodipine prevented the increase in brain and blood corticosterone concentration. The results show that blockade of L-type calcium channels improves memory deficits caused by morphine withdrawal. This indicates that some kind of treatments, such as nimodipine, administrated over the acute withdrawal phase, can prevent memory deficit during withdrawal. Copyright © 2012 Elsevier B.V. All rights reserved.

Treatment of severe cancer pain by low-dose continuous subcutaneous morphine.

PubMed

Drexel, H; Dzien, A; Spiegel, R W; Lang, A H; Breier, C; Abbrederis, K; Patsch, J R; Braunsteiner, H

1989-02-01

In a prospective and intraindividually controlled trial, we have compared the efficacy and safety of a continuous subcutaneous morphine infusion with conventional intermittent oral or subcutaneous morphine application. Twenty-eight in-patients with cancer pain received a short-term infusion lasting 2-42 days, and 8 out-patients underwent long-term infusion from 49 to 197 days during the terminal stage of their disease. Continuous subcutaneous morphine infusion significantly (P less than 0.001) improved both pain and quality of life when compared to conventional morphine application. With continuous infusion, 5-48 mg (median 19 mg) of morphine was required daily, significantly (P less than 0.001) less than the 10-90 mg (median 50 mg) necessary with conventional use. As a result of lower dosage, side effects under continuous infusion were infrequent and mild. Constipation occurred in 3 of the 36 patients and was always controlled by the addition of laxatives; no nausea, sedation or respiratory depression were observed. Signs of tolerance developed in 2 patients on long-term infusion, but the use of continuous subcutaneous methadone for 2 weeks reversed the tolerance. The study presented indicates that low-dose continuous subcutaneous morphine provides a valuable treatment modality for severe terminal cancer pain exhibiting a high degree of both efficacy and safety.

Mitragynine Attenuates Withdrawal Syndrome in Morphine-Withdrawn Zebrafish

PubMed Central

Khor, Beng-Siang; Amar Jamil, Mohd Fadzly; Adenan, Mohamad Ilham; Chong Shu-Chien, Alexander

2011-01-01

A major obstacle in treating drug addiction is the severity of opiate withdrawal syndrome, which can lead to unwanted relapse. Mitragynine is the major alkaloid compound found in leaves of Mitragyna speciosa, a plant widely used by opiate addicts to mitigate the harshness of drug withdrawal. A series of experiments was conducted to investigate the effect of mitragynine on anxiety behavior, cortisol level and expression of stress pathway related genes in zebrafish undergoing morphine withdrawal phase. Adult zebrafish were subjected to two weeks chronic morphine exposure at 1.5 mg/L, followed by withdrawal for 24 hours prior to tests. Using the novel tank diving tests, we first showed that morphine-withdrawn zebrafish display anxiety-related swimming behaviors such as decreased exploratory behavior and increased erratic movement. Morphine withdrawal also elevated whole-body cortisol levels, which confirms the phenotypic stress-like behaviors. Exposing morphine-withdrawn fish to mitragynine however attenuates majority of the stress-related swimming behaviors and concomitantly lower whole-body cortisol level. Using real-time PCR gene expression analysis, we also showed that mitragynine reduces the mRNA expression of corticotropin releasing factor receptors and prodynorphin in zebrafish brain during morphine withdrawal phase, revealing for the first time a possible link between mitragynine's ability to attenuate anxiety during opiate withdrawal with the stress-related corticotropin pathway. PMID:22205946

Pavlovian conditioning analysis of morphine tolerance.

PubMed

Siegel, S

1978-01-01

It has been demonstrated that many conditional responses to a variety of drugs are opposite in direction to the unconditional effects of the drug, and the conditioning analysis of morphine tolerance emphasizes the fact that subjects with a history of morphine administration display morphine-compensatory conditional responses when confronted with the usual administration procedure but without the drug. Thus, when the drug is presented in the context of the usual administration cues, these conditional morphine-compensatory responses would be expected to attenuate the drug-induced unconditional responses, thereby decreasing the observed response to the drug. Research has been summarized which supports this compensatory conditioning model of tolerance by demonstrating that the display of tolerance is specific to the environment in which the drug has been previously administered. Further evidence supporting this theory of tolerance has been provided by studies establishing that extinction, partial reinforcement, and latent inhibition--non-pharmacological manipulations known to be effective in generally affecting the display of conditional responses--similarly affect the display of morphine tolerance. Additional research has suggested many parallels between learning and morphine tolerance: Both processes exhibit great retention, both are disrupted by electroconvulsive shock and frontal cortical stimulation, both are retarded by inhibitors of protein synthesis, and both are facilitated by antagonists of these metabolic inhibitors.

Examining the effect of the CaMKII inhibitor administration in the locus coeruleus on the naloxone-precipitated morphine withdrawal signs in rats.

PubMed

Navidhamidi, M; Semnanian, S; Javan, M; Goudarzvand, M; Rohampour, K; Azizi, H

2012-01-15

Drug addiction is an occurrence with physiological, psychological, and social outcomes. Repeated drug exposure causes neuronal adaptations and dependency. It has been shown that CaMKIIα enzyme contributes to morphine dependency. The locus coeruleus nucleus has been implied in the morphine withdrawal syndrome. This research focuses on the behavioral and molecular adaptations that occur in the locus coeruleus neurons in response to the chronic morphine exposure. Adult male Wistar rats were injected by morphine sulfate (10 mg/kg/s.c.) at an interval of 12 h for a period of nine subsequent days. On the tenth day, naloxone (1 mg/kg/i.p.) was injected 2 h after the morphine administration. Somatic withdrawal signs were investigated for 30 min. We concluded that the inhibition of CaMKIIα by administration of KN-93, the specific inhibitor of this enzyme, significantly attenuated some of the withdrawal signs. In molecular method, the expression of CaMKIIα protein has been enhanced in locus coeruleus of the morphine dependent rats. These findings indicate that CaMKIIα may be involved in the modulation of the naloxone-induced withdrawal syndrome, and treatment with KN-93 may have some effects on this system. Copyright © 2011 Elsevier B.V. All rights reserved.

Acupuncture and pharmacopuncture are as effective as morphine or carprofen for postoperative analgesia in bitches undergoing ovariohysterectomy.

PubMed

Luna, Stelio Pacca Loureiro; Martino, Irene Di; Lorena, Silvia Elaine Rodolfo de Sá; Capua, Maria Luisa Buffo de; Lima, Alfredo Feio da Maia; Santos, Bianca Paiva Costa Rodrigues dos; Brondani, Juliana Tabarelli; Vesce, Giancarlo

2015-12-01

To investigate the analgesic effect of acupuncture (AP) or micro-dose pharmacopuncture (PA), using carprofen or morphine, in bitches undergoing ovariohysterectomy (OHE). Thirty five dogs were randomly assigned to five groups after sedation with acepromazine IM: AP, 0.5 mg.kg(-1) of morphine subcutaneously (SC), 4 mg.kg(-1) of carprofen SC, and PA with 0.05 mg.kg(-1) of morphine or 0.4 mg.kg(-1) of carprofen. Anaesthesia was induced with propofol and maintained with isoflurane. Pain was assessed after OHE by a blind observer for 24h, by dynamic visual analogue scale (DIVAS), Glasgow (CMPS-SF), Melbourne (UMPS) and Colorado University pain scale (CSU). Animals reaching 33% of the UMPS score received rescue analgesia with morphine IM. Non parametric data were analysed by Kruskal-Wallis or Friedman tests where applicable, followed by Dunn's test. Parametric data were analysed by two way ANOVA, followed by Tukey test. There were no differences among groups in number of rescue analgesia. Except for the DIVAS score where animals treated with morphine had the lowest score compared with AP and carprofen, at 1h after surgery, there were no other differences among groups. Acupuncture or pharmacopuncture were equally effective as morphine or carprofen to control postoperative pain in bitches undergoing ovariohysterectomy.

Modulation by alpha-difluoromethyl-ornithine and aminoguanidine of pain threshold, morphine analgesia and tolerance.

PubMed

Lu, Gang; Su, Rui-Bin; Li, Jin; Qin, Bo-Yi

2003-10-08

The effects of alpha-difluoromethyl-ornithine (DFMO) and aminoguanidine, which might influence the metabolism of endogenous agmatine, on pain threshold, morphine analgesia and tolerance were investigated in mice. In the mouse acetic acid writhing test, intracerebroventricular (i.c.v.) injection of DFMO or aminoguanidine significantly elevated the pain threshold as indicated by a decrease in the number of writhings. DFMO or aminoguanidine obviously increased the analgesic effect of morphine in the mouse acetic acid writhing test and the mouse heat radiation tail-flick assay. These effects of DFMO and aminoguanidine were antagonized by idazoxan (3 mg/kg, i.p.), which is a selective antagonist of the imidazoline receptor. In the mouse heat radiation tail-flick assay, aminoguanidine significantly prolonged the tail-flick latency of animals, suggesting that the pain threshold was elevated. Furthermore, both DFMO and aminoguanidine enhanced morphine analgesia and inhibited acute morphine tolerance in the mouse heat radiation tail-flick assay. Neither DFMO nor aminoguanidine inhibited the activity of nitric oxide synthase in different brain areas in mice in vivo. These results indicate that the substances involved in the metabolism of endogenous agmatine could modulate the pain threshold, morphine analgesia and tolerance, indicating the possible role of endogenous agmatine in the pharmacological effects of morphine.

Chronic Morphine Treatment Reduces Recovery from Opioid Desensitization

PubMed Central

Dang, Vu C.; Williams, John T.

2013-01-01

Tolerance and dependence result from long-term exposure to opioids, and there is growing evidence linking acute receptor desensitization to these more long-term processes. Receptor desensitization encompasses a series of events leading to the loss of receptor function and internalization. This study examines the onset and recovery from desensitization in locus ceruleus neurons recorded in brain slices taken from animals that have been chronically treated with morphine. After chronic morphine treatment, desensitization was altered as follows. First, the rate of desensitization was increased. Second, recovery from desensitization was always incomplete, even after a brief (1–2 min) exposure to agonist. This contrasts with experiments in controls in which recovery from desensitization, after a brief exposure to agonist, was complete within 25 min. Finally, morphine-6-β-D-glucuronide, a metabolite of morphine that was ineffective at causing desensitization in controls, induced significant desensitization in slices from morphine-treated animals. When brain slices from controls were treated with inhibitors of PKC or monensin, agents known to compromise G-protein-coupled receptor resensitization, desensitization was increased, and recovery was significantly reduced. These results indicate that receptor resensitization maintains signaling during periods of intense and sustained stimulation. After chronic morphine treatment, desensitization is potentiated, and receptor resensitization is compromised. PMID:15342737

Morphine induces endocytosis of neuronal μ-opioid receptors through the sustained transfer of Gα subunits to RGSZ2 proteins

PubMed Central

Rodríguez-Muñoz, María; de la Torre-Madrid, Elena; Sánchez-Blázquez, Pilar; Garzón, Javier

2007-01-01

Background In general, opioids that induce the recycling of μ-opioid receptors (MORs) promote little desensitization, although morphine is one exception to this rule. While morphine fails to provoke significant internalization of MORs in cultured cells, it does stimulate profound desensitization. In contrast, morphine does promote some internalization of MORs in neurons although this does not prevent this opioid from inducing strong antinociceptive tolerance. Results In neurons, morphine stimulates the long-lasting transfer of MOR-activated Gα subunits to proteins of the RGS-R7 and RGS-Rz subfamilies. We investigated the influence of this regulatory process on the capacity of morphine to promote desensitization and its association with MOR recycling in the mature nervous system. In parallel, we also studied the effects of [D-Ala2, N-MePhe4, Gly-ol5] encephalin (DAMGO), a potent inducer of MOR internalization that promotes little tolerance. We observed that the initial exposure to icv morphine caused no significant internalization of MORs but rather, a fraction of the Gα subunits was stably transferred to RGS proteins in a time-dependent manner. As a result, the antinociception produced by a second dose of morphine administered 6 h after the first was weaker. However, this opioid now stimulated the phosphorylation, internalization and recycling of MORs, and further exposure to morphine promoted little tolerance to this moderate antinociception. In contrast, the initial dose of DAMGO stimulated intense phosphorylation and internalization of the MORs associated with a transient transfer of Gα subunits to the RGS proteins, recovering MOR control shortly after the effects of the opioid had ceased. Accordingly, the recycled MORs re-established their association with G proteins and the neurons were rapidly resensitized to DAMGO. Conclusion In the nervous system, morphine induces a strong desensitization before promoting the phosphorylation and recycling of MORs. The long-term sequestering of morphine-activated Gα subunits by certain RGS proteins reduces the responses to this opioid in neurons. This phenomenon probably increases free Gβγ dimers in the receptor environment and leads to GRK phosphorylation and internalization of the MORs. Although, the internalization of the MORs permits the transfer of opioid-activated Gα subunits to the RGSZ2 proteins, it interferes with the stabilization of this regulatory process and recycled MORs recover the control on these Gα subunits and opioid tolerance develops slowly. PMID:17634133

Does adding ketamine to morphine patient-controlled analgesia safely improve post-thoracotomy pain?

PubMed

Mathews, Timothy J; Churchhouse, Antonia M D; Housden, Tessa; Dunning, Joel

2012-02-01

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'is the addition of ketamine to morphine patient-controlled analgesia (PCA) following thoracic surgery superior to morphine alone'. Altogether 201 papers were found using the reported search, of which nine represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. This consisted of one systematic review of PCA morphine with ketamine (PCA-MK) trials, one meta-analysis of PCA-MK trials, four randomized controlled trials of PCA-MK, one meta-analysis of trials using a variety of peri-operative ketamine regimes and two cohort studies of PCA-MK. Main outcomes measured included pain score rated on visual analogue scale, morphine consumption and incidence of psychotomimetic side effects/hallucination. Two papers reported the measurements of respiratory function. This evidence shows that adding ketamine to morphine PCA is safe, with a reported incidence of hallucination requiring intervention of 2.9%, and a meta-analysis finding an incidence of all central nervous system side effects of 18% compared with 15% with morphine alone, P = 0.31, RR 1.27 with 95% CI (0.8-2.01). All randomized controlled trials of its use following thoracic surgery found no hallucination or psychological side effect. All five studies in thoracic surgery (n = 243) found reduced morphine requirements with PCA-MK. Pain scores were significantly lower in PCA-MK patients in thoracic surgery papers, with one paper additionally reporting increased patient satisfaction. However, no significant improvement was found in a meta-analysis of five papers studying PCA-MK in a variety of surgical settings. Both papers reporting respiratory outcomes found improved oxygen saturations and PaCO(2) levels in PCA-MK patients following thoracic surgery. We conclude that adding low-dose ketamine to morphine PCA is safe and post-thoracotomy may provide better pain control than PCA with morphine alone (PCA-MO), with reduced morphine consumption and possible improvement in respiratory function. These studies thus support the routine use of PCA-MK instead of PCA-MO to improve post-thoracotomy pain control.

Effects of environmental enrichment on behavioral deficits and alterations in hippocampal BDNF induced by prenatal exposure to morphine in juvenile rats.

PubMed

Ahmadalipour, A; Sadeghzadeh, J; Vafaei, A A; Bandegi, A R; Mohammadkhani, R; Rashidy-Pour, A

2015-10-01

Prenatal morphine exposure throughout pregnancy can induce a series of neurobehavioral and neurochemical disturbances by affecting central nervous system development. This study was designed to investigate the effects of an enriched environment on behavioral deficits and changes in hippocampal brain-derived neurotrophic factor (BDNF) levels induced by prenatal morphine in rats. On pregnancy days 11-18, female Wistar rats were randomly injected twice daily with saline or morphine. Offspring were weaned on postnatal day (PND) 21. They were subjected to a standard rearing environment or an enriched environment on PNDs 22-50. On PNDs 51-57, the behavioral responses including anxiety and depression-like behaviors, and passive avoidance memory as well as hippocampal BDNF levels were investigated. The light/dark (L/D) box and elevated plus maze (EPM) were used for the study of anxiety, forced swimming test (FST) was used to assess depression-like behavior and passive avoidance task was used to evaluate learning and memory. Prenatal morphine exposure caused a reduction in time spent in the EPM open arms and a reduction in time spent in the lit side of the L/D box. It also decreased step-through latency and increased time spent in the dark side of passive avoidance task. Prenatal morphine exposure also reduced immobility time and increased swimming time in FST. Postnatal rearing in an enriched environment counteracted with behavioral deficits in the EPM and passive avoidance task, but not in the L/D box. This suggests that exposure to an enriched environment during adolescence period alters anxiety profile in a task-specific manner. Prenatal morphine exposure reduced hippocampal BDNF levels, but enriched environment significantly increased BDNF levels in both saline- and morphine-exposed groups. Our results demonstrate that exposure to an enriched environment alleviates behavioral deficits induced by prenatal morphine exposure and up-regulates the decreased levels of BDNF. BDNF may contribute to the beneficial effects of an enriched environment on prenatal morphine-exposed to rats. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Review of Prescribing Practices for Intermittent Bolus Administration of Morphine

PubMed Central

Sine, Keith; Vaillancourt, Régis; Pascuet, Elena; Martelli, Brenda; Lamontagne, Christine; Ellis, Jacqueline; Wong, Elaine; Gaboury, Isabelle

2011-01-01

Background: Several changes to medication safety practices were proposed in a pediatric hospital, including changing the period of patient observation after administration of opioids and limiting the availability of various concentrations of morphine in the patient care unit. Objective: To document and review postoperative pain management for children on a surgical ward, specifically with regard to intermittent IV bolus administration of morphine, to help in assessing the impact of the proposed nursing practice changes. Methods: Data were collected from records for narcotics and controlled drugs for the surgical ward over a 3-month period (April to June 2006). For each patient, data had been recorded for up to 7 consecutive days after surgery. A patient’s data were included in the review if he or she had received at least 2 doses of morphine by IV bolus, except for the review of weight-based dosing pattern (mg/kg), for which all patients who had received at least one dose of IV morphine were included. Results: Charts for 193 patients were audited. Of these, 163 patients (84.5%) had recieved up to 0.1 mg/kg per dose, and 53 (27.5%) had received only one dose of morphine. Among patients who received more than one dose, the median dose was 0.080 mg/kg on day 1, with a decrease by day 5 to 0.065 mg/kg. Most patients received morphine over the first 2 days after surgery. The median time elapsed between doses was 4.3 h on day 1 and 6.2 h on day 2. Of the 1020 doses included in the analysis, most (801 [78.5%]) were 4 mg or less. Conclusion: The intermittent administration of IV bolus doses of morphine at the study hospital followed common standards for the treatment of postoperative pain. Most doses were no more than 4 mg. On the basis of this information, only 2-mg vials of morphine are now stocked on the ward. The hospital’s change in monitoring practices will increase the surveillance of patients receiving IV bolus doses of morphine. PMID:22479025

Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast)

PubMed Central

Hutchinson, Mark R.; Lewis, Susannah S.; Coats, Benjamen D.; Skyba, David A.; Crysdale, Nicole Y.; Berkelhammer, Debra L.; Brzeski, Anita; Northcutt, Alexis; Vietz, Christine M.; Judd, Charles M.; Maier, Steven F.; Watkins, Linda R.; Johnson, Kirk W.

2009-01-01

Morphine-induced glial proinflammatory responses have been documented to contribute to tolerance to opioid analgesia. Here, we examined whether drugs previously shown to suppress glial proinflammatory responses can alter other clinically relevant opioid effects; namely, withdrawal or acute analgesia. AV411 (ibudilast) and minocycline, drugs with distinct mechanisms of action that result in attenuation of glial proinflammatory responses, each reduced naloxone-precipitated withdrawal. Analysis of brain nuclei associated with opioid withdrawal revealed that morphine altered expression of glial activation markers, cytokines, chemokines, and a neurotrophic factor. AV411 attenuated many of these morphine-induced effects. AV411 also protected against spontaneous withdrawal-induced hyperactivity and weight loss recorded across a 12-day timecourse. Notably, in the spontaneous withdrawal study, AV411 treatment was delayed relative to the start of the morphine regimen so to also test whether AV411 could still be effective in the face of established morphine dependence, which it was. AV411 did not simply attenuate all opioid effects, as co-administering AV411 with morphine or oxycodone caused 3-to-5-fold increases in acute analgesic potency, as revealed by leftward shifts in the analgesic dose response curves. Timecourse analyses revealed that plasma morphine levels were not altered by AV411, suggestive that potentiated analgesia was not simply due to prolongation of morphine exposure or increased plasma concentrations. These data support and extend similar potentiation of acute opioid analgesia by minocycline, again providing converging lines of evidence of glial involvement. Hence, suppression of glial proinflammatory responses can significantly reduce opioid withdrawal, whilst improving analgesia. PMID:18938237

Lidocaine alleviates morphine tolerance via AMPK-SOCS3-dependent neuroinflammation suppression in the spinal cord.

PubMed

Zhang, Yan; Tao, Gao-Jian; Hu, Liang; Qu, Jie; Han, Yuan; Zhang, Guangqin; Qian, Yanning; Jiang, Chun-Yi; Liu, Wen-Tao

2017-11-02

Morphine tolerance is a clinical challenge, and its pathogenesis is closely related to the neuroinflammation mediated by Toll-like receptor 4 (TLR4). In Chinese pain clinic, lidocaine is combined with morphine to treat chronic pain. We found that lidocaine sufficiently inhibited neuroinflammation induced by morphine and improved analgesic tolerance on the basis of non-affecting pain threshold. CD-1 mice were utilized for tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 was utilized to investigate the mechanism of lidocaine. Neuroinflammation-related cytokines were measured by western blotting and real-time PCR. The level of suppressor of cytokine signaling 3 (SOCS3) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-related signaling pathway was evaluated by western blotting, real-time PCR, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining. Lidocaine potentiated an anti-nociceptive effect of morphine and attenuated the chronic analgesic tolerance. Lidocaine suppressed morphine-induced activation of microglia and downregulated inflammatory cytokines, interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) via upregulating SOCS3 by activating AMPK. Lidocaine enhanced AMPK phosphorylation in a calcium-dependent protein kinase kinase β (CaMKKβ)-dependent manner. Furthermore, lidocaine decreased the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and inhibited the nuclear factor-κB (NF-κB) in accordance with the inhibitory effects to TLR4. Lidocaine as a prevalent local anesthetic suppresses morphine tolerance efficiently. AMPK-dependent upregulation of SOCS3 by lidocaine plays a crucial role in the improvement of analgesic tolerance.

Effect of Thymoquinone on Reproductive Parameter in Morphine-treated Male Mice

PubMed Central

Salahshoor, Mohammad Reza; Haghjoo, Mojdeh; Roshankhah, Shiva; Makalani, Fatemeh; Jalili, Cyrus

2018-01-01

Background: Thymoquinone as the main active component of Nigella sativa might have a various pharmacological effects such as antiapoptotic and antioxidant. Morphine is commonly used for the treatment of severe pain that can increase the generation of free radicals and affects the spermatogenesis. This study was designed to evaluate protective effects of thymoquinone against morphine-induced damages, sperm viability, count, motility, morphology and testis histology, and nitric oxide and testosterone hormone of the mice. Materials and Methods: In this experimental study, we divided 48 mice into eight groups (n = 6); various doses of thymoquinone (2, 10, and 20 mg/kg) and morphine (20 mg/kg) plus thymoquinone (2, 10, and 20 mg/kg) were administered intraperitoneally to 48 male mice for 30 consequent days. Male reproductive parameters including testis weight, testosterone hormone, serum nitric oxide, germinal thickness, sperm morphology, count, viability, and motility were analyzed and compared. Results: The results indicated that morphine administration significantly decreased germinal thickness, testis weight, testosterone level, viability, morphology, count, and motility of sperm and increased nitric oxide as compared to saline group (P < 0.05). However, increasing the dose of thymoquinone in the thymoquinone and thymoquinone plus morphine groups significantly decreases nitric oxide level (P < 0.05) while significantly boosted motility, morphology, count, viability of sperm cells, germinal thickness, and testosterone hormone in all groups as compared to morphine group (P < 0.05). Conclusion: It seems that thymoquinone administration could increase the quality some of spermatozoa and improves morphine-induced adverse effects on reproductive parameters in male mice PMID:29456989

An Experimental Itch Model in Monkeys

PubMed Central

Ko, M. C. Holden; Naughton, Norah N.

2007-01-01

Background The most common side effect of spinal opioid administration is pruritus, which has been treated with a variety of agents with variable success. Currently, there are few animal models developed to study this side effect. The aim of this study was to establish a nonhuman primate model to pharmacologically characterize the effects of intrathecal administration of morphine. Methods Eight adult rhesus monkeys were used. Scratching responses were videotaped and counted by observers who were blinded to experimental conditions. Antinociception was measured by a warm-water (50°C) tail-withdrawal assay. The dose-response of intrathecal morphine (1-320 μg) for both scratching and antinociception in all subjects was established. An opioid antagonist, nalmefene, was administered either intravenously or subcutaneously to assess its efficacy against intrathecal morphine. Results Intrathecal morphine (1-32 μg) increased scratching in a dose-dependent manner. Higher doses of intrathecal morphine (10-100 μg) produced thermal antinociception in a dose-dependent manner. On the other hand, nalmefene (10-32 μg/kg intravenously) attenuated maximum scratching responses among subjects. Pretreatment with nalmefene (32μg/kg subcutaneously) produced approximately 10-fold rightward shifts of intrathecal morphine dose-response curves for both behavioral effects. Conclusions These data indicate that intrathecal morphine-induced scratching and antinociception are mediated by opioid receptors. The magnitude of nalmefene antagonism of intrathecal morphine is consistent with μ opioid receptor mediation. This experimental itch model is useful for evaluating different agents that may suppress scratching without interfering with antinociception. It may also facilitate the clarification of mechanisms underlying these phenomena. PMID:10719958

PKMζ Maintains Drug Reward and Aversion Memory in the Basolateral Amygdala and Extinction Memory in the Infralimbic Cortex

PubMed Central

He, Ying-Ying; Xue, Yan-Xue; Wang, Ji-shi; Fang, Qin; Liu, Jian-Feng; Xue, Li-Fen; Lu, Lin

2011-01-01

The intense associative memories that develop between drug-paired contextual cues and rewarding stimuli or the drug withdrawal-associated aversive feeling have been suggested to contribute to the high rate of relapse. Various studies have elucidated the mechanisms underlying the formation and expression of drug-related cue memories, but how this mechanism is maintained is unknown. Protein kinase M ζ (PKMζ) was recently shown to be necessary and sufficient for long-term potentiation maintenance and memory storage. In the present study, we used conditioned place preference (CPP) and aversion (CPA) to examine whether PKMζ maintains both morphine-associated reward memory and morphine withdrawal-associated aversive memory in the basolateral amygdala (BLA). We also investigate the role of PKMζ in the infralimbic cortex in the extinction memory of morphine reward-related cues and morphine withdrawal-related aversive cues. We found that intra-BLA but not central nucleus of the amygdala injection of the selective PKMζ inhibitor ZIP 1 day after CPP and CPA training impaired the expression of CPP and CPA 1 day later, and the effect of ZIP on memory lasted at least 2 weeks. Inhibiting PKMζ activity in the infralimbic cortex, but not prelimbic cortex, disrupted the expression of the extinction memory of CPP and CPA. These results indicate that PKMζ in the BLA is required for the maintenance of associative morphine reward memory and morphine withdrawal-associated aversion memory, and PKMζ in the infralimbic cortex is required for the maintenance of extinction memory of morphine reward-related cues and morphine withdrawal-related aversive cues. PMID:21633338

Low doses of dextromethorphan attenuate morphine-induced rewarding via the sigma-1 receptor at ventral tegmental area in rats.

PubMed

Chen, Shiou-Lan; Hsu, Kuei-Ying; Huang, Eagle Yi-Kung; Lu, Ru-Band; Tao, Pao-Luh

2011-09-01

Chronic use of morphine causes rewarding and behavioral sensitization, which may lead to the development of psychological craving. In our previous study, we found that a widely used antitussive dextromethorphan (known as a low affinity NMDA receptor antagonist), at doses of 10-20 mg/kg (i.p.), effectively decreased morphine rewarding in rats. In this study, we further investigated the effects and mechanisms of low doses of DM (μg/kg range) on morphine rewarding and behavioral sensitization. A conditioned place preference test was used to determine the rewarding and a locomotor activity test was used to determine the behavioral sensitization induced by the drug(s) in rats. When a low dose of DM (3 or 10 μg/kg, i.p.) was co-administered with morphine (5 mg/kg, s.c.), the rewarding effect, but not behavioral sensitization, induced by morphine was inhibited. The inhibiting effect of DM could be blocked by systemically administering a sigma-1 receptor antagonist, BD1047 (3 mg/kg, i.p.). When BD1047 (5 nmole/site) was locally given at the VTA, it also blocked the effects of a low dose of DM in inhibiting morphine rewarding. Our findings suggest that the activation of the sigma-1 receptor at the VTA may be involved in the mechanism of low doses of DM in inhibiting the morphine rewarding effect and the possibility of using extremely low doses of DM in treatment of opioid addiction in clinics. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Region-specific expression of brain-derived neurotrophic factor splice variants in morphine conditioned place preference in mice.

PubMed

Meng, Min; Zhao, Xinhan; Dang, Yonghui; Ma, Jingyuan; Li, Lixu; Gu, Shanzhi

2013-06-26

It is well established that brain-derived neurotrophic factor (BDNF) plays a pivotal role in brain plasticity-related processes, such as learning, memory and drug addiction. However, changes in expression of BDNF splice variants after acquisition, extinction and reinstatement of cue-elicited morphine seeking behavior have not yet been investigated. Real-time PCR was used to assess BDNF splice variants (I, II, IV and VI) in various brain regions during acquisition, extinction and reinstatement of morphine-conditioned place preference (CPP) in mice. Repeated morphine injections (10mg/kg, i.p.) increased expression of BDNF splice variants II, IV and VI in the hippocampus, caudate putamen (CPu) and nucleus accumbens (NAcc). Levels of BDNF splice variants decreased after extinction training and continued to decrease during reinstatement induced by a morphine priming injection (10mg/kg, i.p.). However, after reinstatement induced by exposure to 6 min of forced swimming (FS), expression of BDNF splice variants II, IV and VI was increased in the hippocampus, CPu, NAcc and prefrontal cortex (PFC). After reinstatement induced by 40 min of restraint, expression of BDNF splice variants was increased in PFC. These results show that exposure to either morphine or acute stress can induce reinstatement of drug-seeking, but expression of BDNF splice variants is differentially affected by chronic morphine and acute stress. Furthermore, BDNF splice variants II, IV and VI may play a role in learning and memory for morphine addiction in the hippocampus, CPu and NAcc. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Role of GABAA receptors in dorsal raphe nucleus in stress-induced reinstatement of morphine-conditioned place preference in rats.

PubMed

Li, Chen; Staub, Daniel R; Kirby, Lynn G

2013-12-01

The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Our data indicate that stress inhibits the dorsal raphe nucleus (DRN)-5-HT system via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor and, more recently, that morphine history sensitizes DRN-5-HT neurons to GABAergic inhibitory effects of stress. We tested the hypothesis that DRN GABAA receptors contribute to stress-induced reinstatement of morphine-conditioned place preference (CPP). First, we tested if activation of GABAA receptors in the DRN would reinstate morphine CPP. Second, we tested if blockade of GABAA receptors in the DRN would attenuate swim stress-induced reinstatement of morphine CPP. CPP was induced by morphine (5 mg/kg) in a 4-day conditioning phase followed by a conditioning test. Upon acquiring conditioning criteria, subjects underwent 4 days of extinction training followed by an extinction test. Upon acquiring extinction criteria, animals underwent a reinstatement test. For the first experiment, the GABAA receptor agonist muscimol (50 ng) or vehicle was injected into the DRN prior to the reinstatement test. For the second experiment, the GABAA receptor antagonist bicuculline (75 ng) or vehicle was injected into the DRN prior to a forced swim stress, and then, animals were tested for reinstatement of CPP. Intraraphe injection of muscimol reinstated morphine CPP, while intraraphe injection of bicuculline attenuated swim stress-induced reinstatement. These data provide evidence that GABAA receptor-mediated inhibition of the serotonergic DRN contributes to stress-induced reinstatement of morphine CPP.

Hypoxic ventilatory response in Tac1-/- neonatal mice following exposure to opioids.

PubMed

Berner, J; Shvarev, Y; Zimmer, A; Wickstrom, R

2012-12-01

Morphine is the dominating analgetic drug used in neonates, but opioid-induced respiratory depression limits its therapeutic use. In this study, we examined acute morphine effects on respiration during intermittent hypoxia in newborn Tac1 gene knockout mice (Tac1-/-) lacking substance P and neurokinin A. In vivo, plethysmography revealed a blunted hypoxic ventilatory response (HVR) in Tac1-/- mice. Morphine (10 mg/kg) depressed the HVR in wild-type animals through an effect on respiratory frequency, whereas it increased tidal volumes in Tac1-/- during hypoxia, resulting in increased minute ventilation. Apneas were reduced during the first hypoxic episode in both morphine-exposed groups, but were restored subsequently in Tac1-/- mice. Morphine did not affect ventilation or apnea prevalence during baseline conditions. In vitro, morphine (50 nM) had no impact on anoxic response of brain stem preparations of either strain. In contrast, it suppressed the inspiratory rhythm during normoxia and potentiated development of posthypoxic neuronal arrest, especially in Tac1-/-. Thus this phenotype has a higher sensitivity to the depressive effects of morphine on inspiratory rhythm generation, but morphine does not modify the reactivity to oxygen deprivation. In conclusion, although Tac1-/- mice are similar to wild-type animals during normoxia, they differed by displaying a reversed pattern with an improved HVR during intermittent hypoxia both in vivo and in vitro. These data suggest that opioids and the substance P-ergic system interact in the HVR, and that reducing the activity in the tachykinin system may alter the respiratory effects of opioid treatment in newborns.

Pharmacological evaluation of narcotic antagonist delivery systems in rhesus monkeys.

PubMed

Harrigan, S E; Downs, D A

1981-01-01

Rhesus monkeys were chronically restrained, intravenously catheterized, and allowed to self-administer morphine, methamphetamine, and saline. Various sustained-release systems containing naltrexone were then implanted in the animals and examined for selective morphine blockade. Similarly, continuous intravenous infusions of naltrexone, buprenorphine, and methadone were tested against morphine or heroin self-administration.

Synthetic substances with morphine-like effect

PubMed Central

Braenden, Olav J.; Eddy, Nathan B.; Halbach, H.

1955-01-01

For morphine-, morphinan-, pethidine-, methadone-, and dithienyl-butenylamine groups of analgesic compounds a systematic survey is given of how analgesic activity is quantitatively affected by alteration of the chemical constitution. Features common to the structural formulae of substances with morphine-like analgesic effect are pointed out. ImagesFIG. 1FIG. 1(Contd.) PMID:13284565

Comparison between the analgesic effects of morphine and tramadol delivered epidurally in cats receiving a standardized noxious stimulation.

PubMed

Castro, Douglas S; Silva, Marta F A; Shih, Andre C; Motta, Pedro P A; Pires, Marcos V M; Scherer, Paulo O

2009-12-01

This study compared the analgesic effects of epidural tramadol versus morphine in six healthy cats. Under general anesthesia, each cat received an epidural injection of saline 0.22 ml/kg (control treatment, CT), tramadol 1mg/kg (tramadol treatment, TT), or morphine 0.1mg/kg (morphine treatment, MT). After cats had recovered from anesthesia a simple descriptive scale (SDS), visual analog scale (VAS) and physiological parameters (respiratory and heart rate) were used to assess analgesia level to a noxious stimulus (base of the tail skin fold clamping) at 1, 2, 3, 4, 6, 8, 10, and 12h post-epidural. Group TT had a higher SDS and VAS score when compared to MT at 8, 10 and 12h post-epidural. CT had higher SDS and VAS score at all time points when compared to TT and MT. In conclusion both morphine and tramadol provided analgesia in this model for the first 6h; with epidural morphine resulting in longer lasting analgesia when compared to tramadol.

Differential modulatory effects of morphine on acute and chronic stress induced neurobehavioral and cellular markers in rats.

PubMed

Joshi, Jagdish C; Ray, Arunabha; Gulati, Kavita

2014-04-15

The present study evaluated the effects of morphine treatments on elevated plus maze test parameters, oxidative stress markers and Hsp70 expression in normal and stressed rats. Acute and chronic stress caused neurobehavioral suppression, altered prooxidant-antioxidant balance and increased Hsp70 expression in brain homogenates in a differential manner. Morphine (1 and 5mg/kg) attenuated RS induced anxiogenesis, changes in MDA and GSH but further enhanced Hsp70 expression. Similar anxiolytic and Hsp70 enhancing effects were seen after morphine in normal rats (no RS). Exposure to chronic RS did not elicit any appreciable neurobehavioral response in EPM but enhanced MDA, lowered GSH and exaggerated the Hsp70 expression. Pretreatment with morphine did not affect the neurobehavioral response to chronic RS, but reverted the GSH and Hsp70 expression. The results suggest that morphine differentially influences acute and chronic stress induced changes in anxiety behavior and complex interactions between oxidative stress markers and Hsp70 expression which may contribute to these effects. Copyright © 2014 Elsevier B.V. All rights reserved.

Narp regulates long-term aversive effects of morphine withdrawal

PubMed Central

Reti, Irving M.; Crombag, Hans S.; Takamiya, Kogo; Sutton, Jeffrey M.; Guo, Ning; Dinenna, Megan L.; Huganir, Richard L.; Holland, Peter C.; Baraban, Jay M.

2008-01-01

Although long-lasting effects of drug withdrawal are thought to play a key role in motivating continued drug use, the mechanisms mediating this type of drug-induced plasticity are unclear. As Narp is an immediate early gene product that is secreted at synaptic sites and binds to AMPA receptors, it has been implicated in mediating enduring forms of synaptic plasticity. In previous studies, we found that Narp is selectively induced by morphine withdrawal in the extended amygdala, a group of limbic nuclei that mediate aversive behavioral responses. Accordingly, in this study, we evaluated whether long-term aversive effects of morphine withdrawal are altered in Narp KO mice. We found that acute physical signs of morphine withdrawal are unaffected by Narp deletion. However, Narp KO mice acquire and sustain more aversive responses to the environment conditioned with morphine withdrawal than WT controls. Paradoxically, Narp KO mice undergo accelerated extinction of this heightened aversive response. Taken together, these studies suggest that Narp modulates both acquisition and extinction of aversive responses to morphine withdrawal and, therefore, may regulate plasticity processes underlying drug addiction. PMID:18729628

Attenuation of tolerance to opioid-induced antinociception and protection against morphine-induced decrease of neurofilament proteins by idazoxan and other I2-imidazoline ligands.

PubMed

Boronat, M A; Olmos, G; García-Sevilla, J A

1998-09-01

1. Agmatine, the proposed endogenous ligand for imidazoline receptors, has been shown to attenuate tolerance to morphine-induced antinociception (Kolesnikov el al., 1996). The main aim of this study was to assess if idazoxan, an alpha2-adrenoceptor antagonist that also interacts with imidazoline receptors, could also modulate opioid tolerance in rats and to establish which type of imidazoline receptors (or other receptors) are involved. 2. Antinociceptive responses to opioid drugs were determined by the tail-flick test. The acute administration of morphine (10 mg kg(-1), i.p., 30 min) or pentazocine (10 mg kg(-1), i.p., 30 min) resulted in marked increases in tail-flick latencies (TFLs). As expected, the initial antinociceptive response to the opiates was lost after chronic (13 days) treatment (tolerance). When idazoxan (10 mg kg(-1), i.p.) was given chronically 30 min before the opiates it completely prevented morphine tolerance and markedly attenuated tolerance to pentazocine (TFLs increased by 71-143% at day 13). Idazoxan alone did not modify TFLs. 3. The concurrent chronic administration (10 mg kg(-1), i.p., 13 days) of 2-BFI, LSL 60101, and LSL 61122 (valldemossine), selective and potent I2-imidazoline receptor ligands, and morphine (10 mg kg(-1), i.p.), also prevented or attenuated morphine tolerance (TFLs increased by 64 172% at day 13). This attenuation of morphine tolerance was still apparent six days after discontinuation of the chronic treatment with LSL 60101-morphine. The acute treatment with these drugs did not potentiate morphine-induced antinociception. These drugs alone did not modify TFLs. Together, these results indicated the specific involvement of I2-imidazoline receptors in the modulation of opioid tolerance. 4. The concurrent chronic (13 days) administration of RX821002 (10 mg kg(-1), i.p.) and RS-15385-197 (1 mg kg(-1), i.p.), selective alpha2-adrenoceptor antagonists, and morphine (10 mg kg(-1), i.p.), did not attenuate morphine tolerance. Similarly, the concurrent chronic treatment of moxonidine (1 mg kg(-1), i.p.), a mixed I(1)-imidazoline receptor and alpha2-adrenoceptor agonist, and morphine (10 mg kg(-1), i.p.), did not alter the development of tolerance to the opiate. These results discounted the involvement of alpha2-adrenoceptors and I(1)-imidazoline receptors in the modulatory effect of idazoxan on opioid tolerance. 5. Idazoxan and other imidazol(ine) drugs fully inhibited [3H]-(+)-MK-801 binding to N-methyl-D-aspartate (NMDA) receptors in the rat cerebral cortex with low potencies (Ki: 37-190 microM). The potencies of the imidazolines idazoxan, RX821002 and moxonidine were similar, indicating a lack of relationship between potency on NMDA receptors and ability to attenuate opioid tolerance. These results suggested that modulation of opioid tolerance by idazoxan is not related to NMDA receptors blockade. 6. Chronic treatment (13 days) with morphine (10 mg kg(-1), i.p.) was associated with a marked decrease (49%) in immunolabelled neurofilament proteins (NF-L) in the frontal cortex of morphine-tolerant rats, suggesting the induction of neuronal damage. Chronic treatment (13 days) with idazoxan (10 mg kg(-1)) and LSL 60101 (10 mg kg(-1)) did not modify the levels of NF-L proteins in brain. Interestingly, the concurrent chronic treatment (13 days) of idazoxan or LSL 60101 and morphine, completely reversed the morphine-induced decrease in NF-L immunoreactivity, suggesting a neuroprotective role for these drugs. 7. Together, the results indicate that chronic treatment with I2-imidazoline ligands attenuates the development of tolerance to opiate drugs and may induce neuroprotective effects on chronic opiate treatment. Moreover, these findings offer the I2-imidazoline ligands as promising therapeutic coadjuvants in the management of chronic pain with opiate drugs.

Design of LabVIEW®-based software for the control of sequential injection analysis instrumentation for the determination of morphine

PubMed Central

Lenehan, Claire E.; Lewis, Simon W.

2002-01-01

LabVIEW®-based software for the automation of a sequential injection analysis instrument for the determination of morphine is presented. Detection was based on its chemiluminescence reaction with acidic potassium permanganate in the presence of sodium polyphosphate. The calibration function approximated linearity (range 5 × 10-10 to 5 × 10-6 M) with a line of best fit of y=1.05x+8.9164 (R2 =0.9959), where y is the log10 signal (mV) and x is the log10 morphine concentration (M). Precision, as measured by relative standard deviation, was 0.7% for five replicate analyses of morphine standard (5 × 10-8 M). The limit of detection (3σ) was determined as 5 × 10-11 M morphine. PMID:18924729

Design of LabVIEW-based software for the control of sequential injection analysis instrumentation for the determination of morphine.

PubMed

Lenehan, Claire E; Barnett, Neil W; Lewis, Simon W

2002-01-01

LabVIEW-based software for the automation of a sequential injection analysis instrument for the determination of morphine is presented. Detection was based on its chemiluminescence reaction with acidic potassium permanganate in the presence of sodium polyphosphate. The calibration function approximated linearity (range 5 x 10(-10) to 5 x 10(-6) M) with a line of best fit of y=1.05(x)+8.9164 (R(2) =0.9959), where y is the log10 signal (mV) and x is the log10 morphine concentration (M). Precision, as measured by relative standard deviation, was 0.7% for five replicate analyses of morphine standard (5 x 10(-8) M). The limit of detection (3sigma) was determined as 5 x 10(-11) M morphine.

Intracerebral beta-endorphin, met-enkephalin and morphine: kindling of seizures and handling-induced potentiation of epileptiform effects.

PubMed

Cain, D P; Corcoran, M E

1984-06-18

The effects of repeated infusion of small, initially subconvulsive amounts of beta-endorphin, met-enkephalin or morphine sulfate into the amygdala and hippocampus were investigated. beta-endorphin and met-enkephalin evoked epileptiform spiking when infused into the posterior amygdala or ventral hippocampus. Morphine evoked epileptiform spiking when infused into the anterior amygdala. Naloxone blocked or terminated the spiking. Repetition of the infusions led to the gradual development of bilateral generalized convulsions by beta-endorphin and met-enkephalin and to the development of tolerance to morphine. An unexpected observation was that handling, immobilization or conspecific threat potentiated the epileptiform effects of beta-endorphin and morphine in many cases. These results suggest that endogenous opiate mechanisms might play a role in convulsive seizures and that stressful stimuli can exacerbate opiate seizures.

Hair analysis for opiates: hydromorphone and hydrocodone as indicators of heroin use.

PubMed

Madry, Milena M; Bosshard, Mona M; Kraemer, Thomas; Baumgartner, Markus R

2016-05-01

Identification of external contamination is a challenge in hair analysis. This study investigates metabolite ratios of hydromorphone to morphine and hydrocodone to codeine as indicators to distinguish contamination from heroin use provided that hydromorphone/hydrocodone intake is excluded. Hair samples after external contamination with street heroin proved to be negative for hydromorphone/hydrocodone. Hair samples from individuals with suspected street heroin use/contamination or opiate medication were analyzed for 6-monoacetylmorphine, morphine, acetylcodeine, codeine, hydromorphone and hydrocodone, and metabolite ratios of hydromorphone to morphine and hydrocodone to codeine were assessed. Hair samples from individuals with medicinal heroin/morphine/codeine use displayed significantly higher metabolite ratios than those with suspected street heroin use/contamination. Hydromorphone/hydrocodone are solely formed during body passage. Thus, metabolite ratios can be used to distinguish morphine/heroin use from external contamination.

Role of hippocampal and prefrontal cortical signaling pathways in dextromethorphan effect on morphine-induced memory impairment in rats.

PubMed

Ghasemzadeh, Zahra; Rezayof, Ameneh

2016-02-01

Evidence suggests that dextromethorphan (DM), an NMDA receptor antagonist, induces memory impairment. Considering that DM is widely used in cough-treating medications, and the co-abuse of DM with morphine has recently been reported, the aims of the present study was (1) to investigate whether there is a functional interaction between morphine and DM in passive avoidance learning and (2) to assess the possible role of the hippocampal and prefrontal cortical (PFC) signaling pathways in the effects of the drugs on memory formation. Our findings indicated that post-training or pre-test administration of morphine (2 and 6 mg/kg) or DM (10-30 mg/kg) impaired memory consolidation and retrieval which was associated with the attenuation of the levels of phosphorylated Ca(2+)/calmodulin-dependent protein kinase II (p-CAMKII) and cAMP responsive element-binding protein (p-CREB) in the targeted sites. Moreover, the memory impairment induced by post-training administration of morphine was reversed by pre-test administration of the same dose of morphine or DM (30 mg/kg), indicating state-dependent learning (SDL) and a cross-SDL between the drugs. It is important to note that the levels of p-CAMKII/CAMKII and p-CREB/CREB in the hippocampus and the PFC increased in drugs-induced SDL. In addition, DM administration potentiated morphine-induced SDL which was related to the enhanced levels of hippocampal and PFC CAMKII-CREB signaling pathways. It can be concluded that there is a relationship between the hippocampus and the PFC in the effect of DM and/or morphine on memory retrieval. Moreover, a cross SDL can be induced between the co-administration of DM and morphine. Interestingly, CAMKII-CREB signaling pathways also mediate the drugs-induced SDL. Copyright © 2015 Elsevier Inc. All rights reserved.

Involvement of α₂-adrenoceptors, imidazoline, and endothelin-A receptors in the effect of agmatine on morphine and oxycodone-induced hypothermia in mice.

PubMed

Bhalla, Shaifali; Andurkar, Shridhar V; Gulati, Anil

2013-10-01

Potentiation of opioid analgesia by endothelin-A (ET(A)) receptor antagonist, BMS182874, and imidazoline receptor/α₂-adrenoceptor agonists such as clonidine and agmatine are well known. It is also known that agmatine blocks morphine hyperthermia in rats. However, the effect of agmatine on morphine or oxycodone hypothermia in mice is unknown. The present study was carried out to study the role of α₂-adrenoceptors, imidazoline, and ET(A) receptors in morphine and oxycodone hypothermia in mice. Body temperature was determined over 6 h in male Swiss Webster mice treated with morphine, oxycodone, agmatine, and combination of agmatine with morphine or oxycodone. Yohimbine, idazoxan, and BMS182874 were used to determine involvement of α₂-adrenoceptors, imidazoline, and ET(A) receptors, respectively. Morphine and oxycodone produced significant hypothermia that was not affected by α₂-adrenoceptor antagonist yohimbine, imidazoline receptor/α₂ adrenoceptor antagonist idazoxan, or ET(A) receptor antagonist, BMS182874. Agmatine did not produce hypothermia; however, it blocked oxycodone but not morphine-induced hypothermia. Agmatine-induced blockade of oxycodone hypothermia was inhibited by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared with yohimbine. Combined administration of BMS182874 and agmatine did not produce changes in body temperature in mice. However, when BMS182874 was administered along with agmatine and oxycodone, it blocked agmatine-induced reversal of oxycodone hypothermia. This is the first report demonstrating that agmatine does not affect morphine hypothermia in mice, but reverses oxycodone hypothermia. Imidazoline receptors and α₂-adrenoceptors are involved in agmatine-induced reversal of oxycodone hypothermia. Our findings also suggest that ET(A) receptors may be involved in blockade of oxycodone hypothermia by agmatine. © 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.

Cross State-dependent Learning Interaction Between Scopolamine and Morphine in Mice: The Role of Dorsal Hippocampus

PubMed Central

Maleki, Morteza; Hassanpour-Ezatti, Majid; Navaeian, Majid

2017-01-01

Introduction: The current study aimed at investigating the existence of the cross state-dependent learning between morphine and scopolamine (SCO) in mice by passive avoidance method, pointing to the role of CA1 area. Methods: The effects of pre-training SCO (0.75, 1.5, and 3 μg, Intra-CA1), or morphine (1, 3, and 6 mg/kg, intraperitoneal (i.p.) was evaluated on the retrieval of passive avoidance learning using step-down task in mice (n=10). Then, the effect of pretest administration of morphine (1.5, 3, and 6 mg/kg, i.p.) was examined on passive avoidance retrieval impairment induced by pre-training SCO (3 μg/mice, Intra-CA1). Next, the effect of pretest Intra-CA1 injection of scopolamine (0.75, 1.5, and 3 μg/mice) was evaluated on morphine (6 mg/kg, i.p.) pre-training deficits in this task in mice. Results: The pre-training Intra-CA1 injection of scopolamine (1.5 and 3 μg/mouse), or morphine (3 and 6 mg/kg, i.p.) impaired the avoidance memory retrieval when it was tested 24 hours later. Pretest injection of both drugs improved its pre-training impairing effects on mice memory. Moreover, the amnesia induced by the pre-training injections of scopolamine (3 μg/mice) was restored significantly (P<0.01) by pretest injections of morphine (3 and 6 mg/kg, i.p.). Similarly, pretest injection of scopolamine (3 μg/mice) restored amnesia induced by the pre-training injections of morphine (6 mg/kg, i.p.), significantly (P<0.01). Conclusion: The current study findings indicated a cross state-dependent learning between SCO and morphine at CA1 level. Therefore, it seems that muscarinic and opioid receptors may act reciprocally on modulation of passive avoidance memory retrieval, at the level of dorsal hippocampus, in mice. PMID:28781727

Preliminary investigation comparing a detomidine continuous rate infusion combined with either morphine or buprenorphine for standing sedation in horses.

PubMed

Potter, Joanna J; MacFarlane, Paul D; Love, Emma J; Tremaine, Henry; Taylor, Polly M; Murrell, Joanna C

2016-03-01

To compare sedative and analgesic properties of buprenorphine or morphine for standing procedures combined with a detomidine continuous rate infusion (CRI). Blinded, prospective, randomized clinical pilot study. Ten horses presented for dental or sinus procedures. Horses received 0.02 mg kg(-1) acepromazine intravenously (IV), followed 30 minutes later by detomidine 10 μg kg(-1) IV. Five minutes later, buprenorphine 0.01 mg kg(-1) (n = 6) or morphine 0.1 mg kg(-1) (n = 4) was administered IV. Detomidine was administered by CRI (0.2 μg kg(-1) minute(-1)) and adjusted to maintain appropriate sedation. Heart rate, respiratory frequency, gastrointestinal motility and rectal temperature were measured; pain, ataxia and sedation were scored. Sedation, pain scores and ataxia scores were analysed using a mixed linear model. Detomidine dose and procedure success scores were compared using Wilcoxon's rank sum test. Complications between groups were analysed using Fisher's exact test. Two horses had incomplete data. Weights and ages were not different between groups (p = 0.15 and p = 0.42, respectively). The dose rate for detomidine was not different between groups (0.33 ± 0.02 μg kg(-1) minute(-1) in the buprenorphine group and 0.33 ± 0.05 μg kg(-1) minute(-1), in the morphine group p = 0.89). Intraoperative visual analogue scale scores were greater after buprenorphine than morphine (mean ± SD, buprenorphine 48 ± 4, morphine 40 ± 5, p = 0.0497). Procedure duration was not different between groups (buprenorphine 142 ± 33, morphine 140 ± 12 minutes). All horses treated with buprenorphine experienced complications compared with none in the morphine group (p = 0.0286). At the doses used, buprenorphine produced greater sedation but more post-operative complications than morphine. However, Type I or Type II errors cannot be excluded and larger studies are required to confirm these findings. © 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Effects of perinatal exposure to delta 9-tetrahydrocannabinol on operant morphine-reinforced behavior.

PubMed

González, Begoña; de Miguel, Rosario; Martín, Sonsoles; Pérez-Rosado, Alberto; Romero, Julián; García-Lecumberri, Carmen; Fernández-Ruiz, Javier; Ramos, José Antonio; Ambrosio, Emilio

2003-06-01

The present study examined the effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) when administered during the perinatal period on morphine self-administration in adulthood. To this end, pregnant Wistar rats were daily exposed to Delta(9)-THC from the fifth day of gestation up to pup weaning, when they were separated by gender and left to mature to be used for analyses of operant food- and morphine-reinforced behavior in a progressive ratio (PR) schedule. We also analyzed dopaminergic activity (DOPAC/DA) in reward-related structures during specific phases of the behavioral study. In both reinforcement paradigms, food and morphine, females always reached higher patterns of self-administration than males, but this occurred for the two treatment groups, Delta(9)-THC or vehicle. These higher patterns measured in females corresponded with a higher DOPAC/DA in the nucleus accumbens prior to the onset of morphine self-administration in comparison to males. Interestingly, DOPAC/DA was lower in Delta(9)-THC-exposed females compared to oil-exposed females and similar to oil- and Delta(9)-THC-exposed males. In addition, Delta(9)-THC-exposed females also exhibited a reduction in DOPAC/DA in the ventral tegmental area, which did not exist in males. All these changes, however, disappeared after 15 days of morphine self-administration and they did not reappear after 15 additional days of extinction of this response. Our data suggest that females are more vulnerable than males in a PR schedule for operant food and morphine self-administration; perinatal Delta(9)-THC exposure is not a factor influencing this vulnerability. The neurochemical analysis revealed that the activity of limbic dopaminergic neurons prior to morphine self-administration was higher in females than males, as well as that the perinatal Delta(9)-THC treatment reduced the activity of these neurons only in females, although this had no influence on morphine vulnerability in these animals.

Morphine Modulates Adult Neurogenesis and Contextual Memory by Impeding the Maturation of Neural Progenitors.

PubMed

Zhang, Yue; Xu, Chi; Zheng, Hui; Loh, Horace H; Law, Ping-Yee

2016-01-01

The regulation of adult neurogenesis by opiates has been implicated in modulating different addiction cycles. At which neurogenesis stage opiates exert their action remains unresolved. We attempt to define the temporal window of morphine's inhibition effect on adult neurogenesis by using the POMC-EGFP mouse model, in which newborn granular cells (GCs) can be visualized between days 3-28 post-mitotic. The POMC-EGFP mice were trained under the 3-chambers conditioned place preference (CPP) paradigm with either saline or morphine. We observed after 4 days of CPP training with saline, the number of EGFP-labeled newborn GCs in sub-granular zone (SGZ) hippocampus significantly increased compared to mice injected with saline in their homecage. CPP training with morphine significantly decreased the number of EGFP-labeled GCs, whereas no significant difference in the number of EGFP-labeled GCs was observed with the homecage mice injected with the same dose of morphine. Using cell-type selective markers, we observed that morphine reduced the number of late stage progenitors and immature neurons such as Doublecortin (DCX) and βIII Tubulin (TuJ1) positive cells in the SGZ but did not reduce the number of early progenitors such as Nestin, SOX2, or neurogenic differentiation-1 (NeuroD1) positive cells. Analysis of co-localization between different cell markers shows that morphine reduced the number of adult-born GCs by interfering with differentiation of early progenitors, but not by inducing apoptosis. In addition, when NeuroD1 was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. These results suggest that under the condition of CPP training paradigm, morphine affects the transition of neural progenitor/stem cells to immature neurons via a mechanism involving NeuroD1.

Potentiation of Brain Stimulation Reward by Morphine: Effects of Neurokinin-1 Receptor Antagonism

PubMed Central

Robinson, J.E.; Fish, E.W.; Krouse, M.C.; Thorsell, A.; Heilig, M.; Malanga, C.J.

2012-01-01

Rationale The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists. Objective To measure the effects of opioid and neurokinin-1 (NK1R) receptor blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation (ICSS) method. Methods Adult male C57BL/6J mice (n = 15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation. The BSR threshold (θ0) and maximum response rate (MAX) were determined before and after intraperitoneal administration of saline, morphine (1.0 - 17.0 mg/kg), or the NK1R antagonists L-733,060 (1.0 - 17.0 mg/kg) and L-703,606 (1.0 - 17.0 mg/kg). In morphine antagonism experiments, naltrexone (0.1 – 1.0 mg/kg) or 10.0 mg/kg L-733,060 or L-703,606 was administered 15 minutes before morphine (1.0 - 10.0 mg/kg) or saline. Results Morphine dose-dependently decreased θ0 (maximum effect = 62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered θ0 without affecting MAX. 10.0 mg/kg L-733,060 and L-703,606, which did not affect θ0 or MAX, attenuated the effects of 3.0 and 10.0 mg/kg morphine. 1.0 and 0.3 mg/kg naltrexone blocked the effects of 10.0 mg/kg morphine. Naltrexone given before saline did not affect θ0 or MAX. Conclusions The decrease in θ0 by morphine reflects its rewarding effects, which were attenuated by NK1R and opioid receptor blockade. These results demonstrate the importance of substance P signaling during limbic reward system activation by opioids. PMID:21909635

Ghrelin receptor antagonism of morphine-induced conditioned place preference and behavioral and accumbens dopaminergic sensitization in rats.

PubMed

Jerabek, Pavel; Havlickova, Tereza; Puskina, Nina; Charalambous, Chrysostomos; Lapka, Marek; Kacer, Petr; Sustkova-Fiserova, Magdalena

2017-11-01

An increasing number of studies over the past few years have demonstrated ghrelin's role in alcohol, cocaine and nicotine abuse. However, the role of ghrelin in opioid effects has rarely been examined. Recently we substantiated in rats that ghrelin growth hormone secretagogue receptors (GHS-R1A) appear to be involved in acute opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing. The aim of the present study was to ascertain whether a ghrelin antagonist (JMV2959) was able to inhibit morphine-induced biased conditioned place preference and challenge-morphine-induced accumbens dopaminergic sensitization and behavioral sensitization in adult male rats. In the place preference model, the rats were conditioned for 8 days with morphine (10 mg/kg s.c.). On the experimental day, JMV2959 (3 and 6 mg/kg i.p.) or saline were administered before testing. We used in vivo microdialysis to determine changes of dopamine and its metabolites in the nucleus accumbens in rats following challenge-morphine dose (5 mg/kg s.c.) with or without JMV2959 (3 and 6 mg/kg i.p.) pretreatment, administered on the 12th day of spontaneous abstinence from morphine repeated treatment (5 days, 10-40 mg/kg). Induced behavioral changes were simultaneously monitored. Pretreatment with JMV2959 significantly and dose dependently reduced the morphine-induced conditioned place preference and significantly and dose dependently reduced the challenge-morphine-induced dopaminergic sensitization and affected concentration of by-products associated with dopamine metabolism in the nucleus accumbens. JMV2959 pretreatment also significantly reduced challenge-morphine-induced behavioral sensitization. Our present data suggest that GHS-R1A antagonists deserve to be further investigated as a novel treatment strategy for opioid addiction. Copyright © 2017 Elsevier Ltd. All rights reserved.

Aloe vera Aqueous Extract Effect on Morphine Withdrawal Syndrome in Morphine-Dependent Female Rats.

PubMed

Shahraki, Mohammad Reza; Mirshekari, Hamideh; Sabri, Azame

2014-09-01

Aloe vera is a medicinal herb used as an anti-inflammatory and sedative agent. The current study aimed to evaluate the effect of Aloe vera aqueous extract on morphine withdrawal symptoms in morphine-dependent female rats. The current research was performed on 40 female Wista-Albino rats which were made dependent on morphine using Houshyar protocol and were randomly divided into five groups (A, B, C, D, and E). Group A did not receive any agent in the period of handling but other groups (B, C, D and E) received 5, 10, 20 and 40 mg/kg of Aloe vera aqueous extract by gavage, three times daily for a week, respectively. Withdrawal symptoms, stool form, agitation, disparity, floppy eyelids, and body mass variations were checked for 10 days. The obtained data were analyzed using SPSS v.11 software, and Friedman, Kruskal-Wallis, and Mann-Whitney statistical tests. Statistical difference was considered significant (P < 0.05). The results of the present study showed that agitation, disparity, and floppy eyelids in group E were significantly higher than those of others groups; however, these symptoms in group C were significantly lower than those of the other groups. The results of the present study revealed that the Aloe vera aqueous extract had various effects on morphine withdrawal syndrome in morphine-dependent female rats .

Aloe vera Aqueous Extract Effect on Morphine Withdrawal Syndrome in Morphine-Dependent Female Rats

PubMed Central

Shahraki, Mohammad Reza; Mirshekari, Hamideh; Sabri, Azame

2014-01-01

Background: Aloe vera is a medicinal herb used as an anti-inflammatory and sedative agent. Objectives: The current study aimed to evaluate the effect of Aloe vera aqueous extract on morphine withdrawal symptoms in morphine-dependent female rats. Patients and Methods: The current research was performed on 40 female Wista-Albino rats which were made dependent on morphine using Houshyar protocol and were randomly divided into five groups (A, B, C, D, and E). Group A did not receive any agent in the period of handling but other groups (B, C, D and E) received 5, 10, 20 and 40 mg/kg of Aloe vera aqueous extract by gavage, three times daily for a week, respectively. Withdrawal symptoms, stool form, agitation, disparity, floppy eyelids, and body mass variations were checked for 10 days. The obtained data were analyzed using SPSS v.11 software, and Friedman, Kruskal-Wallis, and Mann-Whitney statistical tests. Statistical difference was considered significant (P < 0.05). Results: The results of the present study showed that agitation, disparity, and floppy eyelids in group E were significantly higher than those of others groups; however, these symptoms in group C were significantly lower than those of the other groups. Conclusions: The results of the present study revealed that the Aloe vera aqueous extract had various effects on morphine withdrawal syndrome in morphine-dependent female rats . PMID:25593890

The effects of preemptive intravenous versus preemptive epidural morphine on postoperative analgesia and surgical stress response after orthopaedic procedures.

PubMed

Kiliçkan, L; Toker, K

2000-09-01

The purpose of this study was to evaluate the effect of pre-emptive intravenous versus pre-emptive epidural morphine on both postoperative analgesic consumption and surgical stress response. Sixty patients, ASA I or II, aged 18-85, undergoing total hip or knee replacement were randomly assigned to three groups of 20 patients. In group pre-emptive epidural, patients were administered an epidural injection of 75 micrograms.kg-1 morphine about 45 minute before dermal incision. In group pre-emptive intravenous, patients were administered 0.15 mg.kg-1 of intravenous morphine following induction before dermal incision. In group control, patients were administered intravenous saline following induction before dermal incision. The pre-i.v. group used significantly less morphine than the pre-epi group (p < 0.0003). In all groups, plasma cortisol levels increased as compared to pre-op values, but plasma cortisol increased more significantly in the pre-i.v. and control groups within 4 hrs of surgery and was still significantly elevated at 7 am of the first postoperative morning compared to the pre-epi group (p < 0.001) and the increase persisted to the next morning in patients pre-i.v. and control groups. Although pre-emptive epidural morphine has failed to decrease postoperative analgesic consumption, it has been able to suppress the surgical stress more significantly than intravenous morphine and a saline control.

An isobolographic analysis of the antinociceptive effect of xylopic acid in combination with morphine or diclofenac

PubMed Central

Woode, Eric; Ameyaw, Elvis Ofori; Abotsi, Wonder Kofi Mensah; Boakye-Gyasi, Eric

2015-01-01

Background: A common practice of managing pain globally is the combination of analgesics and this is aimed at facilitating patient compliance, simplifying prescription, and improving efficacy without increasing adverse effects. Fruit extracts of Xylopia aethiopica are used traditionally in the management of pain disorders and xylopic acid (XA) present in the fruit extract have been shown to possess analgesic properties in animals. There is the likelihood of concomitant use of XA and the commonly used analgesics in traditional settings. This study, therefore, evaluated the pharmacologic interaction between XA/morphine and xylopic/diclofenac combinations. Methods: The formalin test and acetic acid writhing test were used to study the antinociceptive activity of XA, morphine, and diclofenac. The isobolographic analysis was used to study the antinociceptive interactions between XA co-administered with morphine or diclofenac. Results: Results obtained revealed that XA (10–100 mg/kg), morphine (1–10 mg/kg), and diclofenac (1–10 mg/kg) produced dose-related antinociception with different potencies in the formalin and acetic acid writhing tests. Isobolographic analysis of XA/morphine and XA/diclofenac combinations revealed potentiation of their antinociceptive effects. The degree of potentiation calculated as interaction index showed synergism for both combinations in all the nociceptive tests. Conclusion: In conclusion, the present study demonstrated synergism for the co-administration of XA with morphine or diclofenac. PMID:26692735

Utilization of Parenteral Morphine by Application of ATC/DDD Methodology: Retrospective Study in the Referral Teaching Hospital.

PubMed

Dragojevic-Simic, Viktorija; Rancic, Nemanja; Stamenkovic, Dusica; Simic, Radoje

2017-01-01

Few studies analyzed the pattern of opioid analgesic utilization in hospital settings. The aim of this study was to determine the consumption pattern of parenteral morphine in patients hospitalized in the Serbian referral teaching hospital and to correlate it with utilization at the national and international level. In retrospective study, the required data were extracted from medical records of surgical patients who received parenteral morphine in the 5-year period, from 2011 to 2015. We used the Anatomical Therapeutic Chemical Classification/Defined Daily Doses (DDD) international system for consumption evaluation. While the number of performed surgical procedures in our hospital steadily increased from 2011 to 2015, the number of inpatient bed-days decreased from 2012. However, the consumption of parenteral morphine varied and was not more than 0.867 DDD/100 bed-days in the observed period. Based on the available data, parenteral morphine consumption in our hospital was lower compared with international data. The low level of morphine use in the hospital was in accordance with national data, and compared with other countries, morphine consumption applied for medical indications in Serbia was low. Adequate legal provision to ensure the availability of opioids, better education and training of medical personnel, as well as multidisciplinary approach should enable more rational and individual pain management in the future, not only within the hospitals.

Alterations in brain Protein Kinase A activity and reversal of morphine tolerance by two fragments of native Protein Kinase A inhibitor peptide (PKI).

PubMed

Dalton, George D; Smith, Forrest L; Smith, Paul A; Dewey, William L

2005-04-01

Two peptide fragments of native Protein Kinase A inhibitor (PKI), PKI-(6-22)-amide and PKI-(Myr-14-22)-amide, significantly reversed low-level morphine antinociceptive tolerance in mice. The inhibition of Protein Kinase A (PKA) activity by both peptide fragments was then measured in specific brain regions (thalamus, periaqueductal gray (PAG), and medulla) and in lumbar spinal cord (LSC), which in previous studies have been shown to play a role in morphine-induced analgesia. In drug naive animals, cytosolic PKA activity was greater than particulate PKA activity in each region, while cytosolic and particulate PKA activities were greater in thalamus and PAG compared to medulla and LSC. The addition of both peptides to homogenates from each region completely abolished cytosolic and particulate PKA activities in vitro. Following injection into the lateral ventricle of the brain of drug naive mice and morphine-tolerant mice, both peptides inhibited PKA activity in the cytosolic, but not the particulate fraction of LSC. In addition, cytosolic and particulate PKA activities were inhibited by both peptides in thalamus. These results demonstrate that the inhibition of PKA reverses morphine tolerance. Moreover, the inhibition of PKA activity in specific brain regions and LSC from morphine-tolerant mice by PKI analogs administered i.c.v. is evidence that PKA plays a role in morphine tolerance.

Modulation of opioid analgesia by agmatine.

PubMed

Kolesnikov, Y; Jain, S; Pasternak, G W

1996-01-18

Administered alone, agmatine at doses of 0.1 or 10 mg/kg is without effect in the mouse tailflick assay. However, agmatine enhances morphine analgesia in a dose-dependent manner, shifting morphine's ED50 over 5-fold. A far greater effect is observed when morphine is given intrathecally (9-fold shift) than after intracerebroventricular administration (2-fold). In contrast to the potentiation of morphine analgesia, agmatine (10 mg/kg) has no effect on morphine's inhibition of gastrointestinal transit. delta-Opioid receptor-mediated analgesia also is potentiated by agmatine, but kappa1-receptor-mediated (U50,488H; trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetemide) and kappa3-opioid receptor-mediated (naloxone benzoylhydrazone) analgesia is not significantly enhanced by any dose of agmatine tested in this acute model. In chronic studies, agmatine at a low dose (0.1 mg/kg) which does not affect morphine analgesia acutely prevents tolerance following chronic morphine dosing for 10 days. A higher agmatine dose (10 mg/kg) has a similar effect. Agmatine also blocks tolerance to the delta-opioid receptor ligand [D-Pen2,D-Pen5]enkephalin given intrathecally, but not to the kappa3-opioid receptor agonist naloxone benzoylhydrazone. Despite its inactivity on kappa1-opioid analgesia in the acute model, agmatine prevents kappa1-opioid receptor-mediated tolerance. These studies demonstrate the dramatic interactions between agmatine and opioid analgesia and tolerance.

Nurses' perceptions and experiences regarding Morphine usage in burn pain management.

PubMed

Bayuo, J; Agbenorku, P

2015-06-01

Morphine, a classical example of opioid has been described as one of the analgesics of choice for burn pain management but there have been reports of under utilization of the medication and subsequent poor pain management. Nurses have a pivotal role in successful burn pain management and should therefore possess positive perception as well as strong knowledge base of pain care. In light of this realization, this study sought to investigate the perception and experiences of nurses working in the burns unit possess towards the medication. Purposive sampling approach was used to select twenty (20) nurses. Descriptive and themed content analysis approaches were used to analyze data. Mean years in general nursing practice and practice in the burns unit were obtained as 7.4 and 3.4 years respectively. Results indicate that nurses have a clear understanding of the intensity of burn pain but perception towards morphine was mixed and some respondents were unsure about some of the pertinent facts of morphine and thus, would prefer other medications such as paracetamol, diclofenac and pethidine. Addiction to the medication and morphine causing death were major themes identified. The resultant effect of these perception and experiences imply and confirm the under usage of morphine. It is therefore recommended that nurses within the burn unit be taken through training modules on the suitability of morphine in burn pain management. Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.

Short Communication: Lack of Immune Response in Rapid Progressor Morphine-Dependent and SIV/SHIV-Infected Rhesus Macaques Is Correlated with Downregulation of TH1 Cytokines

PubMed Central

Kumar, Rakesh; Noel, Richard J.; Garcia, Yashira; Rodriguez, Idia V.; Martinez, Melween; Sariol, Carlos A.; Kraiselburd, Edmundo; Iszard, Marcus; Mukherji, Mridul; Kumar, Santosh; Giavedoni, Luis D.; Kumar, Anil

2010-01-01

Abstract Our previous studies have shown two distinct disease patterns (rapid and normal onset of clinical symptoms) in morphine-dependent SHIV/SIV-inoculated rhesus macaques. We have also shown that control as well as 50% of morphine-dependent macaques (normal progressor) developed humoral and cellular immune responses whereas the other half of the morphine-dependent macaques (rapid progressor) did not develop antiviral immune responses after infection with SIV/SHIV. In the present study, we analyzed the association between cytokine production, immune response, and disease progression. To study the immunological effects of morphine at cytokine levels in the context of a lentiviral infection, we inoculated rhesus macaques with a mixture of SHIVKU−18, SHIV89.6P, and SIV/17E-Fr. These animals were followed for a period of 56 weeks for cytokine level production in plasma. Drug-dependent rapid disease progressors exhibited an increase in IL-18 and IL-1Ra and a decrease in IL-12 levels in the plasma. Morphine-dependent normal progressors and control macaques exhibited an increase in both IL-18 and IL-12, whereas IL-Ra levels remained constant throughout the observation period. These results suggest that rapid disease progression in relation to morphine dependency may be the result of an altered cytokine profile. PMID:20672973

PBPK Model of Morphine Incorporating Developmental Changes in Hepatic OCT1 and UGT2B7 Proteins to Explain the Variability in Clearances in Neonates and Small Infants.

PubMed

Emoto, Chie; Johnson, Trevor N; Neuhoff, Sibylle; Hahn, David; Vinks, Alexander A; Fukuda, Tsuyoshi

2018-06-19

Morphine has large pharmacokinetic variability, which is further complicated by developmental changes in neonates and small infants. The impacts of organic cation transporter 1 (OCT1) genotype and changes in blood-flow on morphine clearance (CL) were previously demonstrated in children, whereas changes in UDP-glucuronosyltransferase 2B7 (UGT2B7) activity showed a small effect. This study, targeting neonates and small infants, was designed to assess the influence of developmental changes in OCT1 and UGT2B7 protein expression and modified blood-flow on morphine CL using physiologically based pharmacokinetic (PBPK) modeling. The implementation of these three age-dependent factors into the pediatric system platform resulted in reasonable prediction for an age-dependent increase in morphine CL in these populations. Sensitivity of morphine CL to changes in cardiac output increased with age up to 3 years, whereas sensitivity to changes in UGT2B7 activity decreased. This study suggests that morphine exhibits age-dependent extraction, likely due to the developmental increase in OCT1 and UGT2B7 protein expression/activity and hepatic blood-flow. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Role of Medial Prefrontal Cortex Narp in the Extinction of Morphine Conditioned Place Preference

ERIC Educational Resources Information Center

Blouin, Ashley M.; Han, Sungho; Pearce, Anne M.; Cheng, KaiLun; Lee, JongAh J.; Johnson, Alexander W.; Wang, Chuansong; During, Matthew J.; Holland, Peter C.; Shaham, Yavin; Baraban, Jay M.; Reti, Irving M.

2013-01-01

Narp knockout (KO) mice demonstrate an impaired extinction of morphine conditioned place preference (CPP). Because the medial prefrontal cortex (mPFC) has been implicated in extinction learning, we tested whether Narp cells in this region play a role in the extinction of morphine CPP. We found that intracranial injections of adenoassociated virus…

Drug-sensitive reward in crayfish: an invertebrate model system for the study of SEEKING, reward, addiction, and withdrawal.

PubMed

Huber, Robert; Panksepp, Jules B; Nathaniel, Thomas; Alcaro, Antonio; Panksepp, Jaak

2011-10-01

In mammals, rewarding properties of drugs depend on their capacity to activate appetitive motivational states. With the underlying mechanisms strongly conserved in evolution, invertebrates have recently emerged as a powerful new model in addiction research. In crayfish natural reward has proven surprisingly sensitive to human drugs of abuse, opening an unlikely avenue of research into the basic biological mechanisms of drug addiction. In a series of studies we first examined the presence of natural reward systems in crayfish, then characterized its sensitivity to a wide range of human drugs of abuse. A conditioned place preference (CPP) paradigm was used to demonstrate that crayfish seek out those environments that had previously been paired with the psychostimulants cocaine and amphetamine, and the opioid morphine. The administration of amphetamine exerted its effects at a number of sites, including the stimulation of circuits for active exploratory behaviors (i.e., SEEKING). A further study examined morphine-induced reward, extinction and reinstatement in crayfish. Repeated intra-circulatory infusions of morphine served as a reward when paired with distinct visual or tactile cues. Morphine-induced CPP was extinguished after repeated saline injections. Following this extinction phase, morphine-experienced crayfish were once again challenged with the drug. The priming injections of morphine reinstated CPP at all tested doses, suggesting that morphine-induced CPP is unrelenting. In an exploration of drug-associated behavioral sensitization in crayfish we concurrently mapped measures of locomotion and rewarding properties of morphine. Single and repeated intra-circulatory infusions of morphine resulted in persistent locomotory sensitization, even 5 days following the infusion. Moreover, a single dose of morphine was sufficient to induce long-term behavioral sensitization. CPP for morphine and context-dependent cues could not be disrupted over a drug free period of 5 days. This work demonstrates that crayfish offer a comparative and complementary approach in addiction research. Serving as an invertebrate animal model for the exposure to mammalian drugs of abuse, modularly organized and experimentally accessible nervous systems render crayfish uniquely suited for studying (1) the basic biological mechanisms of drug effects, (2) to explore how the appetitive/seeking disposition is implemented in a simple neural system, and (3) how such a disposition is related to the rewarding action of drugs of abuse. This work aimed to contribute an evolutionary, comparative context to our understanding of a key component in learning, and of natural reward as an important life-sustaining process. Copyright © 2010 Elsevier Ltd. All rights reserved.

The effects of compound 48/80, morphine, and mast cell depletion on electroshock seizure in mice.

PubMed

Yillar, D O; Küçükhüseyin, C

2008-01-01

The effects of compound 48/80 (C48/80), morphine, and mast cell depletion on maximal electroshock seizure (MES) were studied in Swiss albino mice. An electrical current (60Hz, 0.2 msec) inducing convulsions in 50% of the animals (CC50) was assessed as 46 mA. Compound 48/80 (5 mg/kg) and morphine (100mg/kg) were administered subcutaneously. CC50 was applied separately to electroshock-unexposed animal groups at 15, 30, 60, 120, and 240 min after the onset of the experiment. In untreated controls, the percent of seizure induced by CC50 and percent of death among mice having convulsions were 50 and 20, respectively. After C48/80, a significant increase in rates of seizure at 60th and 120th min and death beyond 60th min (p < .0001) indicates a pro-convulsive action of the drug, probably caused by a reduction in MES threshold. In contrast, rate of seizure tended to decrease following mast-cell depletion, which was readily reversed by C48/80 at the 60th min (p < .0001). Mast-cell depletion, alone or plus morphine, significantly increased the death percentage of convulsions. Morphine alone reduced the percentage of seizure induced by the application of CC50 in the mast-cell depleted animals (anticonvulsive action) but increased the percent of dying animals by as much as 100% at the 30th and 60th min (p < .0001). Combined morphine + C48/80 not only augmented the anticonvulsive effect of morphine at the 30th min but also nullified the rate of death among mice having convulsions. We concluded that compound 48/80 (1) penetrates into the central nervous system to produce a central effect; (2) acts as pro-convulsive, and (3) paradoxically augments the anticonvulsive action of morphine, likely caused by the ability of the compound to increase the permeability of blood-brain barrier for morphine or by the release of histamine from mast cells in the brain, acting as anticonvulsant through the stimulation of H1 receptors or both. The precise mechanism of the increased death rate by C48/80 or morphine in intact and in mast-cell-depleted mice appears to involve pro-convulsive effects, cardiovascular impairment, and respiratory depression. The nullification of morphine-induced lethal toxicity by C48/80 could be due to the antagonistic interaction of the drug with opiate receptors in the brain.

The effect of morphine added to bupivacaine in ultrasound guided transversus abdominis plane (TAP) block for postoperative analgesia following lower abdominal cancer surgery, a randomized controlled study.

PubMed

El Sherif, Fatma Adel; Mohamed, Sahar Abdel-Baky; Kamal, Shereen Mamdouh

2017-06-01

Transversus abdominis plane (TAP) block used for management of surgical abdominal pain by injecting local anesthetics into the plane between the internal oblique and transversus abdominis muscles. We aimed to explore the effect of adding morphine to bupivacaine in ultrasound guided TAP-block in patients undergoing lower abdominal cancer surgery. Randomized, double-blind, prospective study. Clinical trial identifier: NCT02566096. Academic medical center. Sixty patients were enrolled in this study after ethical committee approval. Patients divided into 2 groups (30 each): Bupivacaine group (GB): given ultrasound guided TAP-block 20ml 0.5% bupivacaine diluted in 20ml saline; Morphine group (GM): given ultrasound guided TAP-block with 20ml 0.5% bupivacaine+10mg morphine sulphate diluted in 20ml saline. Patients were observed for total morphine consumption, time for first request of rescue analgesia, sedation scores, hemodynamics and side effects for 24h postoperatively. Morphine added to bupivacaine in TAP block compared to bupivacaine alone reduced total morphine consumption (5.33±1.28mg) (10.70±3.09mg) respectively (p<0.001), prolonged the time to first request of analgesia (10.40±4.96h) (6.97±3.26h) respectively (p<0.008), with a statistically significant decrease in (VAS-M) in GM compared with GB at 12h postoperatively (p<0.002). No significant differences in hemodynamics, respiratory rate, oxygen saturation, sedation score, and side effects except for nausea were observed (p>0.05). Addition of morphine to bupivacaine in TAP block is effective method for pain management in patients undergoing major abdominal cancer surgery without serious side effects. Copyright © 2017 Elsevier Inc. All rights reserved.

Cerebrolysin Attenuates Heat Shock Protein (HSP 72 KD) Expression in the Rat Spinal Cord Following Morphine Dependence and Withdrawal: Possible New Therapy for Pain Management

PubMed Central

Sharma, Hari S; Ali, Syed F; Patnaik, Ranjana; Zimmermann-Meinzingen, Sibilla; Sharma, Aruna; Muresanu, Dafin F

2011-01-01

The possibility that pain perception and processing in the CNS results in cellular stress and may influence heat shock protein (HSP) expression was examined in a rat model of morphine dependence and withdrawal. Since activation of pain pathways result in exhaustion of growth factors, we examined the influence of cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,) on morphine induced HSP expression. Rats were administered morphine (10 mg/kg, s.c. /day) for 12 days and the spontaneous withdrawal symptoms were developed by cessation of the drug administration on day 13th that were prominent on day 14th and continued up to day 15th (24 to 72 h periods). In a separate group of rats, cerebrolysin was infused intravenously (5 ml/kg) once daily from day one until day 15th. In these animals, morphine dependence and withdrawal along with HSP immunoreactivity was examined using standard protocol. In untreated group mild HSP immunoreaction was observed during morphine tolerance, whereas massive upregulation of HSP was seen in CNS during withdrawal phase that correlated well with the withdrawal symptoms and neuronal damage. Pretreatment with cerebrolysin did not affect morphine tolerance but reduced the HSP expression during this phase. Furthermore, cerebrolysin reduced the withdrawal symptoms on day 14th to 15th. Taken together these observations suggest that cellular stress plays an important role in morphine induced pain pathology and exogenous supplement of growth factors, i.e. cerebrolysin attenuates HSP expression in the CNS and induce neuroprotection. This indicates a new therapeutic role of cerebrolysin in the pathophysiology of drugs of abuse, not reported earlier. PMID:21886595

Initial Dosing and Taper Complexity of Methadone and Morphine for Treatment of Neonatal Abstinence Syndrome

PubMed Central

Ibach, Bethany W.; Johnson, Peter N.; Ernst, Kimberly D.; Harrison, Donald; Miller, Jamie L.

2016-01-01

Background: Methadone and morphine are commonly used to treat neonatal abstinence syndrome (NAS). Limited data exist to describe the most appropriate initial doses and taper regimens of these agents. Objectives: Describe the median initial dose and frequency of methadone and morphine for NAS. Compare dose adjustments, time to symptom relief, and taper complexity between groups. Methods: Retrospective study of neonates receiving enteral methadone or morphine for NAS over a 4-year period. Data collection included medication regimen, abstinence scores based on the Modified Finnegan Neonatal Abstinence Scoring Tool, and adverse events. Planned home taper complexity was assessed using the Medication Taper Complexity Score–Revised (MTCS-R). The primary outcome was initial opioid dose. Secondary outcomes included number of dose adjustments, time to symptom relief, and MTCS-R score. Results: Fifty neonates were initially treated for NAS with methadone (n = 36) or morphine (n = 14). The median initial dose was 0.09 mg/kg (range = 0.03-0.2) for methadone and 0.04 mg/kg (range = 0.03-0.4) for morphine. The most common initial dosing interval was q8h for methadone versus q3h for morphine. Number of dose adjustments and time to symptom relief were similar between groups. Median MTCS-R scores were similar between groups. There was no difference in adverse events between groups. Limitations included small sample size, preference toward methadone use, and variability of initial opioid dosing and titration. Conclusions: There was significant variability in initial doses of both agents. Neonates receiving methadone required less frequent dosing than morphine, which may result in easier administration and may allow for safer outpatient administration.

Demethylation regulation of BDNF gene expression in dorsal root ganglion neurons is implicated in opioid-induced pain hypersensitivity in rats.

PubMed

Chao, Yu-Chieh; Xie, Fang; Li, Xueyang; Guo, Ruijuan; Yang, Ning; Zhang, Chen; Shi, Rong; Guan, Yun; Yue, Yun; Wang, Yun

2016-07-01

Repeated administration of morphine may result in opioid-induced hypersensitivity (OIH), which involves altered expression of numerous genes, including brain-derived neurotrophic factor (BDNF) in dorsal root ganglion (DRG) neurons. Yet, it remains unclear how BDNF expression is increased in DRG neurons after repeated morphine treatment. DNA methylation is an important mechanism of epigenetic control of gene expression. In the current study, we hypothesized that the demethylation regulation of certain BDNF gene promoters in DRG neurons may contribute to the development of OIH. Real-time RT-PCR was used to assess changes in the mRNA transcription levels of major BDNF exons including exon I, II, IV, VI, as well as total BDNF mRNA in DRGs from rats after repeated morphine administration. The levels of exon IV and total BDNF mRNA were significantly upregulated by repeated morphine administration, as compared to that in saline control group. Further, ELISA array and immunocytochemistry study revealed a robust upregulation of BDNF protein expression in DRG neurons after repeated morphine exposure. Correspondingly, the methylation levels of BDNF exon IV promoter showed a significant downregulation by morphine treatment. Importantly, intrathecal administration of a BDNF antibody, but not control IgG, significantly inhibited mechanical hypersensitivity that developed in rats after repeated morphine treatment. Conversely, intrathecal administration of an inhibitor of DNA methylation, 5-aza-2'-deoxycytidine (5-aza-dC) markedly upregulated the BDNF protein expression in DRG neurons and enhanced the mechanical allodynia after repeated morphine exposure. Together, our findings suggest that demethylation regulation of BDNF gene promoter may be implicated in the development of OIH through epigenetic control of BDNF expression in DRG neurons. Copyright © 2016 Elsevier Ltd. All rights reserved.

The proteins interacting with C-terminal of μ receptor are identified by bacterial two-hybrid system from brain cDNA library in morphine-dependent rats.

PubMed

Zhou, Peilan; Jiang, Jiebing; Dong, Zhaoqi; Yan, Hui; You, Zhendong; Su, Ruibin; Gong, Zehui

2015-12-15

Opioid addiction is associated with long-term adaptive changes in the brain that involve protein expression. The carboxyl-terminal of the μ opioid receptor (MOR-C) is important for receptor signal transduction under opioid treatment. However, the proteins that interact with MOR-C after chronic morphine exposure remain unknown. The brain cDNA library of chronic morphine treatment rats was screened using rat MOR-C to investigate the regulator of opioids dependence in the present study. The brain cDNA library from chronic morphine-dependent rats was constructed using the SMART (Switching Mechanism At 5' end of RNA Transcript) technique. Bacterial two-hybrid system was used to screening the rat MOR-C interacting proteins from the cDNA library. RT-qPCR and immunoblotting were used to determine the variation of MOR-C interacting proteins in rat brain after chronic morphine treatment. Column overlay assays, immunocytochemistry and coimmunoprecipitation were used to demonstrate the interaction of MOR-C and p75NTR-associated cell death executor (NADE). 21 positive proteins, including 19 known proteins were screened to interact with rat MOR-C. Expression of several of these proteins was altered in specific rat brain regions after chronic morphine treatment. Among these proteins, NADE was confirmed to interact with rat MOR-C by in vitro protein-protein binding and coimmunoprecipitation in Chinese hamster ovary (CHO) cells and rat brain with or without chronic morphine treatment. Understanding the rat MOR-C interacting proteins and the proteins variation under chronic morphine treatment may be critical for determining the pathophysiological basis of opioid tolerance and addiction. Copyright © 2015. Published by Elsevier Inc.

Population pharmacokinetic modelling of non-linear brain distribution of morphine: influence of active saturable influx and P-glycoprotein mediated efflux

PubMed Central

Groenendaal, D; Freijer, J; de Mik, D; Bouw, M R; Danhof, M; de Lange, E C M

2007-01-01

Background and purpose: Biophase equilibration must be considered to gain insight into the mechanisms underlying the pharmacokinetic-pharmacodynamic (PK-PD) correlations of opioids. The objective was to characterise in a quantitative manner the non-linear distribution kinetics of morphine in brain. Experimental approach: Male rats received a 10-min infusion of 4 mg kg−1 of morphine, combined with a continuous infusion of the P-glycoprotein (Pgp) inhibitor GF120918 or vehicle, or 40 mg kg−1 morphine alone. Unbound extracellular fluid (ECF) concentrations obtained by intracerebral microdialysis and total blood concentrations were analysed using a population modelling approach. Key results: Blood pharmacokinetics of morphine was best described with a three-compartment model and was not influenced by GF120918. Non-linear distribution kinetics in brain ECF was observed with increasing dose. A one compartment distribution model was developed, with separate expressions for passive diffusion, active saturable influx and active efflux by Pgp. The passive diffusion rate constant was 0.0014 min−1. The active efflux rate constant decreased from 0.0195 min−1 to 0.0113 min−1 in the presence of GF120918. The active influx was insensitive to GF120918 and had a maximum transport (Nmax/Vecf) of 0.66 ng min−1 ml−1 and was saturated at low concentrations of morphine (C50=9.9 ng ml−1). Conclusions and implications: Brain distribution of morphine is determined by three factors: limited passive diffusion; active efflux, reduced by 42% by Pgp inhibition; low capacity active uptake. This implies blood concentration-dependency and sensitivity to drug-drug interactions. These factors should be taken into account in further investigations on PK-PD correlations of morphine. PMID:17471182

Attenuation of Morphine-Induced Tolerance and Dependence by Pretreatment with Cerebrolysin in Male rats.

PubMed

Ghavimi, Hamed; Darvishi, Sara; Ghanbarzadeh, Saeed

2018-01-01

Dependence and tolerance to morphine are major problems which limit its chronic clinical application. This study was aimed to investigate the attenuation effect of Cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,), on the development of Morphine-induced dependence and tolerance. Male Wistar rats were selected randomly and divided into different groups (n=8) including: a control group, groups received additive doses of morphine (5-25 mg/kg, ip, at an interval of 12 h until tolerance completion), and groups pretreated with Cerebrolysin (40, 80 and 160 mg/kg, ip, before morphine administration). Development of tolerance was assessed by tail-flick test and the attenuation effect of Cerebrolysin on morphine-induced dependence was evaluated after injection of naloxone (4 mg/kg, ip, 12 h after the morning dose of morphine). Seven distinct withdrawal signs including: jumping, rearing, genital grooming, abdominal writhing, wet dog shake and teeth grinding were recorded for 45 min and total withdrawal score (TWS) was calculated. Results showed that administration of Cerebrolysin could prolonged development (10 and 14 days in administration of 80 mg/kg and 160 mg/kg Cerebrolysin) and completion (4, 10 and 14 days in administration of 40, 80 and 160 mg/kg Cerebrolysin, respectively) of tolerance. Results also indicated that administration of Cerebrolysin (40, 80 and 160 mg/kg) could significantly decreased the TWS value (62±2, 77±4 and 85±6%, respectively). In conclusion, it was found that pretreatment with Cerebrolysin could attenuated morphine-induced tolerance and dependence. © Georg Thieme Verlag KG Stuttgart · New York.

Modeling the Effects of Morphine on Simian Immunodeficiency Virus Dynamics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vaidya, Naveen K.; Ribeiro, Ruy M.; Perelson, Alan S.

Complications of HIV-1 infection in individuals who utilize drugs of abuse is a significant problem, because these drugs have been associated with higher virus replication and accelerated disease progression as well as severe neuropathogenesis. To gain further insight it is important to quantify the effects of drugs of abuse on HIV-1 infection dynamics. Here, we develop a mathematical model that incorporates experimentally observed effects of morphine on inducing HIV-1 co-receptor expression. For comparison we also considered viral dynamic models with cytolytic or noncytolytic effector cell responses. Based on the small sample size Akaike information criterion, these models were inferior tomore » the new model based on changes in co-receptor expression. The model with morphine affecting co-receptor expression agrees well with the experimental data from simian immunodeficiency virus infections in morphine-addicted macaques. Our results show that morphine promotes a target cell subpopulation switch from a lower level of susceptibility to a state that is about 2-orders of magnitude higher in susceptibility to SIV infection. As a result, the proportion of target cells with higher susceptibility remains extremely high in morphine conditioning. Such a morphine-induced population switch not only has adverse effects on the replication rate, but also results in a higher steady state viral load and larger CD4 count drops. Moreover, morphine conditioning may pose extra obstacles to controlling viral load during antiretroviral therapy, such as pre-exposure prophylaxis and post infection treatments. In conclusion, this study provides, for the first time, a viral dynamics model, viral dynamics parameters, and related analytical and simulation results for SIV dynamics under drugs of abuse.« less

The α3β4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies.

PubMed

Muldoon, P P; Jackson, K J; Perez, E; Harenza, J L; Molas, S; Rais, B; Anwar, H; Zaveri, N T; Maldonado, R; Maskos, U; McIntosh, J M; Dierssen, M; Miles, M F; Chen, X; De Biasi, M; Damaj, M I

2014-08-01

Recent data have indicated that α3β4* neuronal nicotinic (n) ACh receptors may play a role in morphine dependence. Here we investigated if nACh receptors modulate morphine physical withdrawal. To assess the role of α3β4* nACh receptors in morphine withdrawal, we used a genetic correlation approach using publically available datasets within the GeneNetwork web resource, genetic knockout and pharmacological tools. Male and female European-American (n = 2772) and African-American (n = 1309) subjects from the Study of Addiction: Genetics and Environment dataset were assessed for possible associations of polymorphisms in the 15q25 gene cluster and opioid dependence. BXD recombinant mouse lines demonstrated an increased expression of α3, β4 and α5 nACh receptor mRNA in the forebrain and midbrain, which significantly correlated with increased defecation in mice undergoing morphine withdrawal. Mice overexpressing the gene cluster CHRNA5/A3/B4 exhibited increased somatic signs of withdrawal. Furthermore, α5 and β4 nACh receptor knockout mice expressed decreased somatic withdrawal signs compared with their wild-type counterparts. Moreover, selective α3β4* nACh receptor antagonists, α-conotoxin AuIB and AT-1001, attenuated somatic signs of morphine withdrawal in a dose-related manner. In addition, two human datasets revealed a protective role for variants in the CHRNA3 gene, which codes for the α3 nACh receptor subunit, in opioid dependence and withdrawal. In contrast, we found that the α4β2* nACh receptor subtype is not involved in morphine somatic withdrawal signs. Overall, our findings suggest an important role for the α3β4* nACh receptor subtype in morphine physical dependence. © 2014 The British Pharmacological Society.

A Subanalgesic Dose of Morphine Eliminates Nalbuphine Anti-analgesia in Postoperative Pain

PubMed Central

Gear, Robert W.; Gordon, Newton C.; Hossaini-Zadeh, Mehran; Lee, Janice S.; Miaskowski, Christine; Paul, Steven M.; Levine, Jon D.

2008-01-01

The agonist-antagonist kappa-opioid nalbuphine administered for postoperative pain produces greater analgesia in females than in males. In fact, males administered nalbuphine (5 mg) experience pain greater than those receiving placebo, suggesting the existence of an anti-analgesic effect. These sexually dimorphic effects on postoperative pain can be eliminated by co-administration of a fixed ratio of the prototypical opioid receptor antagonist naloxone with nalbuphine, implying a role for opioid receptors in the anti-analgesic as well as analgesic effects of nalbuphine. In the present study, we further evaluated the role of opioid receptors in the sex-specific effects on pain produced by nalbuphine by co-administering a dose of morphine low enough that it does not produce analgesia. Following extraction of bony impacted third molar teeth, nalbuphine (5 mg) was administered alone or in combination with either of two low doses of morphine (2 mg or 4 mg). Both doses of morphine reversed nalbuphine-induced anti-analgesia in males, but only the lower dose (2 mg) reached statistical significance. Neither dose affected nalbuphine-induced analgesia in females, and when administered alone in either males or females, morphine (2 mg) had no analgesic effect. Though not observed in females, the effect of morphine in males argues that, like naloxone, low dose morphine may act as an anti-analgesia opioid receptor antagonist. Perspective Previously we reported that the nalbuphine produces both analgesic and anti-analgesic effects, and that the opioid antagonist naloxone can enhance nalbuphine analgesia by selectively antagonizing the anti-analgesic effect. Here we show that morphine, given in a subanalgesic dose, reverses nalbuphine-induced anti-analgesia in males, perhaps by a similar mechanism. PMID:18201935

Daily morphine administration increases impulsivity in rats responding under a 5‐choice serial reaction time task

PubMed Central

Maguire, DR; Henson, C

2016-01-01

Background and Purpose Repeated administration of a μ opioid receptor agonist can enhance some forms of impulsivity, such as delay discounting. However, it is unclear whether repeated administration alters motor impulsivity. Experimental Approach We examined the effects of acute administration of morphine and amphetamine prior to and during daily morphine administration in rats responding under a five‐choice serial reaction time task. Rats (n = 5) were trained to detect a brief flash of light presented randomly in one of five response holes; responding in the target hole delivered food, whereas responding in the wrong hole or responding prior to illumination of the target stimulus (premature response) initiated a timeout. Premature responding served as an index of motor impulsivity. Key Results Administered acutely, morphine (0.1–10 mg·kg−1, i.p.) increased omissions and modestly, although not significantly, premature responding without affecting response accuracy; amphetamine (0.1–1.78 mg·kg−1, i.p.) increased premature responding without changing omissions or response accuracy. After 3 weeks of 10 mg·kg−1·day−1 morphine, tolerance developed to its effects on omissions whereas premature responding increased approximately fourfold, compared with baseline. Effects of amphetamine were not significantly affected by daily morphine administration. Conclusions and Implications These data suggest that repeated administration of morphine increased effects of morphine on motor impulsivity, although tolerance developed to other effects, such as omissions. To the extent that impulsivity is a risk factor for drug abuse, repeated administration of μ opioid receptor agonists, for recreational or therapeutic purposes, might increase impulsivity and thus the risk for drug abuse. PMID:26776751

Modeling the Effects of Morphine on Simian Immunodeficiency Virus Dynamics

DOE PAGES

Vaidya, Naveen K.; Ribeiro, Ruy M.; Perelson, Alan S.; ...

2016-09-26

Complications of HIV-1 infection in individuals who utilize drugs of abuse is a significant problem, because these drugs have been associated with higher virus replication and accelerated disease progression as well as severe neuropathogenesis. To gain further insight it is important to quantify the effects of drugs of abuse on HIV-1 infection dynamics. Here, we develop a mathematical model that incorporates experimentally observed effects of morphine on inducing HIV-1 co-receptor expression. For comparison we also considered viral dynamic models with cytolytic or noncytolytic effector cell responses. Based on the small sample size Akaike information criterion, these models were inferior tomore » the new model based on changes in co-receptor expression. The model with morphine affecting co-receptor expression agrees well with the experimental data from simian immunodeficiency virus infections in morphine-addicted macaques. Our results show that morphine promotes a target cell subpopulation switch from a lower level of susceptibility to a state that is about 2-orders of magnitude higher in susceptibility to SIV infection. As a result, the proportion of target cells with higher susceptibility remains extremely high in morphine conditioning. Such a morphine-induced population switch not only has adverse effects on the replication rate, but also results in a higher steady state viral load and larger CD4 count drops. Moreover, morphine conditioning may pose extra obstacles to controlling viral load during antiretroviral therapy, such as pre-exposure prophylaxis and post infection treatments. In conclusion, this study provides, for the first time, a viral dynamics model, viral dynamics parameters, and related analytical and simulation results for SIV dynamics under drugs of abuse.« less

A morphine/heroin vaccine with new hapten design attenuates behavioral effects in rats.

PubMed

Li, Qian-Qian; Luo, Yi-Xiao; Sun, Cheng-Yu; Xue, Yan-Xue; Zhu, Wei-Li; Shi, Hai-Shui; Zhai, Hai-Feng; Shi, Jie; Lu, Lin

2011-12-01

Heroin use has seriously threatened public heath in many countries, but the existing therapies continue to have many limitations. Recently, immunotherapy has shown efficacy in some clinical studies, including vaccines against nicotine and cocaine, but no opioid vaccines have been introduced in clinical studies. The development of a novel opioid antigen designed specifically for the prevention of heroin addiction is necessary. A morphine-keyhole limpet hemocyanin conjugate was prepared and administered subcutaneously in rats. Antibody titers in plasma were measured using an enzyme-linked immunosorbent assay (ELISA). Competitive ELISA was used to assess the selectivity of the antibodies. Dopamine concentrations in the nucleus accumbens in rats after vaccine administration were determined by high-performance liquid chromatography with electrochemical detection. The effects of the vaccine on the heroin-primed restatement of self-administration and locomotor sensitization were evaluated. A novel hapten, 6-glutarylmorphine, was produced, and the vaccine generated a high antibody titer response. This vaccine displayed specificity for both morphine and heroin, but the anti-morphine antibodies could not recognize dissimilar therapeutic opioid compounds, such as buprenorphine, methadone, naloxone, naltrexone, codeine, and nalorphine. The morphine antibody significantly decreased morphine-induced locomotor activity in rats after immunization. Importantly, rats immunized with this vaccine did not exhibit heroin-primed reinstatement of heroin seeking when antibody levels were sufficiently high. The vaccine reduced dopamine levels in the nucleus accumbens after morphine administration, which is consistent with its behavioral effects. These results suggest that immunization with a novel vaccine is an effective means of inducing a morphine-specific antibody response that is able to attenuate the behavioral and psychoactive effects of heroin. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Intra-accumbal administration of AMN082, a metabotropic glutamate receptor type 7 allosteric agonist, inhibits the acquisition but not the expression of morphine-induced conditioned place preference in rats.

PubMed

Vatankhah, Mahsaneh; Karimi-Haghighi, Saeideh; Sarihi, Abdolrahman; Haghparast, Abbas

2018-05-22

The nucleus accumbens (NAc) plays a primary role in opioid reward. The actions of glutamate are mediated by the activation of ionotropic and metabotropic glutamate receptors (mGluRs). Previous documents have shown the extensive distributions of the different types of mGluRs, including mGluR7, in regions that are involved in opioid reward, such as the NAc. In this study, seventy male Wistar rats were used to investigate the role of mGluR7 receptors in the NAc on the acquisition and expression of morphine-induced conditioned place preference (CPP). In Experiment 1, to determine the effect of AMN082, a selective mGluR7 allosteric agonist, on the acquisition of morphine-induced conditioned place preference (CPP), the rats bilaterally received AMN082 (1, 3 and 5 μg/0.5 μL DMSO) during three-day conditioning by morphine (5 mg/kg). In Experiment 2, the rats bilaterally received AMN082 (5 μg/0.5 μL DMSO) 5 min prior to the post-conditioning test to investigate the effect of AMN082 on the expression of morphine-induced CPP. The results showed that the intra-accumbal injection of AMN082 prevents the acquisition of morphine-induced CPP in a dose-dependent manner. However, intra-accumbal injection of AMN082 had no effect on the expression of morphine-induced CPP. The findings propose that the mGluR7 in the NAc inhibits the acquisition of morphine-induced CPP that could be mediated by inhibition of NMDA receptors in the NAc. Copyright © 2018 Elsevier B.V. All rights reserved.

AMN082-a metabotropic glutamate receptor type 7 allosteric agonist in the NAc facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats.

PubMed

Vatankhah, Mahsaneh; Sarihi, Abdolrahman; Komaki, Alireza; Shahidi, Siamak; Haghparast, Abbas

2018-03-29

Nucleus accumbens (NAc) plays a primary role in opioid reward. The actions of glutamate (which is the most extensive excitatory neurotransmitter in the mammalian central nervous system) are mediated through the activation of the ionotropic and metabotropic glutamate receptors (mGluRs). Previous studies have shown the extensive distributions of the different types of mGluRs, including mGluR7, in regions that are involved in opioid reward, such as NAc. In this study, CPP was used to investigate the effect of mGluR7 on the extinction period, and the reinstatement of morphine. The animals received bilaterally microinjections of AMN082, a selective mGluR 7 allosteric agonist, into the NAc. In Experiment 1, the rats received AMN082 (1 and 5 μg/0.5 μl) during the extinction period. In Experiment 2, the CPP morphine-extinguished rats received AMN082 (1, 3 and 5 μg/0.5 μl) five minutes prior to the administration of an ineffective dosage of morphine (1 mg/kg) in order to reinstate the extinguished morphine. The results of the recorded conditioning scores in this study showed that the intra-accumbal administration of AMN08 reduced the extinction period of morphine. Moreover, the administration of AMN082 into the NAc dose-dependently inhibited the reinstatement of morphine. The findings suggested that the mGluR7 in the NAc facilitates the extinction and inhibits the reinstatement of the morphine-induced CPP that could have been mediated by an increase in the release of extracellular glutamate. Copyright © 2018 Elsevier Inc. All rights reserved.

Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression

PubMed Central

Song, Zhi-Jing; Miao, Shuai; Zhao, Ye; Wang, Xiu-Li; Liu, Yue-Peng

2018-01-01

Purpose Preventing opioid-induced hyperalgesia and tolerance continues to be a major clinical challenge, and the underlying mechanisms of hyperalgesia and tolerance remain elusive. Here, we investigated the role of sonic hedgehog (Shh) signaling in opioid-induced hyperalgesia and tolerance. Methods Shh signaling expression, behavioral changes, and neurochemical alterations induced by morphine were analyzed in male adult CD-1 mice with repeated administration of morphine. To investigate the contribution of Shh to morphine-induced hyperalgesia (MIH) and tolerance, Shh signaling inhibitor cyclopamine and Shh small interfering RNA (siRNA) were used. To explore the mechanisms of Shh signaling in MIH and tolerance, brain-derived neurotrophic factor (BDNF) inhibitor K252 and anti-BDNF antibody were used. Results Repeated administration of morphine produced obvious hyperalgesia and tolerance. The behavioral changes were correlated with the upregulation and activation of morphine treatment-induced Shh signaling. Pharmacologic and genetic inhibition of Shh signaling significantly delayed the generation of MIH and tolerance and associated neurochemical changes. Chronic morphine administration also induced upregulation of BDNF. Inhibiting BDNF effectively delayed the generation of MIH and tolerance. The upregulation of BDNF induced by morphine was significantly suppressed by inhibiting Shh signaling. In naïve mice, exogenous activation of Shh signaling caused a rapid increase of BDNF expression, as well as thermal hyperalgesia. Inhibiting BDNF significantly suppressed smoothened agonist-induced hyperalgesia. Conclusion These findings suggest that Shh signaling may be a critical mediator for MIH and tolerance by regulating BDNF expression. Inhibiting Shh signaling, especially during the early phase, may effectively delay or suppress MIH and tolerance. PMID:29662325

Comparative analgesic efficacy of morphine sulfate and butorphanol tartrate in koi (Cyprinus carpio) undergoing unilateral gonadectomy

PubMed Central

Baker, Tracie R.; Baker, Bridget B.; Johnson, Stephen M.; Sladky, Kurt K.

2016-01-01

Objective To identify pain-related behaviors and assess the effects of butorphanol tartrate and morphine sulfate in koi (Cyprinus carpio) undergoing unilateral gonadectomy. Design Prospective study. Animals 90 adult male and female koi. Procedures Each fish received saline (0.9% NaCl) solution (which is physiologically compatible with fish) IM, butorphanol (10 mg/kg [4.5 mg/lb], IM), or morphine (5 mg/kg [2.3 mg/lb], IM) as an injection only (6 fish/treatment); an injection with anesthesia and surgery (12 fish/treatment); or an injection with anesthesia but without surgery (12 fish/treatment). Physiologic and behavioral data were recorded 12 hours before and at intervals after treatment. Results Compared with baseline values, the saline solution–surgery group had significantly decreased respiratory rates (at 12 to 24 hours), food consumption assessed as a percentage of floating pellets consumed (at 0 to 36 hours), and activity score (at 0 to 48 hours). Respiratory rate decreased in all butorphanol-treated fish; significant decreases were detected at fewer time points following morphine administration. In the butorphanol-surgery group, the value for food consumption initially decreased but returned to baseline values within 3 hours after treatment; food consumption did not change in the morphine-surgery group. Surgery resulted in decreased activity, regardless of treatment, with the most pronounced effect in the saline solution–surgery group. Changes in location in water column, interactive behavior, and hiding behavior were not significantly different among groups. Butorphanol and morphine administration was associated with temporary buoyancy problems and temporary bouts of excessive activity, respectively. Conclusions and Clinical Relevance Butorphanol and morphine appeared to have an analgesic effect in koi, but morphine administration caused fewer deleterious adverse effects. Food consumption appeared to be a reliable indicator of pain in koi. PMID:24004238

Comparative analgesic efficacy of morphine sulfate and butorphanol tartrate in koi (Cyprinus carpio) undergoing unilateral gonadectomy.

PubMed

Baker, Tracie R; Baker, Bridget B; Johnson, Stephen M; Sladky, Kurt K

2013-09-15

To identify pain-related behaviors and assess the effects of butorphanol tartrate and morphine sulfate in koi (Cyprinus carpio) undergoing unilateral gonadectomy. Design-Prospective study. 90 adult male and female koi. Each fish received saline (0.9% NaCl) solution (which is physiologically compatible with fish) IM, butorphanol (10 mg/kg [4.5 mg/lb], IM), or morphine (5 mg/kg [2.3 mg/lb], IM) as an injection only (6 fish/treatment); an injection with anesthesia and surgery (12 fish/treatment); or an injection with anesthesia but without surgery (12 fish/treatment). Physiologic and behavioral data were recorded 12 hours before and at intervals after treatment. Compared with baseline values, the saline solution-surgery group had significantly decreased respiratory rates (at 12 to 24 hours), food consumption assessed as a percentage of floating pellets consumed (at 0 to 36 hours), and activity score (at 0 to 48 hours). Respiratory rate decreased in all butorphanol-treated fish; significant decreases were detected at fewer time points following morphine administration. In the butorphanol-surgery group, the value for food consumption initially decreased but returned to baseline values within 3 hours after treatment; food consumption did not change in the morphine-surgery group. Surgery resulted in decreased activity, regardless of treatment, with the most pronounced effect in the saline solution-surgery group. Changes in location in water column, interactive behavior, and hiding behavior were not significantly different among groups. Butorphanol and morphine administration was associated with temporary buoyancy problems and temporary bouts of excessive activity, respectively. Butorphanol and morphine appeared to have an analgesic effect in koi, but morphine administration caused fewer deleterious adverse effects. Food consumption appeared to be a reliable indicator of pain in koi.

Intrathecal substance P augments morphine-induced antinociception: possible relevance in the production of substance P N-terminal fragments.

PubMed

Komatsu, Takaaki; Sasaki, Mika; Sanai, Kengo; Kuwahata, Hikari; Sakurada, Chikai; Tsuzuki, Minoru; Iwata, Yohko; Sakurada, Shinobu; Sakurada, Tsukasa

2009-09-01

The present study sought to examine the mechanism of substance P to modulate the antinociceptive action of intrathecal (i.t.) morphine in paw-licking/biting response evoked by subcutaneous injection of capsaicin into the plantar surface of the hindpaw in mice. The i.t. injection of morphine inhibited capsaicin-induced licking/biting response in a dose-dependent manner. Substance P (25 and 50 pmol) injected i.t. alone did not alter capsaicin-induced nociception, whereas substance P at a higher dose of 100 pmol significantly reduced the capsaicin response. Western blots showed the constitutive expression of endopeptidase-24.11 in the dorsal and ventral parts of lumbar spinal cord of mice. The N-terminal fragment of substance P (1-7), which is known as a major product of substance P by endopeptidase-24.11, was more effective than substance P on capsaicin-induced nociception. Combination treatment with substance P (50 pmol) and morphine at a subthreshold dose enhanced the antinociceptive effect of morphine. The enhanced effect of the combination of substance P with morphine was reduced significantly by co-administration of phosphoramidon, an inhibitor of endopeptidase-24.11. Administration of D-isomer of substance P (1-7), [D-Pro(2), D-Phe(7)]substance P (1-7), an inhibitor of [(3)H] substance P (1-7) binding, or antisera against substance P (1-7) reversed the enhanced antinociceptive effect by co-administration of substance P and morphine. Taken together these data suggest that morphine-induced antinociception may be enhanced through substance P (1-7) formed by the enzymatic degradation of i.t. injected substance P in the spinal cord.

Pharmacological Consequence of the A118G Mu Opioid Receptor Polymorphism on Morphine- and Fentanyl-mediated Modulation of Ca2+ Channels in Humanized Mouse Sensory Neurons

PubMed Central

Mahmoud, Saifeldin; Thorsell, Annika; Sommer, Wolfgang H.; Heilig, Markus; Holgate, Joan K.; Bartlett, Selena E.; Ruiz-Velasco, Victor

2011-01-01

Background The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with inter-individual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of the present study was to examine whether this polymorphism would modulate the morphine and fentanyl pharmacological profile of sensory neurons isolated from a humanized mouse model homozygous for either the 118A or 118G allele. Methods The coupling of wild-type and mutant mu opioid receptors to voltage-gated Ca2+ channels after exposure to either ligand was examined by employing the whole-cell variant of the patch-clamp technique in acutely dissociated trigeminal ganglion neurons. Morphine-mediated antinociception was measured in mice carrying either the 118AA or 118GG allele. Results The biophysical parameters (cell size, current density, and peak current amplitude potential) measured from both groups of sensory neurons were not significantly different. In 118GG neurons, morphine was approximately 5-fold less potent and 26% less efficacious than that observed in 118AA neurons. On the other hand, the potency and efficacy of fentanyl were similar for both groups of neurons. Morphine-mediated analgesia in 118GG mice was significantly reduced compared to the 118AA mice. Conclusions This study provides evidence to suggest that the diminished clinical effect observed with morphine in 118G carriers results from an alteration of the receptor’s pharmacology in sensory neurons. Additionally, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids. PMID:21926562

Morphine induces μ opioid receptor endocytosis in guinea pig enteric neurons following prolonged receptor activation

PubMed Central

Patierno, Simona; Anselmi, Laura; Jaramillo, Ingrid; Scott, David; Garcia, Rachel; Sternini, Catia

2010-01-01

Background & Aims The μ opioid receptor (μOR) undergoes rapid endocytosis following acute stimulation with opioids and most opiates, but not with morphine. We investigated whether prolonged activation of μOR affects morphine’s ability to induce receptor endocytosis in enteric neurons. Methods We compared the effects of morphine, a poor μOR-internalizing opiate, and [D-Ala2, MePhe4,Gly-ol5] enkephalin (DAMGO), a potent μOR-internalizing agonist, on μOR trafficking in enteric neurons and on the expression of dynamin and β-arrestin immunoreactivity in the ileum of guinea pigs rendered tolerant by chronic administration of morphine. Results Morphine (100 µM) strongly induced endocytosis of μOR in tolerant but not naïve neurons (55.7%±9.3% vs. 24.2%±7.3%, P<0.001) whereas DAMGO (10 µM) strongly induced internalization of μOR in neurons from tolerant and naïve animals (63.6%±8.4% and 66.5%±3.6%). Morphine- or DAMGO-induced μOR endocytosis resulted from direct interactions between the ligand and the μOR, because endocytosis was not affected by tetrodotoxin, a blocker of endogenous neurotransmitter release. Ligand-induced μOR internalization was inhibited by pretreatment with the dynamin inhibitor, dynasore. Chronic morphine administration resulted in a significant increase in dynamin and translocation of dynamin immunoreactivity from the intracellular pool to the plasma membrane, but did not affect β arrestin immunoreactivity. Conclusion Chronic activation of μORs increases the ability of morphine to induce μOR endocytosis in enteric neurons, which depends on the level and cellular localization of dynamin, a regulatory protein that has an important role in receptor-mediated signal transduction in cells. PMID:21070774

Exposure to opiates in female adolescents alters mu opiate receptor expression and increases the rewarding effects of morphine in future offspring.

PubMed

Vassoler, Fair M; Wright, Siobhan J; Byrnes, Elizabeth M

2016-04-01

Prescription opiate use and abuse has increased dramatically over the past two decades, including increased use in adolescent populations. Recently, it has been proposed that use during this critical period may affect future offspring even when use is discontinued prior to conception. Here, we utilize a rodent model to examine the effects of adolescent morphine exposure on the reward functioning of the offspring. Female Sprague Dawley rats were administered morphine for 10 days during early adolescence (post-natal day 30-39) using an escalating dosing regimen. Animals then remained drug free until adulthood at which point they were mated with naïve males. Adult offspring (F1 animals) were tested for their response to morphine-induced (0, 1, 2.5, 5, and 10 mg/kg, s.c.) conditioned place preference (CPP) and context-independent morphine-induced sensitization. Naïve littermates were used to examine mu opiate receptor expression in the nucleus accumbens and ventral tegmental area. Results indicate that F1 females whose mothers were exposed to morphine during adolescence (Mor-F1) demonstrate significantly enhanced CPP to the lowest doses of morphine compared with Sal-F1 females. There were no differences in context-independent sensitization between maternal treatment groups. Protein expression analysis showed significantly increased levels of accumbal mu opiate receptor in Mor-F1 offspring and decreased levels in the VTA. Taken together, these findings demonstrate a shift in the dose response curve with regard to the rewarding effects of morphine in Mor-F1 females which may in part be due to altered mu opiate receptor expression in the nucleus accumbens and VTA. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dexmedetomidine in a surgically inserted catheter for transversus abdominis plane block in donor hepatectomy: A prospective randomized controlled study.

PubMed

Aboelela, Mohamed Adel; Kandeel, Al-Refaey; Elsayed, Usama; Elmorshedi, Mohamed; Elsarraf, Waleed; Elsayed, Eman; Elgawalby, Ahmed; Sultan, Ahmed Mohamed; Wahab, Mohamed Abdel; Yassen, Amr

2018-01-01

Transversus abdominis plane (TAP) block is a promising technique for analgesia after abdominal surgery. This prospective, randomized controlled trial assessed the effect of adding dexmedetomidine to bupivacaine in TAP block for donor hepatectomy. We hypothesized that this would improve postoperative morphine consumption and reduce analgesia related complication and inflammation. A total of 50 donor hepatectomy were enrolled in this study. Patients divided into two equal groups according to drugs used for TAP block. Group (B) received 20 ml of bupivacaine hydrochloride 0.25%, Group (BD) received 20 ml of bupivacaine hydrochloride 0.25% and 0.3 μg/kg dexmedetomidine, on both sides at the end of surgery and every 8 h for 48 h at right side only through inserted catheter. Primary outcome objective was morphine consumption at first 72 h. Secondary outcome objectives were morphine requirement, numbers of intake, time to first intake, pain score numerical analog scale (NAS), postoperative analgesia related complications, recovery of intestinal motility, and inflammatory markers. Data were analyzed, rescue morphine analgesia was significantly lower in (BD) group compared with (B) groups as considering total morphine consumption (B 4 ± 1.9, BD 1.5 ± 0.5, P = 0.03), numbers of morphine intake ( P = 0.04), morphine requirement ( P = 0.03), and first time of analgesia intake ( P = 0.04). NAS was significantly lower in group (BD) compared with group (B) group in the first 12 h (NAS 0 - P = 0.001, NAS 1 - P = 0.03). Adding dexmedetomidine improved gut motility, first oral intake without detectable anti-inflammatory effect. Adding dexmedetomidine to bupivacine in a surgically inserted catheter for TAP block in donor hepatectomy reduced morphine consumption without detectable anti-inflammatory effect.

Morphine history sensitizes postsynaptic GABA receptors on dorsal raphe serotonin neurons in a stress-induced relapse model in rats.

PubMed

Staub, D R; Lunden, J W; Cathel, A M; Dolben, E L; Kirby, L G

2012-06-01

The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Previous work has shown that the dorsal raphe nucleus (DR)-5-HT system is inhibited by swim stress via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor (CRF). Additionally, the DR 5-HT system is regulated by opioids. The present study tests the hypothesis that the DR 5-HT system regulates stress-induced opioid relapse. In the first experiment, electrophysiological recordings of GABA synaptic activity in 5-HT DR neurons were conducted in brain slices from Sprague-Dawley rats that were exposed to swim stress-induced reinstatement of previously extinguished morphine conditioned place preference (CPP). Behavioral data indicate that swim stress triggers reinstatement of morphine CPP. Electrophysiology data indicate that 5-HT neurons in the morphine-conditioned group exposed to stress had increased amplitude of inhibitory postsynaptic currents (IPSCs), which would indicate greater postsynaptic GABA receptor density and/or sensitivity, compared to saline controls exposed to stress. In the second experiment, rats were exposed to either morphine or saline CPP and extinction, and then 5-HT DR neurons from both groups were examined for sensitivity to CRF in vitro. CRF induced a greater inward current in 5-HT neurons from morphine-conditioned subjects compared to saline-conditioned subjects. These data indicate that morphine history sensitizes 5-HT DR neurons to the GABAergic inhibitory effects of stress as well as to some of the effects of CRF. These mechanisms may sensitize subjects with a morphine history to the dysphoric effects of stressors and ultimately confer an enhanced vulnerability to stress-induced opioid relapse. Copyright © 2011 Elsevier Ltd. All rights reserved.

Parvalbumin Interneurons of Central Amygdala Regulate the Negative Affective States and the Expression of Corticotrophin-Releasing Hormone During Morphine Withdrawal

PubMed Central

Wang, Li; Shen, Minjie; Jiang, Changyou

2016-01-01

Background: The central nucleus of the amygdala (CeA) is a crucial component of the neuronal circuitry mediating aversive emotion. Its role in the negative affective states during drug withdrawal includes changes in opioidergic, GABAergic, and corticotropin-releasing factor neurotransmission. However, the modulation of the neurobiological interconnectivity in the CeA and its effects in the negative reinforcement of drug dependents are poorly understood. Method: We performed electrophysiological recordings to assess the membrane excitability of parvalbumin (PV)+ interneurons in the CeA during chronic morphine withdrawal. We tested the morphine withdrawal–induced negative affective states, such as the aversive (assessed by conditioned place aversion), anxiety (assessed by elevated plus maze), and anhedonic-like (assessed by saccharin preference test) behaviors, as well as the mRNA level of corticotropin-releasing hormone (CRH) via optogenetic inhibition or activation of PV+ interneurons in the CeA. Result: Chronic morphine withdrawal increased the firing rate of CeA PV+ interneurons. Optogenetic inhibition of the activity of CeA PV+ interneurons attenuated the morphine withdrawal–induced negative affective states, such as the aversive, anxiety, and anhedonic-like behaviors, while direct activation of CeA PV+ interneurons could trigger those negative affective-like behaviors. Optogenetic inhibition of the CeA PV+ interneurons during the morphine withdrawal significantly attenuated the elevated CRH mRNA level in the CeA. Conclusion: The activity of PV+ interneurons in the CeA was up-regulated during chronic morphine withdrawal. The activation of PV+ interneurons during morphine withdrawal was crucial for the induction of the negative emotion and the up-regulation of CRH mRNA levels in the CeA. PMID:27385383

Adult responses to an ischemic stroke in a rat model of neonatal stress and morphine treatment.

PubMed

Hays, Sarah L; Valieva, Olga A; McPherson, Ronald J; Juul, Sandra E; Gleason, Christine A

2013-02-01

Critically ill newborn infants experience stressors that may alter brain development. Using a rodent model, we previously showed that neonatal stress, morphine, and stress plus morphine treatments each influence early gene expression and may impair neurodevelopment and learning behavior. We hypothesized that the combination of neonatal stress with morphine may alter neonatal angiogenesis and/or adult cerebral blood vessel density and thus increase injury after cerebral ischemia in adulthood. To test this, neonatal Lewis rats underwent 8 h/d maternal separation, plus morning/afternoon hypoxia exposure and either saline or morphine treatment (2 mg/kg s.c.) from postnatal day 3-7. A subset received bromodeoxyuridine to track angiogenesis. Adult brains were stained with collagen IV to quantify cerebral blood vessel density. To examine vulnerability to brain injury, postnatal day 80 adult rats underwent right middle cerebral artery occlusion (MCAO) to produce unilateral ischemic lesions. Brains were removed and processed for histology 48 h after injury. Brain injury was assessed by histological evaluation of hematoxylin and eosin, and silver staining. In contrast to our hypothesis, neither neonatal morphine, stress, nor the combination affected cerebral vessel density or MCAO-induced brain injury. Neonatal angiogenesis was not detected in adult rats possibly due to turnover of endothelial cells. Although unrelated to angiogenesis, hippocampal granule cell neurogenesis was detected and there was a trend (P = 0.073) toward increased bromodeoxyuridine incorporation in rats that underwent neonatal stress. These findings are discussed in contrast to other data concerning the effects of morphine on cerebrovascular function, and acute effects of morphine on hippocampal neurogenesis. Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.

Exposure to Opiates in Female Adolescents Alters Mu Opiate Receptor Expression and Increases the Rewarding Effects of Morphine in Future Offspring

PubMed Central

Vassoler, Fair M.; Wright, Siobhan J.; Byrnes, Elizabeth M.

2016-01-01

Prescription opiate use and abuse has increased dramatically over the past two decades, including increased use in adolescent populations. Recently, it has been proposed that use during this critical period may affect future offspring even when use is discontinued prior to conception. Here, we utilize a rodent model to examine the effects of adolescent morphine exposure on the reward functioning of the offspring. Female Sprague Dawley rats were administered morphine for 10 days during early adolescence (post-natal day 30–39) using an escalating dosing regimen. Animals then remained drug free until adulthood at which point they were mated with naïve males. Adult offspring (F1 animals) were tested for their response to morphine-induced (0, 1, 2.5, 5, and 10 mg/kg, s.c.) conditioned place preference (CPP) and context-independent morphine-induced sensitization. Naïve littermates were used to examine mu opiate receptor expression in the nucleus accumbens and ventral tegmental area. Results indicate that F1 females whose mothers were exposed to morphine during adolescence (Mor-F1) demonstrate significantly enhanced CPP to the lowest doses of morphine compared with Sal-F1 females. There were no differences in context-independent sensitization between maternal treatment groups. Protein expression analysis showed significantly increased levels of accumbal mu opiate receptor in Mor-F1 offspring and decreased levels in the VTA. Taken together, these findings demonstrate a shift in the dose response curve with regard to the rewarding effects of morphine in Mor-F1 females which may in part be due to altered mu opiate receptor expression in the nucleus accumbens and VTA. PMID:26700246

Low- and high-intensity treadmill exercise attenuates chronic morphine-induced anxiogenesis and memory impairment but not reductions in hippocampal BDNF in female rats.

PubMed

Ghodrati-Jaldbakhan, Shahrbanoo; Ahmadalipour, Ali; Rashidy-Pour, Ali; Vafaei, Abbas Ali; Miladi-Gorji, Hossein; Alizadeh, Maryam

2017-05-15

Previous studies from our laboratory have shown that treadmill exercise alleviates the deficits in cognitive functions and anxiety behaviors induced by chronic exposure to morphine in male rats. In this study, we investigated the effects of low and high intensities of treadmill exercise on spatial memory, anxiety-like behaviors, and biochemical changes in the hippocampus and serum of morphine-treated female rats. The adult virgin female rats were injected with bi-daily doses (10mg/kg, at 12h intervals) of morphine over a period of 10days. Following these injections, the rats were exercised under low or high intensities for 30min per session on five days a week for four weeks. After exercise training, object location memory, anxiety profile, hippocampal BDNF, and serum corticosterone and BDNF were examined. Morphine-treated animals exhibited increased anxiety levels, impaired object location memory, and reduced hippocampal BDNF. Exercise alleviated these impairing effects on anxiety profile and memory but not hippocampal BDNF. The high-intensity exercise even further reduced the hippocampal BDNF. Additionally, both exercise regimens in the morphine group and the high exercise in the saline group reduced serum BDNF. Finally, the high-intensity exercise enhanced corticosterone serum. These findings indicate that the negative cognitive and behavioral effects of chronic exposure to morphine could be relieved by forced exercise in female rats. However, the exercise intensity is an important factor to be considered during exercise training. Finally, the correlation between changes of brain and serum BDNF and cognitive functions following morphine exposure needs further research. Copyright © 2017 Elsevier B.V. All rights reserved.

Anxiety profile in morphine-dependent and withdrawn rats: effect of voluntary exercise.

PubMed

Miladi-Gorji, Hossein; Rashidy-Pour, Ali; Fathollahi, Yaghoub

2012-01-18

Withdrawal from chronic opiates is associated with an increase in anxiogenic-like behaviours, but the anxiety profile in the morphine-dependent animals is not clear. Thus, one of the aims of the present study was to examine whether morphine-dependent rats would increase the expression of anxiogenic-like behaviours in novel and stressful conditions. Additionally, recent studies have shown that voluntary exercise can reduce anxiety levels in rodents. Therefore, another aim of this study was to examine the effect of voluntary exercise on the anxiety profile in both morphine-dependent animals and animals experiencing withdrawal. Rats were injected with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine over a period of 10 days in which they were also allowed voluntary exercise. Following these injections, anxiety-like behaviours were tested in the elevated plus-maze (EPM) model and the light/dark (L/D) box. We found reductions in time spent in, and entries into, the EPM open arms and reductions in time spent in the lit side of the L/D box for both sedentary morphine-dependent and withdrawn rats as compared to the sedentary control groups. The exercising morphine-dependent and withdrawn rats exhibited an increase in EPM open arm time and entries and L/D box lit side time as compared with the sedentary control groups. We conclude that voluntary exercise decreases the severity of the anxiogenic-like behaviours in both morphine-dependent and withdrawn rats. Thus, voluntary exercise could be a potential natural method to ameliorate some of the deleterious behavioural consequences of opiate abuse. Copyright © 2011 Elsevier Inc. All rights reserved.

Modulation of opiate-related signaling molecules in morphine-dependent conditioned behavior: conditioned place preference to morphine induces CREB phosphorylation.

PubMed

Morón, José A; Gullapalli, Srinivas; Taylor, Chirisse; Gupta, Achla; Gomes, Ivone; Devi, Lakshmi A

2010-03-01

Opiate addiction is a chronic, relapsing behavioral disorder where learned associations that develop between the abused opiate and the environment in which it is consumed are brought about through Pavlovian (classical) conditioning processes. However, the signaling mechanisms/pathways regulating the mechanisms that underlie the responses to opiate-associated cues or the development of sensitization as a consequence of repeated context-independent administration of opiates are unknown. In this study we examined the phosphorylation levels of various classic signaling molecules in brain regions implicated in addictive behaviors after acute and repeated morphine administration. An unbiased place conditioning protocol was used to examine changes in phosphorylation that are associated with (1) the expression of the rewarding effects of morphine and (2) the sensitization that develops to this effect. We also examined the effects of a delta-receptor antagonist on morphine-induced conditioned behavior and on the phosphorylation of classic signaling molecules in view of data showing that blockade of delta-opioid receptor (deltaOR) prevents the development of sensitization to the rewarding effects of morphine. We find that CREB phosphorylation is specifically induced upon the expression of a sensitized response to morphine-induced conditioned behavior in brain areas related to memory consolidation, such as the hippocampus and cortex. A similar effect is also observed, albeit to a lesser extent, in the case of the GluR1 subunit of AMPA glutamate receptor. These increases in the phosphorylation levels of CREB and pGluR1 are significantly blocked by pretreatment with a deltaOR antagonist. These results indicate a critical role for phospho-CREB, AMPA, and deltaOR activities in mediating the expression of a sensitized response to morphine-dependent conditioned behavior.

Morphine and MK-801 administration leads to alternative NMDAR1 splicing and associated changes in reward seeking behavior and nociception on an operant orofacial assay

PubMed Central

Anderson, Ethan M.; Del Valle-Pinero, Arseima Y.; Suckow, Shelby K.; Nolan, Todd A.; Neubert, John K.; Caudle, Robert M.

2012-01-01

The NMDA receptor plays a large role in opioid-induced plastic changes in the nervous system. The expression levels of its NR1 subunit are altered dramatically by morphine but no changes in its alternative splicing have been reported. Changes in the splicing of the N1, C1, C2, and C2’ cassettes can alter the pharmacology and regulation of this receptor. Western blots run on brain tissue from rats made tolerant to morphine revealed altered splicing of the N1 cassettes in the accumbens and amygdala, and the C1 cassette in the amygdala and the dorsal hippocampus. After three days of withdrawal C2’-containing NR1 subunits were down-regulated in each of these areas. These were not due to acute doses of morphine and may represent long term alterations in drug-induced neuroplasticity. We also examined the effects of morphine tolerance on an operant orofacial nociception assay which forces an animal to endure an aversive heat stimulus in order to receive a sweet milk reward. Morphine decreased pain sensitivity as expected but also increased motivational reward seeking in this task. NMDAR antagonism potentiated this reward seeking behavior suggesting that instead of attenuating tolerance, MK-801 may actually alter the rewarding and/or motivational properties of morphine. When combined, MK-801 and morphine had an additive effect which led to altered splicing in the accumbens, amygdala, and the dorsal hippocampus. In conclusion, NR1 splicing may play a major role in the cognitive behavioral aspects especially in motivational reward seeking behaviors. PMID:22531378

Inhibition of alpha7 nicotinic receptors in the ventral hippocampus selectively attenuates reinstatement of morphine-conditioned place preference and associated changes in AMPA receptor binding.

PubMed

Wright, Victoria L; Georgiou, Polymnia; Bailey, Alexis; Heal, David J; Bailey, Christopher P; Wonnacott, Susan

2018-04-17

Recurrent relapse is a major problem in treating opiate addiction. Pavlovian conditioning plays a role in recurrent relapse whereby exposure to cues learned during drug intake can precipitate relapse to drug taking. α7 nicotinic acetylcholine receptors (nAChRs) have been implicated in attentional aspects of cognition and mechanisms of learning and memory. In this study we have investigated the role of α7 nAChRs in morphine-conditioned place preference (morphine-CPP). CPP provides a model of associative learning that is pertinent to associative aspects of drug dependence. The α7 nAChR antagonist methyllycaconitine (MLA; 4 mg/kg s.c.) had no effect on the acquisition, maintenance, reconsolidation or extinction of morphine-CPP but selectively attenuated morphine-primed reinstatement of CPP, in both mice and rats. Reinstatement of morphine-CPP in mice was accompanied by a selective increase in [ 3 H]-AMPA binding (but not in [ 3 H]-MK801 binding) in the ventral hippocampus that was prevented by prior treatment with MLA. Administration of MLA (6.7 μg) directly into the ventral hippocampus of rats prior to a systemic priming dose of morphine abolished reinstatement of morphine-CPP, whereas MLA delivered into the dorsal hippocampus or prefrontal cortex was without effect. These results suggest that α7 nAChRs in the ventral hippocampus play a specific role in the retrieval of associative drug memories following a period of extinction, making them potential targets for the prevention of relapse. © 2018 The Authors.Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

Differential effects of ibogaine on local cerebral glucose utilization in drug-naive and morphine-dependent rats.

PubMed

Levant, Beth; Pazdernik, Thomas L

2004-04-02

Ibogaine, a hallucinogenic indole alkaloid, has been proposed as a treatment for addiction to opioids and other drugs of abuse. The mechanism for its putative anti-addictive effects is unknown. In this study, the effects of ibogaine on local cerebral glucose utilization (LCGU) were determined in freely moving, drug-naive, or morphine-dependent adult, male, Sprague-Dawley rats using the [(14)C]2-deoxyglucose (2-DG) method. Morphine-dependent rats were treated with increasing doses of morphine (5-25 mg/kg, s.c., b.i.d.) and then maintained at 25 mg/kg (b.i.d.) for 4-7 days. For the 2-DG procedure, rats were injected with saline or ibogaine (40 mg/kg, i.p.). 2-DG was administered 1 h after administration of ibogaine. The rate of LCGU was determined by quantitative autoradiography in 46 brain regions. In drug-naive animals, ibogaine produced significant increases in LCGU in the parietal, cingulate, and occipital cortices and cerebellum compared to controls consistent with its activity as a hallucinogen and a tremorogen. Morphine-dependent rats had only minor alterations in LCGU at the time assessed in this experiment. However, in morphine-dependent animals, ibogaine produced a global decrease in LCGU that was greatest in brain regions such as the lateral and medial preoptic areas, nucleus of the diagonal band, nucleus accumbens shell, inferior colliculus, locus coeruleus, and flocculus compared to morphine-dependent animals treated with saline. These findings indicate that ibogaine produces distinctly different effects on LCGU in drug-naive and morphine-dependent rats. This suggests that different mechanisms may underlie ibogaine's hallucinogenic and anti-addictive effects.

Brief early handling increases morphine dependence in adult rats.

PubMed

Vazquez, Vincent; Penit-Soria, Jacqueline; Durand, Claudette; Besson, Marie-Jo; Giros, Bruno; Daugé, Valérie

2006-06-30

Short early manipulations of rodent postnatal environment may trigger long-term effects on neurobiological and behavioural phenotypes in adulthood. However, little is known about such effects of handling on the vulnerability to develop drug dependence. The present study aimed to analyze the long-term effects of a brief handling (1 min) on morphine and ethanol dependence and on the preproenkephalin (PPE) mRNA and mu opioid receptor levels. Handled rats showed a significant increase in morphine (25mg/l) but not ethanol (10%) consumption and preference after 7 weeks and no difference in morphine (2 and 5mg/kg) conditioned place preference. No difference of preproenkephalin mRNA and mu opioid receptor levels was detected in the mesolimbic system between both groups. These data emphasize that human brief handling, which can lead to morphine dependence development, constitutes in itself an experimental treatment and not a control condition.

Polyglycerol-opioid conjugate produces analgesia devoid of side effects.

PubMed

González-Rodríguez, Sara; Quadir, Mohiuddin A; Gupta, Shilpi; Walker, Karolina A; Zhang, Xuejiao; Spahn, Viola; Labuz, Dominika; Rodriguez-Gaztelumendi, Antonio; Schmelz, Martin; Joseph, Jan; Parr, Maria K; Machelska, Halina; Haag, Rainer; Stein, Christoph

2017-07-04

Novel painkillers are urgently needed. The activation of opioid receptors in peripheral inflamed tissue can reduce pain without central adverse effects such as sedation, apnoea, or addiction. Here, we use an unprecedented strategy and report the synthesis and analgesic efficacy of the standard opioid morphine covalently attached to hyperbranched polyglycerol (PG-M) by a cleavable linker. With its high-molecular weight and hydrophilicity, this conjugate is designed to selectively release morphine in injured tissue and to prevent blood-brain barrier permeation. In contrast to conventional morphine, intravenous PG-M exclusively activated peripheral opioid receptors to produce analgesia in inflamed rat paws without major side effects such as sedation or constipation. Concentrations of morphine in the brain, blood, paw tissue, and in vitro confirmed the selective release of morphine in the inflamed milieu. Thus, PG-M may serve as prototype of a peripherally restricted opioid formulation designed to forego central and intestinal side effects.

Convulsions may alter the specificity of kappa-opiate receptors.

PubMed

Mansour, A; Valenstein, E S

1986-06-01

Morphine, a mu-opiate agonist, and ethylketazocine, a kappa-opiate agonist, produce distinct behavioral, pharmacologic, and biochemical effects. In the mouse, large doses of morphine produce convulsions that are usually lethal and that cannot be blocked by naltrexone, whereas ethylketazocine produces nonlethal clonic convulsions that can be blocked by naltrexone. Moreover, mice made tolerant to morphine failed to show cross-tolerance to ethylketazocine, suggesting that the convulsions induced by these drugs are not mediated via a common opioid mechanism. Following a series of electroconvulsive shocks, both morphine and ethylketazocine produced clonic convulsions that were not lethal and that could be blocked by naltrexone. Furthermore, electroconvulsive shock-treated animals made tolerant to morphine-induced convulsions showed cross-tolerance to ethylketazocine. These data suggest that electroconvulsive shock may alter kappa-opioid systems in such a way as to allow mu-agonists to be functional at these sites.

Spinal Ceramide and Neuronal Apoptosis in Morphine Antinociceptive Tolerance

PubMed Central

Bryant, Leesa; Doyle, Tim; Chen, Zhoumo; Cuzzocrea, Salvatore; Masini, Emanuela; Vinci, M. Cristina; Esposito, Emanuela; Mazzon, Emanuela; Petrusca, Daniela Nicoleta; Petrache, Irina; Salvemini, Daniela

2009-01-01

Opiates, like morphine, are the most effective analgesics for treating acute and chronic severe pain, but their use is limited by the development of analgesic tolerance and hypersensitivity to innocuous and noxious stimuli. Because opioids are a mainstay of pain management, restoring their efficacy has great clinical importance. We have recently demonstrated that spinal ceramide, a sphingolipid signaling molecule plays a central role in the development of morphine antinociceptive tolerance. We now report that ceramide up-regulation in dorsal horn tissues in response to chronic morphine administration is associated with significant neuronal apoptosis. Inhibition of ceramide biosynthesis attenuated both the increase in neuronal apoptosis and the development of antinociceptive tolerance. These findings indicate that spinal ceramide upregulation is a key pro-apoptotic event that occurs upstream of the development of morphine antinociceptive tolerance and support the rationale for development of inhibitors of ceramide biosynthesis as adjuncts to opiates for the management of chronic pain. PMID:19631718

Physician attitudes and beliefs about use of morphine for cancer pain.

PubMed

Elliott, T E; Elliott, B A

1992-04-01

The recent literature asserts that mistaken physician beliefs and attitudes are critical barriers to adequate cancer pain relief. To determine the prevalence of 12 proposed myths or misconceptions about morphine use in cancer pain management (CPM), we surveyed all physicians engaged in direct patient care in Duluth, Minnesota (N = 243). A 62% response was obtained. Many physicians misunderstood concepts of morphine tolerance, both to analgesia (51%) and to side effects (39%). Many were unaware of the use of adjuvant analgesics (29%), efficacy of oral morphine (27%), and nonexistent risk of addiction in CPM (20%). Analysis of result by physician age and specialy groups confirmed significant levels of misunderstanding in all subsets. Strategies to change physician attitudes and beliefs regarding morphine in CPM should focus on tolerance concepts, dosing schemes, safety, efficacy, lack of addictive risk, use of drug combinations, and the fact that cancer pain can be relieved.

Comparison of the antinociceptive activities of physostigmine, oxotremorine and morphine in the mouse

PubMed Central

Pleuvry, Barbara J.; Tobias, M. A.

1971-01-01

1. Morphine, oxotremorine and physostigmine showed antinociceptive activity in mice using the hot plate reaction time test. 2. The action of morphine, but not that of oxotremorine, was antagonized by naloxone and by nalorphine, whereas the effect of physostigmine was unaffected by naloxone and increased by nalorphine. 3. The antinociceptive effects of morphine and of physostigmine were increased by procedures reported to increase the ratio of 5-hydroxytryptamine to dopamine in the brain. It was decreased by procedures reported to cause a fall in brain 5-hydroxytryptamine or a rise in dopamine relative to 5-hydroxytryptamine. 4. The antinociceptive effect of oxotremorine was potentiated by procedures reported to decrease brain noradrenaline and was unaffected by procedures altering brain 5-hydroxytryptamine. 5. The results suggest differences in the mode of action of morphine and physostigmine on the one hand and of oxotremorine on the other. PMID:4261560

[Pain control by continuous infusion of morphine using subarachnoid catheter access to the port--a report of a home death case].

PubMed

Kawagoe, Koh; Matsuura, Shinobu

2008-12-01

This is a case of a 50s male with cecal cancer suffering from severe pain caused by osteolytic metastasis to the lumbar vertebra, right iliac bone, and the head of the right femur. The pain was palliated by continuous infusion of morphine using a subarachnoid catheter that had access to the subcutaneous "Port". The maximum dose of morphine used a day was 384 mg, which corresponded to 57,600 mg/day of oral morphine. Sixty eight days after the start of home hospice care, the patient died at home because of diffuse peritonitis caused by intestinal rupture.

Effects of morphine and naloxone on feline colonic transit

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krevsky, B.; Libster, B.; Maurer, A.H.

1989-01-01

The effects of endogenous and exogenous opioid substances on feline colonic transit were evaluated using colonic transit scintigraphy. Naloxone accelerated emptying of the cecum and ascending colon, and filling of the transverse colon. Endogenous opioid peptides thus appear to play a significant role in the regulation of colonic transit. At a moderate dose of morphine cecum and ascending colon transit was accelerated, while at a larger dose morphine had no effect. Since naloxone, a relatively nonspecific opioid antagonist, and morphine, a principally mu opioid receptor agonist, both accelerate proximal colonic transit, a decelerating role for at least one of themore » other opioid receptors is inferred.« less

Tolerance to the anticonvulsant effect of morphine in mice: blockage by ultra-low dose naltrexone.

PubMed

Roshanpour, Maryam; Ghasemi, Mehdi; Riazi, Kiarash; Rafiei-Tabatabaei, Neda; Ghahremani, Mohammad Hossein; Dehpour, Ahmad Reza

2009-02-01

The present study evaluated the development of tolerance to the anticonvulsant effect of morphine in a mouse model of clonic seizures induced by pentylenetetrazole, and whether ultra-low doses of the opioid receptor antagonist naltrexone which selectively block G(s) opioid receptors were capable of preventing the observed tolerance. The results showed that the morphine anticonvulsant effect could be subject to tolerance after repeated administration. Both the development and expression of tolerance were inhibited by ultra-low doses of naltrexone, suggesting the possible involvement of G(s)-coupled opioid receptors in the development of tolerance to the anticonvulsant effect of morphine.

Inhibition of Morphine Tolerance and Dependence by the NMDA Receptor Antagonist MK-801

NASA Astrophysics Data System (ADS)

Trujillo, Keith A.; Akil, Huda

1991-01-01

The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.

Inhibitory effect of bacopasides on spontaneous morphine withdrawal induced depression in mice.

PubMed

Rauf, Khalid; Subhan, Fazal; Abbas, Muzaffar; Ali, Syed Mobasher; Ali, Gowhar; Ashfaq, Muhammad; Abbas, Ghulam

2014-06-01

Bacopa monnieri is a perennial herb with a world known image as a nootropic. We investigated the effect of Bacopa monnieri methanolic extract (Mt Ext BM) 10, 20, and 30 mg/kg body weight (b.w) on acquisition and expression of morphine withdrawal induced depression in mice. Locally available Bacopa monnieri (BM) was screened for contents of Bacoside A3, Bacopasaponin C, and Bacopaside II using HPLC with UV. Morphine dependence was induced in mice using twice daily escalating chronic morphine treatments (20-65 mg/kg b.w) for eight consecutive days. Morphine withdrawal induced depression was assayed in animals using forced swimming test (FST), three days after last morphine injection. The HPLC analysis revealed that Mt-ext BM contained Bacoside A3 as major component, i.e. 4 µg in each mg of extract. The chronic treatment with Met Ext BM 10, 20, and 30 mg/kg b.w. dosing significantly inhibited opioid withdrawal induced depression in mice. These findings imply a newer potential role of Bacopa monnieri in the clinical management of opioid withdrawal induced depression which can be attributed to Bacoside A3. Copyright © 2013 John Wiley & Sons, Ltd.

Comparing of the Effects of Hypericin and Synthetic Antidepressants on the Expression of Morphine-Induced Conditioned Place Preference

PubMed Central

Assadi, Assad; Zarrindast, Mohammad Reza; Jouyban, Abolghasem; Samini, Morteza

2011-01-01

The effect of hypericin on the expression of morphine-induced conditioned place preference (CPP) was investigated and compared with the effect of the synthetic antidepressants. The CPP paradigms took place over six days using an unbiased procedure. The results demonstrate that intra-peritoneal (IP) injection of morphine sulfate (2.5, 5 and 10 mg/Kg) significantly induce the CPP in rat. Intra-peritoneal and intracerebroventricular (ICV) injection of hypericin and/or synthetic antidepressants augmented morphine-induced CPP. It has been suggested that the adrenergic, serotonergic and dopaminergic neurotransmissions play an important role in mediating the antidepressant effect of hypericin and this effect may be due to its inhibitory effect on the reuptake of neurotransmitters. Morphine produces a reinforcement (reward) effect by activating. The μ-receptors that facilitate dopaminergic transmission. Serotonin is also a potent stimulator of dopamine release in such a way that an increase in brain serotonin could possibly stimulate the dopaminergic system. In conclusion, it may suggest that the augmentation of morphine-induced CPP by hypericin and synthetic antidepressants may be related to the increasing dopamine and serotonin concentrations in synaptic clefts. PMID:24250400

Pro- and anticonvulsant actions of morphine and the endogenous opioids: involvement and interactions of multiple opiate and non-opiate systems.

PubMed

Frenk, H

1983-10-01

The proconvulsant actions of high doses of systemic morphine are probably mediated by 3 different systems. One of them produces non-convulsant electrographic seizures and can be activated separately from the others both by intracerebroventricular injections as well as microinjections into discrete subcortical areas. The enkephalins and beta-endorphin, when administered to the same loci, produce similar effects. Pharmacological evidence suggests that specific opiate receptors of the delta-subtype mediate the epileptiform effects produced by this system. The second system mediating proconvulsant effects of systemic morphine is not mediated by stereo-specific opiate receptors. It produces behavioral convulsions, and the GABA-ergic system has been implicated in its action. A third proconvulsant action of systemic morphine can be activated separately from the other two systems by administering this compound with other convulsive agents or manipulations. Specific mu-type opiate receptors are implicated in this effect. In addition to potent proconvulsant effects, systemic morphine also has anticonvulsant properties which are mediated by specific opiate mu-receptors. The conditions under which morphine acts as a proconvulsant rather than an anticonvulsant agent are, as yet, not understood.

Efficacy of clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for neonatal abstinence syndrome. A prospective randomized clinical trial.

PubMed

Surran, B; Visintainer, P; Chamberlain, S; Kopcza, K; Shah, B; Singh, R

2013-12-01

To compare the efficacy of clonidine versus phenobarbital in reducing morphine sulfate treatment days for neonatal abstinence syndrome (NAS). Prospective, non-blinded, block randomized trial at a single level III NICU (Neonatal Intensive Care Unit). Eligible infants were treated with a combination of medications as per protocol. Primary outcome was treatment days with morphine sulfate. Secondary outcomes were the mean total morphine sulfate dose, outpatient phenobarbital days, adverse events and treatment failures. A total of 82 infants were eligible, of which 68 were randomized with 34 infants in each study group. Adjusting for covariates phenobarbital as compared with clonidine had shorter morphine sulfate treatment days (-4.6, 95% confidence interval (CI): -0.3, -8.9; P=0.037) with no difference in average morphine sulfate total dose (1.1 mg kg(-1), 95% CI: -0.1, 2.4; P=0.069). Post-discharge phenobarbital was continued for an average of 3.8 months (range 1 to 8 months). No other significant differences were noted. Phenobarbital as adjunct had clinically nonsignificant shorter inpatient but significant overall longer therapy time as compared with clonidine.

A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia.

PubMed

Gomes, Ivone; Gupta, Achla; Filipovska, Julija; Szeto, Hazel H; Pintar, John E; Devi, Lakshmi A

2004-04-06

Opiates such as morphine are the choice analgesic in the treatment of chronic pain. However their long-term use is limited because of the development of tolerance and dependence. Due to its importance in therapy, different strategies have been considered for making opiates such as morphine more effective, while curbing its liability to be abused. One such strategy has been to use a combination of drugs to improve the effectiveness of morphine. In particular, delta opioid receptor ligands have been useful in enhancing morphine's potency. The underlying molecular basis for these observations is not understood. We propose the modulation of receptor function by physical association between mu and delta opioid receptors as a potential mechanism. In support of this hypothesis, we show that mu-delta interacting complexes exist in live cells and native membranes and that the occupancy of delta receptors (by antagonists) is sufficient to enhance mu opioid receptor binding and signaling activity. Furthermore, delta receptor antagonists enhance morphine-mediated intrathecal analgesia. Thus, heterodimeric associations between mu-delta opioid receptors can be used as a model for the development of novel combination therapies for the treatment of chronic pain and other pathologies.

Inhibition of phosphodiesterase10A attenuates morphine-induced conditioned place preference.

PubMed

Mu, Ying; Ren, Zhaoxiang; Jia, Jia; Gao, Bo; Zheng, Longtai; Wang, Guanghui; Friedman, Eitan; Zhen, Xuechu

2014-09-25

Phosphodiesterase (PDE) 10A is selectively expressed in medium spiny neurons of the striatum. Nucleus accumbens (NAc) is a key region that mediates drug reward and addiction-related behaviors. To investigate the potential role of PDE10A in the reinforcement properties of morphine, we tested the effect of MP-10, a selective inhibitor of PDE10A, on acquisition, expression, and extinction of morphine-induced conditioned place preference (CPP). The results show that 2.5 mg/kg MP-10, administered subcutaneously, significantly inhibited the acquisition of morphine-induced CPP. The same dose of MP-10 alone did not result in the CPP. Moreover, MP-10 did not alter the expression of morphine-induced CPP, but did accelerate the extinction of morphine-induced CPP. Additionally, chronic treatment with 2.5 mg/kg MP-10 decreased expression of phosphorylated CREB (pCREB), activated cAMP response element binding protein, in dorsomedial striatum, in shell of NAc, and in anterior cingulate cortex (ACC) as well as decreased expression of ΔFosB in the shell of NAc and ACC. The results suggest that inhibition of PDE10A may have therapeutic potential in the treatment of opioid addiction.

Narp regulates long-term aversive effects of morphine withdrawal.

PubMed

Reti, Irving M; Crombag, Hans S; Takamiya, Kogo; Sutton, Jeffrey M; Guo, Ning; Dinenna, Megan L; Huganir, Richard L; Holland, Peter C; Baraban, Jay M

2008-08-01

Although long-lasting effects of drug withdrawal are thought to play a key role in motivating continued drug use, the mechanisms mediating this type of drug-induced plasticity are unclear. Because Narp is an immediate early gene product that is secreted at synaptic sites and binds to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, it has been implicated in mediating enduring forms of synaptic plasticity. In previous studies, the authors found that Narp is selectively induced by morphine withdrawal in the extended amygdala, a group of limbic nuclei that mediate aversive behavioral responses. Accordingly, in this study, the authors evaluate whether long-term aversive effects of morphine withdrawal are altered in Narp knockout (KO) mice. The authors found that acute physical signs of morphine withdrawal are unaffected by Narp deletion. However, Narp KO mice acquire and sustain more aversive responses to the environment conditioned with morphine withdrawal than do wild type (WT) controls. Paradoxically, Narp KO mice undergo accelerated extinction of this heightened aversive response. Taken together, these studies suggest that Narp modulates both acquisition and extinction of aversive responses to morphine withdrawal and, therefore, may regulate plasticity processes underlying drug addiction.

Do Resting Plasma β-Endorphin Levels Predict Responses to Opioid Analgesics?

PubMed

Bruehl, Stephen; Burns, John W; Gupta, Rajnish; Buvanendran, Asokumar; Chont, Melissa; Orlowska, Daria; Schuster, Erik; France, Christopher R

2017-01-01

Clinically feasible predictors of opioid analgesic responses for use in precision pain medicine protocols are needed. This study evaluated whether resting plasma β-endorphin (BE) levels predicted responses to an opioid analgesic, and whether chronic pain status or sex moderated these effects. Participants included 73 individuals with chronic low back pain (CLBP) and 88 pain-free controls, all using no daily opioid analgesics. Participants attended 2 identical laboratory sessions during which they received either intravenous morphine (0.08 mg/kg) or saline placebo, with blood samples obtained before drug administration to assay resting plasma BE levels. Once peak drug activity was achieved in each session, participants engaged in an ischemic forearm pain task (ISC) and a heat pain task. Morphine analgesic effects were derived reflecting the difference in pain outcomes between placebo and morphine conditions. In hierarchical regressions, significant Type (CLBP vs. control)×BE interactions (Ps<0.05) were noted for morphine effects on ISC tolerance, ISC intratask pain ratings, and thermal VAS unpleasantness ratings. These interactions derived primarily from associations between higher BE levels and smaller morphine effects restricted to the CLBP subgroup. All other BE-related effects, including sex interactions, for predicting morphine analgesia failed to reach statistical significance. BE was a predictor of morphine analgesia for only 3 out of 9 outcomes examined, with these effects moderated by chronic pain status but not sex. On the whole, results do not suggest that resting plasma BE levels are likely to be a clinically useful predictor of opioid analgesic responses.

Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury

PubMed Central

Ellis, Amanda; Grace, Peter M.; Wieseler, Julie; Favret, Jacob; Springer, Kendra; Skarda, Bryce; Hutchinson, Mark R.; Falci, Scott; Rice, Kenner C.; Maier, Steven F.; Watkins, Linda R.

2016-01-01

Central neuropathic pain (CNP) is a pervasive, debilitating problem that impacts thousands of people living with central nervous system disorders, including spinal cord injury (SCI). Current therapies for treating this type of pain are ineffective and often have dose-limiting side effects. Although opioids are one of the most commonly used CNP treatments, recent animal literature has indicated that administering opioids shortly after a traumatic injury can actually have deleterious effects on long-term health and recovery. In order to study the deleterious effects of administering morphine shortly after trauma, we employed our low thoracic (T13) dorsal root avulsion model (Spinal Neuropathic Avulsion Pain, SNAP). Administering a weeklong course of 10 mg/kg/day morphine beginning 24 hr after SNAP resulted in amplified mechanical allodynia. Co-administering the non-opioid toll-like receptor 4 (TLR4) antagonist (+)-naltrexone throughout the morphine regimen prevented morphine-induced amplification of SNAP. Exploration of changes induced by early post-trauma morphine revealed that this elevated gene expression of TLR4, TNF, IL-1β, and NLRP3, as well as IL-1β protein at the site of spinal cord injury. These data suggest that a short course of morphine administered early after spinal trauma can exacerbate CNP in the long term. TLR4 initiates this phenomenon and, as such, may be potential therapeutic targets for preventing the deleterious effects of administering opioids after traumatic injury. PMID:27519154

Selective Effects of a Morphine Conjugate Vaccine on Heroin and Metabolite Distribution and Heroin-Induced Behaviors in Rats

PubMed Central

Pravetoni, M.; Harris, A.C.; Birnbaum, A.K.; Pentel, P.R.

2013-01-01

Morphine conjugate vaccines have effectively reduced behavioral effects of heroin in rodents and primates. To better understand how these effects are mediated, heroin and metabolite distribution studies were performed in rats in the presence and absence of vaccination. In non-vaccinated rats 6-monoacetylmorphine (6-MAM) was the predominant opioid in plasma and brain as early as 1 minute after i.v. administration of heroin and for up to 14 minutes. Vaccination with morphine conjugated to keyhole limpet hemocyanin (M-KLH) elicited high titers and concentrations of antibodies with high affinity for heroin, 6-MAM, and morphine. Four minutes after heroin administration vaccinated rats showed substantial retention of all three opioids in plasma compared to controls and reduced 6-MAM and morphine, but not heroin, distribution to brain. Administration of 6-MAM rather than heroin in M-KLH vaccinated rats showed a similar drug distribution pattern. Vaccination reduced heroin-induced analgesia and blocked heroin-induced locomotor activity throughout 2 weeks of repeated testing. Higher serum opioid-specific antibody concentrations were associated with higher plasma opioid concentrations, lower brain 6-MAM and morphine concentrations, and lower heroin-induced locomotor activity. Serum antibody concentrations over 0.2 mg/ml were associated with substantial effects on these measures. These data support a critical role for 6-MAM in mediating the early effects of i.v. heroin and suggest that reducing 6-MAM concentration in brain is essential to the efficacy of morphine conjugate vaccines. PMID:23220743

Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats.

PubMed

Wang, Xiao-Fei; Zhao, Tai-Yun; Su, Rui-Bin; Wu, Ning; Li, Jin

2016-12-01

Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was down-regulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.

Effects of voluntary exercise on the viability, proliferation and BDNF levels of bone marrow stromal cells in rat pups born from morphine- dependent mothers during pregnancy.

PubMed

Haydari, Sakineh; Safari, Manouchehr; Zarbakhsh, Sam; Bandegi, Ahmad Reza; Miladi-Gorji, Hossein

2016-11-10

This study was designed to investigate whether free access to a running wheel during pregnancy in morphine-dependent mothers would influence the viability, proliferation and BDNF levels of bone marrow stromal cells in rat pups. Pregnant rats were made dependent by chronic administration of morphine in drinking water simultaneously with free access to a running wheel. Male pups are weaned at 21days of birth and their bones marrows were aspirated from the femurs and tibias and also the bone marrow stromal cells (BMSCs) cultured. MTT assay was used to determine cell viability and proliferation rate. The level of BDNF was measured in the supernant of BMSCs culture by ELISA. The sedentary morphine-dependent mothers' pups showed a significant increase in the percentage cell viability and proliferation rate and also a significant decrease in the BDNF protein levels in BMSCs. The rat pups borne from exercising the control and morphine-dependent mothers exhibited an increase in the percentage viability, proliferation rate and BDNF levels of the BMSCs. This study showed that maternal exercise during pregnancy in morphine-dependent and non-dependent mothers, with increasing of BDNF levels increased the proliferation and viability of BMSCs in the rat pups. Also, chronic administration of morphine during pregnancy was able to increase the proliferation and viability of BMSCs in the rat pups. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of D-cycloserine on extinction and reinstatement of morphine-induced conditioned place preference.

PubMed

Lu, Guan-Yi; Wu, Ning; Zhang, Zhao-Long; Ai, Jing; Li, Jin

2011-10-10

d-Cycloserine (DCS), a partial agonist at the strychnine-insensitive glycine recognition site on the N-methyl-d-aspartate (NMDA) receptor complex, has been shown to facilitate the extinction and prevent the relapse of cocaine-induced conditioned place preference (CPP) when administered before or after each extinction trail. However, some studies have suggested that DCS does not influence or even enhance relapse of seeking behavior on cocaine self-administration (SA) in rats or cocaine-dependent individuals undergoing clinical exposure treatment. Furthermore, there are no reports on the effects of DCS and the extinction of morphine-conditioned behaviors in mice. The present study investigated the effects of DCS on extinction by exposing mice to drug-paired cues and the subsequent reinstatement of morphine-primed CPP. Our results showed that DCS at doses of 7.5, 15, and 30mg/kg did not induce conditioned appetitive or aversive effects and DCS combined with morphine conditioning failed to affect the acquisition of morphine-induced CPP. Moreover, pretreatment with DCS (7.5, 15, and 30mg/kg, i.p.) prior to extinction training had no significant effects on the extinction and subsequent morphine-primed reinstatement of morphine-induced CPP. These results suggested that DCS may not be a powerful adjunct for cue exposure therapy of opioid addiction. In view of differing outcomes in both preclinical and clinical studies, the potential of DCS in exposure treatment of drug-seeking behaviors should be carefully evaluated. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

The extinction of morphine-induced conditioned place preference by histone deacetylase inhibition.

PubMed

Wang, Ru; Zhang, Yan; Qing, Hua; Liu, Mei; Yang, Peng

2010-10-11

Recent evidence suggests that epigenetic mechanisms have an important role in the development of addictive behavior. However, little is known about the role of epigenetic mechanisms in the extinction of morphine-induced behavioral changes. In this study, we will examine the effect of histone deacetylase (HDAC) inhibitors on extinction of morphine-induced conditioned place preference (CPP). To facilitate extinction, rats will be administered an HDAC inhibitor (HDACi) following nonreinforced exposure to the conditioned context. To measure persistence, rats were subject to a reinstatement test using 3 mg/kg dose of morphine. To exclude the effect of repeated NaBut injections themselves on morphine-CPP in the absence of extinction session, rats received injection of either NaBut or vehicle for 8 days. We found that HDAC inhibition during nonconfined extinction or confined extinction consolidation can facilitate extinction of morphine-induced CPP. We also showed that the extinction of drug seeking via HDAC inhibition modulates extinction learning such that reinstatement behavior is significantly attenuated. There is no effect of repeated NaBut injections themselves on morphine-CPP in the absence of extinction session. In conclusion, our results extend earlier reports on the ability of HDACi to modify the behavioral effects of drugs of abuse. Our increasing understanding of these epigenetic mechanisms will provide key answers to basic processes in drug addiction and hopefully provide insight into designing improved treatments for drug addiction. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Glasgow Coma Scale Scores, Early Opioids, and 4-year Psychological Outcomes among Combat Amputees

DTIC Science & Technology

2014-01-01

psychological outcomes, loss of consciousness, military and VA health data, morphine , posttraumatic stress disorder, traumatic brain injury. INTRODUCTION...appropriate for postinjury analgesia [15–17]. Unfortu- nately, little research has compared the psychological benefits of morphine or fentanyl...that morphine reduced PTSD compared with fentanyl because mor- phine produced more long-lasting pain relief and/or was more effective at blocking

NAc Shell Arc/Arg3.1 Protein Mediates Reconsolidation of Morphine CPP by Increased GluR1 Cell Surface Expression: Activation of ERK-Coupled CREB is Required

PubMed Central

Lv, Xiu-Fang; Sun, Lin-Lin; Han, Ji-Sheng

2015-01-01

Background: Relapse into drug abuse evoked by reexposure to the drug-associated context has been a primary problem in the treatment of drug addiction. Disrupting the reconsolidation of drug-related context memory would therefore limit the relapse susceptibility. Methods: Morphine conditioned place preference (CPP) was used to assess activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and correlative molecule expression in the Nucleus accumbens (NAc) shell during the reconsolidation of morphine CPP. U0126 and Arc/Arg3.1 antisense oligodeoxynucleotide were adapted to evaluate the role and the underlying mechanism of Arc/Arg3.1 during the reconsolidation. Results: The retrieval of morphine CPP in rats specifically increased the Arc/Arg3.1 protein level in the NAc shell, accompanied simultaneously by increases in the phosphorylation of extracellular signal-regulated kinase1/2 (pERK1/2), the phosphorylation of Cyclic Adenosine monophosphate (cAMP) response element-binding (pCREB), and the up-regulation of the membrane α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors GluR1 subunit level. Intra-NAc shell infusion U0126, an inhibitor of the Mitogen-activated protein kinase kinase (MEK), prevented the retrieval-induced up-regulation of pERK1/2, pCREB, Arc/Arg3.1, and membrane GluR1 immediately after retrieval of morphine CPP. The effect of disrupting the reconsolidation of morphine CPP by U0126 could last for at least 14 days, and could not be evoked by a priming injection of morphine. Furthermore, the specific knockdown of Arc/Arg3.1 in the NAc shell decreased the membrane GluR1 level, and impaired both the reconsolidation and the reinstatement of morphine CPP. Conclusions: Arc/Arg3.1 in the NAc shell mediates the reconsolidation of morphine-associated context memory via up-regulating the level of membrane of GluR1, for which the local activation of the ERK-CREB signal pathway, as an upstream mechanism of Arc/Arg3.1, is required. PMID:25746394

Patient-controlled Intermittent Epidural Bolus Versus Epidural Infusion for Posterior Spinal Fusion After Adolescent Idiopathic Scoliosis: Prospective, Randomized, Double-blinded Study.

PubMed

Erdogan, Mehmet Ali; Ozgul, Ulku; Ucar, Muharrem; Korkmaz, Mehmet Fatih; Aydogan, Mustafa Said; Ozkan, Ahmet Selim; Colak, Cemil; Durmus, Mahmut

2017-06-15

A prospective, randomized, double-blinded study. The aim of this study was to compare the efficacy and side effects of patient-controlled intermittent bolus epidural analgesia (PCIEA) and patient-controlled continuous epidural analgesia (PCCEA) for postoperative pain control in adolescent idiopathic scoliosis. Epidural analgesia is an accepted efficacious and safe procedure for postoperative pain management in scoliosis surgery. However, the PCIEA has not been adequately investigated for postoperative pain control in adolescent idiopathic scoliosis. Forty-seven patients, 8 to 18 years of age, who were undergoing posterior spinal fusion for idiopathic scoliosis were randomized to either the PCIEA or PCCEA group. An epidural catheter was inserted by a surgeon under direct visualization. The PCIEA group received 0.2 mg/mL of morphine, 0.25 mL/kg of morphine bolus, additional doses of 0.25 mL/kg morphine with a 1-hour lockout given by patient-controlled demand, and no infusion. The PCCEA group received the following: 0.2 mg/mL morphine, an initial morphine loading set at 0.1 mL/kg, followed by a 0.05 mL/kg/h continuous infusion of morphine, and a 0.025 mL/kg bolus dose of morphine. There was a 30-minute lockout interval. The primary outcome was morphine usage. The secondary outcomes were pain score, postoperative nausea and vomiting, and pruritus. Cumulative morphine consumption was lower in the PCIEA group than in the PCCEA group. Both methods provided effective pain control. There were no differences in pain scores between the groups. Postoperative nausea, vomiting, and pruritus were lower in the PCIEA group. The two epidural analgesia techniques studied are both safe and effective methods for postoperative pain control after posterior spinal fusion in idiopathic scoliosis. Nausea, vomiting and pruritus were considerably higher in the PCCEA group. Concerns regarding side effects associated with epidural opioids can be avoided by an intermittent bolus with a relatively lower amount of opioid. 2.

Cardioprotective Effects of Intracoronary Morphine in ST-Segment Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention: A Prospective, Randomized Trial.

PubMed

Gwag, Hye Bin; Kim, Eun Kyoung; Park, Taek Kyu; Lee, Joo Myung; Yang, Jeong Hoon; Song, Young Bin; Choi, Jin-Ho; Choi, Seung-Hyuk; Lee, Sang Hoon; Chang, Sung-A; Park, Sung-Ji; Lee, Sang-Chol; Park, Seung Woo; Jang, Woo Jin; Lee, Mirae; Chun, Woo Jung; Oh, Ju Hyeon; Park, Yong Hwan; Choe, Yeon Hyeon; Gwon, Hyeon-Cheol; Hahn, Joo-Yong

2017-04-03

A cardioprotective role of morphine acting via opioid receptors has been demonstrated, and previous preclinical studies have reported that morphine could reduce reperfusion injury and myocardial infarct size in a way similar to that of ischemic periconditioning. This study aimed to evaluate the effect of intracoronary morphine on myocardial infarct size in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. This study was designed as a 2-center, prospective, randomized, open-label, blinded end point trial. A total of 91 ST-elevation myocardial infarction patients with thrombolysis in myocardial infarction flow grade of 0 to 1 undergoing primary percutaneous coronary intervention were randomly assigned to a morphine or control group at a 1:1 ratio. The morphine group received 3 mg of morphine sulfate diluted with 3 mL of normal saline, and the control group received 3 mL of normal saline into a coronary artery immediately after restoration of coronary flow. The primary end point was myocardial infarct size assessed by cardiac magnetic resonance imaging The cardiac magnetic resonance images were evaluated for 42 and 38 patients in the morphine and control groups, respectively. Myocardial infarct size was not different between the 2 groups (25.6±11.2% versus 24.6±10.5%, P =0.77), nor was the extent of microvascular obstruction or myocardial salvage index (6.0±6.3% versus 5.1±4.6%, P =0.91; 31.1±15.2% versus 30.3±10.9%, P =0.75, respectively). There was no difference in peak creatine kinase-MB level, final thrombolysis in myocardial infarction flow, myocardial brush grade, or complete resolution of ST-segment. Intracoronary morphine administration could not reduce myocardial infarct size in ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01738100. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Intrathecal morphine for postoperative analgesia in patients with idiopathic scoliosis undergoing posterior spinal fusion.

PubMed

Tripi, Paul A; Poe-Kochert, Connie; Potzman, Jennifer; Son-Hing, Jochen P; Thompson, George H

2008-09-15

A retrospective study of postoperative pain management with intrathecal morphine. Identify the dosing regimen of intrathecal morphine that safely and effectively provides postoperative analgesia with minimal complications in patients with idiopathic scoliosis undergoing posterior spinal fusion (PSF) and segmental spinal instrumentation (SSI). Postoperative pain after surgery for idiopathic scoliosis is a concern. Intrathecal morphine has been used to decrease pain. However, the most appropriate dose has not been determined. We retrospectively analyzed 407 consecutive patients with idiopathic scoliosis who underwent PSF and SSI at our institution from 1992 through 2006. Patients were divided into 3 groups based on the intrathecal morphine dose: no dose (n = 68); moderate dose of 9 to 19 microg/kg, mean 14 microg/kg (n = 293); and high dose of 20 microg/kg or greater, mean 24 microg/kg (n = 46). Data included demographics, Wong-Baker visual analog scale postoperative pain scores, postoperative intravenous morphine requirements, time to first rescue dose of intravenous morphine, and postoperative complications of pruritus, nausea/vomiting, respiratory depression, and pediatric intensive care unit (PICU) admission. The demographics of the 3 study groups showed no statistical differences. The mean Wong-Baker visual analog scale pain score in the post anesthesia care unit was 5.2, 0.5, and 0.2, and the mean time to first morphine rescue was 6.6, 16.7, and 22.9 hours, respectively. In the first 48 postoperative hours, respiratory depression occurred in 1 (1.5%), 8 (2.7%), and 7 (15.2%) patients, whereas PICU admission occurred in 0 (0%), 6 (2%), and 8 (17.4%) patients, respectively. The majority of PICU admissions were the result of respiratory depression. Frequency of pruritus and nausea/vomiting was similar in all 3 groups. Intrathecal morphine in the moderate dose range of 9 to 19 microg/kg (mean 14 microg/kg), provides safe and effective postoperative analgesia in the immediate postoperative period for patients with idiopathic scoliosis undergoing PSF and SSI. Higher doses did not result in significantly better analgesia and had a greater frequency of respiratory depression requiring PICU admission.

Ontogenesis of morphine-induced behavior in the cat.

PubMed

Burgess, J Wesley; Villablanca, Jaime R

2007-02-23

We analyzed the behavioral responses to a single dose of morphine in kittens at postnatal (P) ages 7, 15, 30, 60, 90, and 120 days. Each kitten received 0.5 or 3.0 mg/kg i.p. of morphine sulphate or saline vehicle. An average of 6.5 kittens were studied at each dose and age. An ethogram was constructed, based on morphine effects in adult cats, to score appropriate behaviors from direct observation and video sampling. After injection behaviors were sampled for periods of 2 min every 15-30 min for a total of 4 h. The frequency of each selected behavior was scored at 2 s intervals during each of the 2 min periods and it was expressed as a percent of all time samples scored for the 4 h period. Statistical comparisons were made with control (saline) littermates. At P7-15 the drug's main effect was behavioral depression; i.e., kittens, away from the litter, laid sprawled as if with no muscle tonus; Nursing was suppressed and Vocalization was distressed. Mainly with the higher dose, at P30, morphine-specific behaviors appeared for the first time. With the kitten in a Sitting position, these included stereotypical Head and Paw Movements and body Torsion. At P60 other drug-elicited behaviors emerged, including Spinning, Retching, and Vomiting. By P90-120 the frequency of Head (16.0%) and Paw (16.9%) Movements doubled relative to P30-60. Morphine significantly changed frequencies of newly matured behaviors (in control kittens) including Sniffing and Licking (increased), and Grooming (decreased/blocked). Retching and Vomiting increased to adult levels. Morphine-induced hyperthermia was first detected at P60 and peaked by P90-P120. The early behavioral depression shifted to a pattern of increasing activity starting at P30 and peaking at P90-120, at which time Sleep was absent and Laying was reduced, while Walking and Sitting were increased. We concluded that the maturation of the stereotypical behavioral responses to morphine in cats begins at about P30 and is completed between P90 and 120. Results are discussed in terms of developmental parameters and putative brain sites of morphine's actions.

Sympathetic activity induced by naloxone-precipitated morphine withdrawal is blocked in genetically engineered mice lacking functional CRF1 receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

García-Carmona, Juan-Antonio; Martínez-Laorden, Elena; Milanés, María-Victoria

There is large body evidence indicating that stress can lead to cardiovascular disease. However, the exact brain areas and the mechanisms involved remain to be revealed. Here, we performed a series of experiments to characterize the role of CRF1 receptor (CRF1R) in the stress response induced by naloxone-precipitated morphine withdrawal. The experiments were performed in the hypothalamic paraventricular nucleus (PVN) ventrolateral medulla (VLM), brain regions involved in the regulation of cardiovascular activity, and in the right ventricle by using genetically engineered mice lacking functional CRF1R levels (KO). Mice were treated with increasing doses of morphine and withdrawal was precipitated bymore » naloxone administration. Noradrenaline (NA) turnover, c-Fos, expression, PKA and TH phosphorylated at serine 40, was evaluated by high-performance liquid chromatography (HPLC), immunohistochemistry and immunoblotting. Morphine withdrawal induced an enhancement of NA turnover in PVN in parallel with an increase in TH neurons expressing c-Fos in VLM in wild-type mice. In addition we have demonstrated an increase in NA turnover, TH phosphorylated at serine 40 and PKA levels in heart. The main finding of the present study was that NA turnover, TH positive neurons that express c-Fos, TH phosphorylated at serine 40 and PKA expression observed during morphine withdrawal were significantly inhibited in CRF1R KO mice. Our results demonstrate that CRF/CRF1R activation may contribute to the adaptive changes induced by naloxone-precipitated withdrawal in the heart and in the brain areas which modulate the cardiac sympathetic function and suggest that CRF/CRF1R pathways could be contributing to cardiovascular disease associated to opioid addiction. - Highlights: • Naloxone-precipitated morphine withdrawal increases sympathetic activity in the PVN and heart. • Co-localization of TH phosphorylated at serine 40/c-Fos in the VLM after morphine withdrawal • Naloxone-precipitated morphine withdrawal increases PKA expression in the heart. • CRF1 receptor is implicated in the sympathetic activity induced by morphine withdrawal.« less

Pharmacodynamic effect of morphine-6-glucuronide versus morphine on hypoxic and hypercapnic breathing in healthy volunteers.

PubMed

Romberg, Raymonda; Olofsen, Erik; Sarton, Elise; Teppema, Luc; Dahan, Albert

2003-10-01

Morphine-6-glucuronide (M6G) is an active metabolite of morphine that is generally associated with less respiratory depression than morphine. Because M6G will be on the market in the near future, the authors assessed the time profile and relative potency of M6G's effect versus morphine's effect on carbon dioxide-driven and hypoxic breathing. In nine healthy female volunteers, the effects of 0.2 mg/kg intravenous M6G, 0.13 mg/kg intravenous morphine, and intravenous placebo were tested on ventilation at a fixed end-tidal pressure of carbon dioxide (Petco2) of 45 mmHg (Vi45) and on the acute hypoxic ventilatory response (AHR). All subjects participated in all three arms of the study. Respiratory studies were performed at 1-h intervals for 7 h after drug infusion. The data were analyzed using a population dose-driven approach, which uses a dose rate in function of time as input function driving the pharmacodynamics, and a population pharmacokinetic-pharmacodynamic (PK/PD) approach in which fixed pharmacokinetic parameter values from the literature were used as input function to the respiratory model. From the latter analysis, the authors obtained the blood effect-site equilibration half-life (t1/2ke0) and the effect-site concentration producing 25% depression of Vi45 and AHR (C25). Values reported are mean +/- SE. Placebo had no effect on Vi45 or AHR over time. Both analysis approaches yielded good descriptions of the data with comparable model parameters. M6G PK/PD model parameters for Vi45 were t1/2ke0 2.1 +/- 0.2 h and C25 528 +/- 88 nm and for AHR were t1/2ke0 1.0 +/- 0.1 h and C25 873 +/- 81 nm. Morphine PK/PD model parameters for Vi45 were t1/2ke0 3.8 +/- 0.9 h and C25 28 +/- 6 nm and for AHR were t1/2ke0 4.3 +/- 0.6 h and C25 16 +/- 2 nm. Morphine is more potent in affecting hypoxic ventilatory control than M6G, with a potency ratio ranging from 1:19 for Vi45 to 1:50 for AHR. At drug concentrations causing 25% depression of Vi45, M6G caused only 15% depression of AHR, whereas morphine caused greater than 50% depression of AHR. Furthermore, the speed of onset/offset of M6G is faster than morphine by a factor of approximately 2. The authors discuss some of the possible mechanisms for the observed differences in opioid behavior.

[Continuous subcutaneous morphine to patients with terminal cancer. Analgesia at home].

PubMed

Laursen, J O

1994-04-04

Since 1992 it has been possible for cancer patients in the county of Southern Jutland to receive terminal care in their own homes. An essential part of this management is effective pain relief; more than 60% of cancer patients have chronic pain. In cases where oral medication or epidural administration of morphine is insufficient or complicated by side-effects continuous subcutaneous morphine administration may be suitable. The patient may be treated in this latter manner for long periods of time. A case story is described where a cancer patient was treated with continuous subcutaneous morphine in his home for more than 257 days without complications or major side-effects.

L-type calcium channel blockade attenuates morphine withdrawal: in vivo interaction between L-type calcium channels and corticosterone.

PubMed

Esmaeili-Mahani, Saeed; Fathi, Yadollah; Motamedi, Fereshteh; Hosseinpanah, Farhad; Ahmadiani, Abolhassan

2008-02-01

Both opioids and calcium channel blockers could affect hypothalamic-pituitary-adrenal (HPA) axis function. Nifedipine, as a calcium channel blocker, can attenuate the development of morphine dependence; however, the role of the HPA axis in this effect has not been elucidated. We examined the effect of nifedipine on the induction of morphine dependency in intact and adrenalectomized (ADX) male rats, as assessed by the naloxone precipitation test. We also evaluated the effect of this drug on HPA activity induced by naloxone. Our results showed that despite the demonstration of dependence in both groups of rats, nifedipine is more effective in preventing of withdrawal signs in ADX rats than in sham-operated rats. In groups that received morphine and nifedipine concomitantly, naloxone-induced corticosterone secretion was attenuated. Thus, we have shown the involvement of the HPA axis in the effect of nifedipine on the development of morphine dependency and additionally demonstrated an in vivo interaction between the L-type Ca2+ channels and corticosterone.

A comparison of intraoperative morphine sulfate and methadone hydrochloride on postoperative visual analogue scale pain scores and narcotic requirements.

PubMed

Laur, D F; Sinkovich, J; Betley, K

1995-02-01

Morphine sulfate and methadone hydrochloride exhibit very different half-lives but are described as having an analgesic potency of one. The use of a drug like methadone may provide prolonged and constant analgesia in the perioperative setting. This double-blinded investigation used methadone and morphine intraoperatively and measured pain scores and narcotic requirements in the first 24 hours postoperatively. Thirty American Society of Anesthesiology (ASA) patients, physical status I through III, between the ages of 18 to 65 years were scheduled for orthopedic surgery and randomly assigned to receive morphine or methadone at 0.30 mg/kg. Fifteen patients received morphine and fifteen patients received methadone. There was no significant difference between the two groups in terms of age, height, weight, and ASA status. No statistically significant difference was observed among the two groups between the amount of analgesic requirements postoperatively or in the visual analogue scale pain score.

Identification of a µ opiate receptor signaling mechanism in human placenta.

PubMed

Mantione, Kirk J; Angert, Robert M; Cadet, Patrick; Kream, Richard M; Stefano, George B

2010-11-01

Previous studies report that genes in the morphine biosynthetic pathway have been found in placental tissue. Prior researchers have shown that kappa opioid receptors are present in human placenta. We determined if a µ opiate receptor was present and which subtype was expressed in human placenta. We also sought to demonstrate a functional µ opiate receptor in human placenta. Polymerase chain reactions as well as DNA sequencing were performed to identify the µ opiate receptor subtypes present in human placenta. The functionality of the receptor was demonstrated by real time amperometric measurements of morphine induced NO release. The µ4 opiate receptor sequence was present as well as the µ1 opioid receptor transcript. The addition of morphine to placental tissue resulted in immediate nitric oxide release and this effect was blocked by naloxone. In the present study, an intact morphine signaling system has been demonstrated in human placenta. Morphine signaling in human placenta probably functions to regulate the immune, vascular, and endocrine functions of this organ via NO.

Glasgow Coma Scores, Early Opioids, and Posttraumatic Stress Disorder Among Combat Amputees

DTIC Science & Technology

2014-04-01

icz, Johnson, & Mosely, 2008). Little research has compared how morphine and fentanyl might impact later psychological outcomes such as PTSD. In the...Fox, Saunders, Menk, & Middaugh, 1995). Because the analgesic effect of fentanyl is approximately 100 times more than morphine , the median Level 2...dosages administered to patients for these opioids appeared equivalent for analgesic effectiveness (Fox et al., 1995). Of the morphine -treated pa

Effect of morphine on sympathetic nerve activity in humans

NASA Technical Reports Server (NTRS)

Carter, Jason R.; Sauder, Charity L.; Ray, Chester A.

2002-01-01

There are conflicting reports for the role of endogenous opioids on sympathetic and cardiovascular responses to exercise in humans. A number of studies have utilized naloxone (an opioid-receptor antagonist) to investigate the effect of opioids during exercise. In the present study, we examined the effect of morphine (an opioid-receptor agonist) on sympathetic and cardiovascular responses at rest and during isometric handgrip (IHG). Eleven subjects performed 2 min of IHG (30% maximum) followed by 2 min of postexercise muscle ischemia (PEMI) before and after systemic infusion of morphine (0.075 mg/kg loading dose + 1 mg/h maintenance) or placebo (saline) in double-blinded experiments on separate days. Morphine increased resting muscle sympathetic nerve activity (MSNA; 17 +/- 2 to 22 +/- 2 bursts/min; P < 0.01) and increased mean arterial pressure (MAP; 87 +/- 2 to 91 +/- 2 mmHg; P < 0.02), but it decreased heart rate (HR; 61 +/- 4 to 59 +/- 3; P < 0.01). However, IHG elicited similar increases for MSNA, MAP, and HR between the control and morphine trial (drug x exercise interaction = not significant). Moreover, responses to PEMI were not different. Placebo had no effect on resting, IHG, and PEMI responses. We conclude that morphine modulates cardiovascular and sympathetic responses at rest but not during isometric exercise.

Analgesia or addiction?: implications for morphine use after spinal cord injury.

PubMed

Woller, Sarah A; Moreno, Georgina L; Hart, Nigel; Wellman, Paul J; Grau, James W; Hook, Michelle A

2012-05-20

Opioid analgesics are among the most effective agents for treatment of moderate to severe pain. However, the use of morphine after a spinal cord injury (SCI) can potentiate the development of paradoxical pain symptoms, and continuous administration can lead to dependence, tolerance, and addiction. Although some studies suggest that the addictive potential of morphine decreases when it is used to treat neuropathic pain, this has not been studied in a SCI model. Accordingly, the present studies investigated the addictive potential of morphine in a rodent model of SCI using conditioned place preference (CPP) and intravenous self-administration paradigms. A contusion injury significantly increased the expression of a CPP relative to sham and intact controls in the acute phase of injury. However, contused animals self-administered significantly less morphine than sham and intact controls, but this was dose-dependent; at a high concentration, injured rats exhibited an increase in drug-reinforced responses over time. Exposure to a high concentration of morphine impeded weight gain and locomotor recovery. We suggest that the increased preference observed in injured rats reflects a motivational effect linked in part to the drug's anti-nociceptive effect. Further, although injured rats exhibited a suppression of opiate self-administration, when given access to a high concentration, addictive-like behavior emerged and was associated with poor recovery.

The influence of modulation of P-glycoprotein and /or cytochrome P450 3A on the pharmacokinetics and pharmacodynamics of orally administered morphine in dogs.

PubMed

Gadeyne, C; Van der Heyden, S; Gasthuys, F; Croubels, S; Schauvliege, S; Polis, I

2011-10-01

The influence of pretreatment with ketoconazole [cytochrome P450 3A (CYP3A) + P-glycoprotein (P-gp) inhibitor], elacridar (selective P-gp inhibitor) and rifampicin (CYP3A + P-gp inducer) on oral morphine pharmacokinetics and pharmacodynamics was investigated in experimental dogs. Seven beagles were used in a four-way crossover design. Morphine hydrochloride was administered orally (2.5 mg/kg) alone (control group CON) or after pretreatment with ketoconazole (group KETO), elacridar (group ELA) or rifampicin (group RIF). Morphine plasma concentrations were analysed by liquid chromatography-tandem mass spectrometry. Sedation scores (none, mild, moderate or severe) were evaluated subjectively. Dogs were significantly (P < 0.05) more sedated after ketoconazole pretreatment. There were no significant differences between group CON and the other pretreatment groups in pharmacokinetic parameters taking both sexes into account. Sex differences were apparent in some pharmacokinetic parameters of morphine. The area under the plasma concentration time curve (AUC(0-∞) ) was significantly higher, and the total body clearance was significantly lower in male compared to female dogs in all treatment groups. Ketoconazole, rifampicin and elacridar pretreatment had no significant effects on morphine pharmacokinetics, although dogs in the ketoconazole group showed higher sedation scores. © 2011 Blackwell Publishing Ltd.

Ethnic differences in pain perception and patient-controlled analgesia usage for postoperative pain.

PubMed

Tan, Ene-Choo; Lim, Yvonne; Teo, Yik-Ying; Goh, Rachelle; Law, Hai-Yang; Sia, Alex T

2008-09-01

There are reports suggesting that sensitivity to and tolerance of both clinical and experimental pain differ among ethnic groups. We examined self-rated pain score and morphine usage in 1034 women who underwent elective lower cesarian section (LSCS) for their deliveries. Data on pain scores and amount of total morphine use according to patient-controlled analgesia were collected every 4 hours. Overall, lowest pain scores were recorded 12 hours after surgery and highest at 24 hours. Morphine consumption was highest within the first 4 hours and lowest between 12 and 16 hours. There were statistically significant ethnic group differences in pain scores (P = 1.7 x 10(-7)) and morphine usage (P = 2.8 x 10(-15)) between ethnic groups, with Indians having the highest mean pain score and using the highest amount of morphine. The ethnic differences in pain score and morphine self-administration persisted after controlling for age, body mass index, and duration of operation. Our findings of highly significant ethnic group difference in self-reported pain level and the amount of analgesia self-administered may have implications on optimal management of acute postoperative pain. Inadequate management of pain after cesarian deliveries might affect the emotional well-being and physical recovery of patients and affect mother-child bonding.

Efficacy and tolerability of intravenous morphine patient-controlled analgesia (PCA) in women undergoing cesarean delivery.

PubMed

Andziak, Marta; Beta, Jarosław; Barwijuk, Michal; Issat, Tadeusz; Jakimiuk, Artur J

2015-06-01

The aim of the study was to evaluate analgesic efficacy and tolerability of patient-controlled analgesia (PCA) with intravenous morphine. Our observational study included 50 women who underwent a Misgav-Ladach or modified Misgav-Ladach cesarean section. Automated PCA infusion device (Medima S-PCA Syringe Pump, Medima, Krakow, Poland) was used for postoperative pain control. Time of morphine administration or initiation of intravenous patient-controlled analgesia (IV PCA) with morphine was recorded, as well as post-operative pain at rest assessed by a visual analogue scale (VAS). All patients were followed up for 24 hours after discharge from the operating room, taking into account patient records, worst pain score at rest, number of IV PCA attempts, and drug consumption. Median of total morphine doses used during the postoperative period was 42.9mg (IQR 35.6-48.5), with median infusion time of 687.0 min. (IQR 531.0-757.5). Pain severity and total drug consumption improved after the first 3 hours following cesarean delivery (p < 0.01). Mean number of PCA attempts per patient was 33 (IQR: 24-37), with median of 11 placebo attempts (IQR: 3-27). Patient-controlled analgesia with morphine is an efficient and acceptable analgesic method in women undergoing cesarean section.

Locomotor activity: A distinctive index in morphine self-administration in rats.

PubMed

Zhang, Jian-Jun; Kong, Qingyao

2017-01-01

Self-administration of addictive drugs is a widely used tool for studying behavioral, neurobiological, and genetic factors in addiction. However, how locomotor activity is affected during self-administration of addictive drugs has not been extensively studied. In our present study, we tested the locomotor activity levels during acquisition, extinction and reinstatement of morphine self-administration in rats. We found that compared with saline self-administration (SA), rats that trained with morphine SA had higher locomotor activity. Rats that successfully acquired SA also showed higher locomotor activity than rats that failed in acquiring SA. Moreover, locomotor activity was correlated with the number of drug infusions but not with the number of inactive pokes. We also tested the locomotor activity in the extinction and the morphine-primed reinstatement session. Interestingly, we found that in the first extinction session, although the number of active pokes did not change, the locomotor activity was significantly lower than in the last acquisition session, and this decrease can be maintained for at least six days. Finally, morphine priming enhanced the locomotor activity during the reinstatement test, regardless of if the active pokes were significantly increased or not. Our results clearly suggest that locomotor activity, which may reflect the pharmacological effects of morphine, is different from drug seeking behavior and is a distinctive index in drug self-administration.

Reversal effect of intra-central amygdala microinjection of L-arginine on place aversion induced by naloxone in morphine conditioned rats.

PubMed

Karimi, Sara; Karami, Manizheh; Sahraei, Hedayat; Rahimpour, Mahnaz

2011-01-01

Role of nitric oxide (NO) on expression of morphine conditioning using a solely classic task has been proposed previously. In this work, the involvement of NO on the expression of opioid-induced conditioning in the task paired with an injection of naloxone was investigated. Conditioning was established in adult male Wistar rats (weighing 200-250 g) using an unbiased procedure. Naloxone (0.05-0.4 mg/kg, i.p.), a selective antagonist of mu-opioid receptor, was administered once prior to morphine response testing. NO agents were administered directly into the central amygdala (CeA) prior to naloxone injection pre-testing. Morphine (2.5-10 mg/kg, s.c.) produced a significant dose-dependent place preference in experimental animals. When naloxone (0.05-0.4 mg/kg, i.p.) was injected before testing of morphine (5 mg/kg, s.c.) response, the antagonist induced a significant aversion. This response was reversed due to injection of L-arginine (0.3-3 microg/rat), intra-CeA prior to naloxone administration. However, pre-injection of L-NAME (intra-CeA), an inhibitor of NO production, blocked this effect. The finding may reflect that NO in the nucleus participates in morphine plus naloxone interaction.

Sex-dependent effects of periadolescent exposure to the cannabinoid agonist CP-55,940 on morphine self-administration behaviour and the endogenous opioid system.

PubMed

Biscaia, Miguel; Fernández, Beatriz; Higuera-Matas, Alejandro; Miguéns, Miguel; Viveros, Maria-Paz; García-Lecumberri, Carmen; Ambrosio, Emilio

2008-04-01

Early cannabinoid consumption may predispose individuals to the misuse of addictive drugs later in life. However, there is a lack of experimental evidence as to whether cannabinoid exposure during adolescence might differently affect opiate reinforcing efficacy and the opioid system in adults of both sexes. Our aim was to examine whether periadolescent chronic exposure to the cannabinoid agonist CP-55,940 could exert sex-dependent effects on morphine reinforcing and the opioid system in adulthood. Morphine reinforcing was studied under a progressive ratio (PR) reinforcement schedule in adult male and female rats that previously acquired morphine self-administration under a fixed ratio 1 (FR1) schedule. Binding levels and functionality of mu-opioid receptors were also evaluated. Periadolescent cannabinoid exposure altered morphine self-administration and the opioid system in adult rats in a sex-dependent manner. CP-55,940-exposed males exhibited higher self-administration rates under a FR1, but not under a PR schedule. In females, CP-55,940 did not modify morphine self-administration under either schedule. Moreover, CP-55,940 also increased mu-opioid receptor levels in the subcallosal streak of pre-treated animals and decreased mu-opioid receptor functionality in the nucleus accumbens shell but again, only in males. Our data indicate that adult male rats exposed to the cannabinoid in adolescence self-administer more morphine than females, but only when the demands required by the schedule of reinforcement are low, which might be related to the decrease in mu-opioid receptor functionality in the NAcc-shell observed in these animals.

Effect of estrogen on morphine- and oxycodone-induced antinociception in a female femur bone cancer pain model.

PubMed

Ono, Hiroko; Nakamura, Atsushi; Kanemasa, Toshiyuki; Sakaguchi, Gaku; Shinohara, Shunji

2016-02-15

Although estrous cycle has been reported to influence antiociceptive effect of morphine in several pain conditions, its effect on cancer pain is not well established. We investigated the effect of estrogen on morphine antinociception using a bone cancer pain model and compared its potency with that of oxycodone. Female mice were ovariectomized (OVX) for preparation of a femur bone cancer pain (FBC) model. β-estradiol was subcutaneously (s.c.) administered and antinociceptive effects of opioids was assessed using the von Frey monofilament test. Although morphine (5-20mg/kg, s.c.) did have significant antinociceptive effects in the FBC-OVX group, its effects in the FBC-OVX+β-estradiol (OVX+E) group was limited. Oxycodone (1-5mg/kg, s.c.) exhibited significant effects in both groups. Expression changes in opioid-related genes (μ-, κ-, δ-opioid receptors, prodynorphin, proenkephalin, proopiomelanocortin) in the spinal and supraspinal sites were examined among the sham-OVX, sham-OVX+E, FBC-OVX, and FBC-OVX+E groups by in situ hybridization. These studies detected a significant increase in prodynorphin in the spinal dorsal horn of the FBC-OVX+E group. Spinal injection of a dynorphin-A antibody to FBC-OVX+E mice restored antinociception of morphine. In conclusion, we detected a differential effect of estrogen on morphine- and oxycodone-induced antinociception in a female FBC model. The effect of morphine was limited with estrogen exposure, which may be due to estrogen- and pain-mediated spinal expression of dynorphin-A. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparative study of fentanyl and morphine in addition to hyperbaric or isobaric bupivacaine in combined spinal anaesthesia for caesarean section

PubMed Central

Saracoglu, Ayten; Saracoglu, Kemal T.; Eti, Zeynep

2011-01-01

Introduction The aim of our study was to compare the effects of isobaric and hyperbaric bupivacaine combined with morphine or fentanyl in patients undergoing caesarean section. We assessed quality and spread of analgesia and anaesthesia, postoperative analgesic requirement and side effects. Material and methods Hundred patients with American Society of Anesthesiologists physical status (ASA) I-II, age 18 to 40 years, were randomized to 4 groups. The intrathecal solutions were isobaric bupivacaine + morphine (group A), isobaric bupivacaine + fentanyl (group B), heavy bupivacaine + + morphine (group C) and heavy bupivacaine + fentanyl (group D). Mean arterial pressure, heart rate, oxygen saturation, ephedrine consumption, analgesic requirement time and additional analgesic needs were recorded. Results The 1st min value of mean arterial pressure was the lowest one in all groups. Heart rate decreased significantly in group A at the 10th min but not in the other groups. The decrease of visual analogue scale (VAS) pain scores began in the groups after the 4th postoperative h (p < 0.05) and the VAS value of group B at the 8th h was significantly higher than the other groups. The first analgesic requirement time in the postoperative period was longer in patients who had intrathecal morphine than those who had fentanyl. The duration of analgesia with isobaric bupivacaine and morphine was the longest one. Conclusions We concluded that intrathecal morphine provides a long duration of postoperative analgesia but the duration gets longer when it is combined with plain bupivacaine instead of heavy bupivacaine. PMID:22291807

Do Diuretics have Antinociceptive Actions: Studies of Spironolactone, Eplerenone, Furosemide and Chlorothiazide, Individually and with Oxycodone and Morphine.

PubMed

Jokinen, Viljami; Lilius, Tuomas; Laitila, Jouko; Niemi, Mikko; Kambur, Oleg; Kalso, Eija; Rauhala, Pekka

2017-01-01

Spironolactone, eplerenone, chlorothiazide and furosemide are diuretics that have been suggested to have antinociceptive properties, for example via mineralocorticoid receptor antagonism. In co-administration, diuretics might enhance the antinociceptive effect of opioids via pharmacodynamic and pharmacokinetic mechanisms. Effects of spironolactone (100 mg/kg, i.p.), eplerenone (100 mg/kg, i.p.), chlorothiazide (50 mg/kg, i.p.) and furosemide (100 mg/kg, i.p.) were studied on acute oxycodone (0.75 mg/kg, s.c.)- and morphine (3 mg/kg, s.c.)-induced antinociception using tail-flick and hot plate tests in male Sprague Dawley rats. The diuretics were administered 30 min. before the opioids, and behavioural tests were performed 30 and 90 min. after the opioids. Concentrations of oxycodone, morphine and their major metabolites in plasma and brain were quantified by mass spectrometry. In the hot plate test at 30 and 90 min., spironolactone significantly enhanced the antinociceptive effect (% of maximum possible effect) of oxycodone from 10% to 78% and from 0% to 50%, respectively, and that of morphine from 12% to 73% and from 4% to 83%, respectively. The brain oxycodone and morphine concentrations were significantly increased at 30 min. (oxycodone, 46%) and at 90 min. (morphine, 190%). We did not detect any independent antinociceptive effects with the diuretics. Eplerenone and chlorothiazide did not enhance the antinociceptive effect of either opioid. The results suggest that spironolactone enhances the antinociceptive effect of both oxycodone and morphine by increasing their concentrations in the central nervous system. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Pharmacodynamics and Pharmacokinetics of Morphine After Cardiac Surgery in Children With and Without Down Syndrome.

PubMed

Valkenburg, Abraham J; Calvier, Elisa A M; van Dijk, Monique; Krekels, Elke H J; O'Hare, Brendan P; Casey, William F; Mathôt, Ron A A; Knibbe, Catherijne A J; Tibboel, Dick; Breatnach, Cormac V

2016-10-01

To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two groups of children-those with and without Down syndrome. Prospective, single-center observational trial. PICU in a university-affiliated pediatric teaching hospital. Twenty-one children with Down syndrome and 17 without, 3-36 months old, scheduled for cardiac surgery with cardiopulmonary bypass. A loading dose of morphine (100 μg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 μg/kg/hr. During intensive care, nurses regularly assessed pain and discomfort with validated observational instruments (COMFORT-Behavior scale and Numeric Rating Scale-for pain). These scores guided analgesic and sedative treatment. Plasma samples were obtained for pharmacokinetic analysis. Median COMFORT-Behavior and Numeric Rating Scale scores were not statistically significantly different between the two groups. The median morphine infusion rate during the first 24 hours after surgery was 31.3 μg/kg/hr (interquartile range, 23.4-36.4) in the Down syndrome group versus 31.7 μg/kg/hr (interquartile range, 25.1-36.1) in the control group (p = 1.00). Population pharmacokinetic analysis revealed no statistically significant differences in any of the pharmacokinetic variables of morphine between the children with and without Down syndrome. This prospective trial showed that there are no differences in pharmacokinetics or pharmacodynamics between children with and without Down syndrome if pain and distress management is titrated to effect based on outcomes of validated assessment instruments. We have no evidence to adjust morphine dosing after cardiac surgery in children with Down syndrome.

A randomised controlled trial comparing three analgesia regimens following total knee joint replacement: continuous femoral nerve block, intrathecal morphine or both.

PubMed

Olive, D J; Barrington, M J; Simone, S A; Kluger, R

2015-07-01

This randomised controlled trial compared three analgesia regimens following primary unilateral total knee joint replacement: continuous femoral nerve block (CFNB), intrathecal morphine (ITM), and both. The primary outcome was pain ratings over the first 24 hours. Secondary outcomes included morphine consumption, nausea, pruritus and sedation ratings, oxygen saturation (SpO2) ratings, and ability to mobilise postoperatively. All patients received a spinal anaesthetic and a postoperative patient-controlled morphine pump. Patients were randomised to receive CFNB, ITM, or both. In patients with no CFNB, the use of ITM was blinded. Eighty-one patients were randomised and there were no withdrawals. At 24 hours, the ITM-only group had higher pain ratings than either of the other groups (P=0.04 versus CFNB, P=0.01 versus combination). In the 18 to 24 hour period, the ITM group used more morphine than either of the other groups. There were no statistically significant differences in pain ratings or morphine consumption at earlier time intervals. The ITM group were less likely to be able to sit out of bed on day one. Patients who received ITM were more likely to have pruritus. There were no statistically significant differences in nausea, SpO₂or sedation ratings. This study showed that a CFNB resulted in reduced pain and was also associated with less morphine consumption and improved mobilisation at 24 hours compared to ITM. This study did not show any statistically significant differences between CFNB alone and CFNB+ITM.

Pain Levels Within 24 Hours After UFE: A Comparison of Morphine and Fentanyl Patient-Controlled Analgesia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Hyun S., E-mail: sikhkim@jhmi.edu; Czuczman, Gregory J.; Nicholson, Wanda K.

The purpose of this study was to assess the presence and severity of pain levels during 24 h after uterine fibroid embolization (UFE) for symptomatic leiomyomata and compare the effectiveness and adverse effects of morphine patient-controlled analgesia (PCA) versus fentanyl PCA. We carried out a prospective, nonrandomized study of 200 consecutive women who received UFE and morphine or fentanyl PCA after UFE. Pain perception levels were obtained on a 0-10 scale for the 24-h period after UFE. Linear regression methods were used to determine pain trends and differences in pain trends between two groups and the association between pain scoresmore » and patient covariates. One hundred eighty-five patients (92.5%) reported greater-than-baseline pain after UFE, and 198 patients (99%) required IV opioid PCA. One hundred thirty-six patients (68.0%) developed nausea during the 24-h period. Seventy-two patients (36%) received morphine PCA and 128 (64%) received fentanyl PCA, without demographic differences. The mean dose of morphine used was 33.8 {+-} 26.7 mg, while the mean dose of fentanyl was 698.7 {+-} 537.4 {mu}g. Using this regimen, patients who received morphine PCA had significantly lower pain levels than those who received fentanyl PCA (p < 0.0001). We conclude that patients develop pain requiring IV opioid PCA within 24 h after UFE. Morphine PCA is more effective in reducing post-uterine artery embolization pain than fentanyl PCA. Nausea is a significant adverse effect from opioid PCA.« less

Low-dose memantine attenuated morphine addictive behavior through its anti-inflammation and neurotrophic effects in rats.

PubMed

Chen, Shiou-Lan; Tao, Pao-Luh; Chu, Chun-Hsien; Chen, Shih-Heng; Wu, Hsiang-En; Tseng, Leon F; Hong, Jau-Shyong; Lu, Ru-Band

2012-06-01

Opioid abuse and dependency are international problems. Studies have shown that neuronal inflammation and degeneration might be related to the development of opioid addiction. Thus, using neuroprotective agents might be beneficial for treating opioid addiction. Memantine, an Alzheimer's disease medication, has neuroprotective effects in vitro and in vivo. In this study, we evaluated whether a low dose of memantine prevents opioid-induced drug-seeking behavior in rats and analyzed its mechanism. A conditioned-place-preference test was used to investigate the morphine-induced drug-seeking behaviors in rats. We found that a low-dose (0.2-1 mg/kg) of subcutaneous memantine significantly attenuated the chronic morphine-induced place-preference in rats. To clarify the effects of chronic morphine and low-dose memantine, serum and brain levels of cytokines and brain-derived neurotrophic factor (BDNF) were measured. After 6 days of morphine treatment, cytokine (IL-1β, IL-6) levels had significantly increased in serum; IL-1β and IL-6 mRNA levels had significantly increased in the nucleus accumbens and medial prefrontal cortex, both addiction-related brain areas; and BDNF levels had significantly decreased, both in serum and in addiction-related brain areas. Pretreatment with low-dose memantine significantly attenuated chronic morphine-induced increases in serum and brain cytokines. Low-dose memantine also significantly potentiated serum and brain BDNF levels. We hypothesize that neuronal inflammation and BDNF downregulation are related to the progression of opioid addiction. We hypothesize that the mechanism low-dose memantine uses to attenuate morphine-induced addiction behavior is its anti-inflammatory and neurotrophic effects.

Analgesic efficacy of butorphanol and morphine in bearded dragons and corn snakes.

PubMed

Sladky, Kurt K; Kinney, Matthew E; Johnson, Stephen M

2008-07-15

To test the hypothesis that administration of butorphanol or morphine induces antinociception in bearded dragons and corn snakes. Prospective crossover study. 12 juvenile and adult bearded dragons and 13 corn snakes. Infrared heat stimuli were applied to the plantar surface of bearded dragon hind limbs or the ventral surface of corn snake tails. Thermal withdrawal latencies (TWDLs) were measured before (baseline) and after SC administration of physiologic saline (0.9% NaCl) solution (equivalent volume to opioid volumes), butorphanol tartrate (2 or 20 mg/kg [0.91 or 9.1 mg/lb]), or morphine sulfate (1, 5, 10, 20, or 40 mg/kg [0.45, 2.27, 4.5, 9.1, or 18.2 mg/lb]). For bearded dragons, butorphanol (2 or 20 mg/kg) did not alter hind limb TWDLs at 2 to 24 hours after administration. However, at 8 hours after administration, morphine (10 and 20 mg/kg) significantly increased hind limb TWDLs from baseline values (mean +/- SEM maximum increase, 2.7+/-0.4 seconds and 2.8+/-0.9 seconds, respectively). For corn snakes, butorphanol (20 mg/kg) significantly increased tail TWDLs at 8 hours after administration (maximum increase from baseline value, 3.0+/-0.8 seconds); the low dose had no effect. Morphine injections did not increase tail TWDLs at 2 to 24 hours after administration. Compared with doses used in most mammalian species, high doses of morphine (but not butorphanol) induced analgesia in bearded dragons, whereas high doses of butorphanol (but not morphine) induced analgesia in corn snakes.

Total morphine stability in urine specimens stored under various conditions.

PubMed

Chang, B L; Huang, M K; Tsai, Y Y

2000-09-01

The stability of total morphine in urine stored under various conditions was studied using control and experimental specimens. Samples in the control group were prepared using drug-free urine spiked with morphine at three concentration levels (300, 1000, and 2500 ng/mL), each with the pH adjusted to 5.5, 6.5, and 7.5. Samples in the experimental group came from 20 alleged heroin addicts (provided by Taipei Municipal Psychiatric Hospital). Samples in both groups were divided into two categories--one with and one without the precipitate (formed at 0 degrees C) removed. Samples in each of these two categories were further divided into two sub-groups--one with and one without sodium azide (0.05%) added. Total morphine contents in these samples were first determined by gas chromatography-mass spectrometry prior to storage and at 6, 12, 18, and 24 months following storage at -20, 4, 25, and 35 degrees C. Effects of sample treatment (azide addition and precipitate removal), pH, and storage temperature and length were evaluated by examining the percentage of total morphine remaining at the four time intervals following the initial determination. Major findings were as follows: (1) total morphine decomposition was minimal when stored for 12 months at -20 degrees C, which is a common current practice; (2) samples with lower initial sample pH had slower total morphine decomposition rates; and (3) azide addition appeared to have no detectable effect, whereas precipitate removal appeared to marginally reduce the decomposition rate, especially for samples with lower pH.

Role of opioid system in verapamil-induced antinociception in a rat model of orofacial pain

PubMed Central

Tamaddonfard, Esmaeal; Erfanparast, Amir; Taati, Mina; Dabbaghi, Milad

2014-01-01

Calcium, through its various channels involves in local, spinal and supra-spinal transmission of pain. In the present study, we investigated the separate and combined treatment effects of verapamil (a calcium channel blocker), morphine (an opioid agonist) and naloxone (an opioid antagonist) on pain in the orofacial region of rats. Orofacial pain was induced by subcutaneous (SC) injection of formalin (50 µL, 1.5%) into the left upper lip side, and the time durations spent face rubbing with epsilateral forepaw were recorded in three min blocks for a period of 45 min. Formalin induced a biphasic pattern (first phase: 0-3 min; second phase: 15-33 min) of pain. Intraperitoneal (IP) injections of verapamil (2 and 8 mg kg-1) and morphine (2 and 4 mg kg-1) suppressed orofacial pain. Co-administration of sub-analgesic doses of verapamil (0.5 mg kg-1) and morphine (1 mg kg-1) produced second phase analgesia. Both phases of formalin-induced pain were suppressed when an analgesic dose (2 mg kg-1) of verapamil co-administered with a sub-analgesic dose (1 mg kg-1) of morphine. The SC injection of naloxone (2 mg kg-1) alone with no effect on pain intensity, prevented the antinociceptive effects induced by morphine (2 mg kg-1), but not verapamil (2 mg kg-1). The obtained results showed antinociceptive effects for verapamli and morphine on orofacial pain. Co-administrations of verapamil and morphine produced antinociceptive effects. It seems that opioid analgesic system may not have a role in the verapamil-induced antinociception. PMID:25568692

Increased impulsive action in rats: effects of morphine in a short and long fixed-delay response inhibition task.

PubMed

Mahoney, Megan K; Silveira, Mason M; Olmstead, Mary C

2013-12-01

Impulsive action is mediated through several neurochemical systems, although it is not clear which role each of these plays in the inability to withhold inappropriate responses. Manipulations of the opioid system alter impulsive action in rodents, although the effects are not consistent across tasks. Previously, we speculated that these discrepancies reflect differences in the cognitive mechanisms that control responding in each task. We investigated whether the effect of morphine, a mu opioid receptor (MOR) agonist, on impulsive action depends on the ability of the subjects to time the interval during which they must inhibit a response. Male Long-Evans rats were trained in a response inhibition (RI) task to withhold responding for sucrose during a 4- or 60-s delay; impulsive action was assessed as increased responding during the delay. The rats were tested following an injection of morphine (0, 1, 3, 6 mg/kg). In a subsequent experiment, the effects of morphine (6 mg/kg) plus the MOR antagonist naloxone (0, 0.3, 1, 3 mg/kg) were investigated. Morphine increased impulsive action, but had different effects in the two conditions: the drug increased the proportion of premature responses as the 4-s interval progressed and produced a general increase in responding across the 60-s interval. Naloxone blocked all morphine-induced effects. The finding that morphine increases impulsive action in a fixed-delay RI task contrasts with our previous evidence which shows no effect in the same task with a variable delay. Thus, MORs disrupt impulsive action only when rats can predict the delay to respond.

Effects of chronic morphine and morphine withdrawal on gene expression in rat peripheral blood mononuclear cells.

PubMed

Desjardins, Stephane; Belkai, Emilie; Crete, Dominique; Cordonnier, Laurie; Scherrmann, Jean-Michel; Noble, Florence; Marie-Claire, Cynthia

2008-12-01

Chronic morphine treatment alters gene expression in brain structures. There are increasing evidences showing a correlation, in gene expression modulation, between blood cells and brain in psychological troubles. To test whether gene expression regulation in blood cells could be found in drug addiction, we investigated gene expression profiles in peripheral blood mononuclear (PBMC) cells of saline and morphine-treated rats. In rats chronically treated with morphine, the behavioral signs of spontaneous withdrawal were observed and a withdrawal score was determined. This score enabled to select the time points at which the animals displayed the mildest and strongest withdrawal signs (12 h and 36 h after the last injection). Oligonucleotide arrays were used to assess differential gene expression in the PBMCs and quantitative real-time RT-PCR to validate the modulation of several candidate genes 12 h and 36 h after the last injection. Among the 812 differentially expressed candidates, several genes (Adcy5, Htr2a) and pathways (Map kinases, G-proteins, integrins) have already been described as modulated in the brain of morphine-treated rats. Sixteen out of the twenty-four tested candidates were validated at 12 h, some of them showed a sustained modulation at 36 h while for most of them the modulation evolved as the withdrawal score increased. This study suggests similarities between the gene expression profile in PBMCs and brain of morphine-treated rats. Thus, the searching of correlations between the severity of the withdrawal and the PBMCs gene expression pattern by transcriptional analysis of blood cells could be promising for the study of the mechanisms of addiction.

Depression of home cage wheel running is an objective measure of spontaneous morphine withdrawal in rats with and without persistent pain

PubMed Central

Kandasamy, Ram; Lee, Andrea T.; Morgan, Michael M.

2017-01-01

Opioid withdrawal in humans is often subtle and almost always spontaneous. In contrast, most preclinical studies precipitate withdrawal by administration of an opioid receptor antagonist such as naloxone. These animal studies rely on measurement of physiological symptoms (e.g., wet dog shakes) in the period immediately following naloxone administration. To more closely model the human condition, we tested the hypothesis that depression of home cage wheel running will provide an objective method to measure the magnitude and duration of spontaneous morphine withdrawal. Rats were allowed access to a running wheel in their home cage for 8 days prior to implantation of two 75 mg morphine or placebo pellets. The pellets were removed 3 or 5 days later to induce spontaneous withdrawal. In normal pain-free rats, removal of the morphine pellets depressed wheel running for 48 hours compared to rats that had placebo pellets removed. Morphine withdrawal-induced depression of wheel running was greatly enhanced in rats with persistent inflammatory pain induced by injection of Complete Freund’s Adjuvant (CFA) into the hindpaw. Removal of the morphine pellets following 3 days of treatment depressed wheel running in these rats for over 6 days. These data demonstrate that home cage wheel running provides an objective and more clinically relevant method to assess spontaneous morphine withdrawal compared to precipitated withdrawal in laboratory rats. Moreover, the enhanced withdrawal in rats with persistent inflammatory pain suggests that pain patients may be especially susceptible to opioid withdrawal. PMID:28366799

Analgesic tolerance to morphine is regulated by PPARγ

PubMed Central

de Guglielmo, Giordano; Kallupi, Marsida; Scuppa, Giulia; Stopponi, Serena; Demopulos, Gregory; Gaitanaris, George; Ciccocioppo, Roberto

2014-01-01

Background and Purpose Opioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of significant side effects, including drug dependence and addiction. Here, we investigated the role of PPARγ in the development of analgesic tolerance to morphine in mice. Experimental Approach We monitored analgesia on alternate days using the tail immersion test. Key Results Daily administration of morphine (30 mg·kg−1, bid) resulted in the rapid development of tolerance to thermal analgesia. Co-administration of pioglitazone (10 and 30 mg·kg−1, bid) significantly attenuated the development and expression of tolerance. However, pretreatment with GW-9662 (5 mg·kg−1, bid), a selective PPARγ antagonist, completely abolished this effect. Injection of GW-9662 and a lower dose of morphine (15 mg·kg−1, bid) accelerated the development of tolerance to its antinociceptive effect. Subsequently, we found that conditional neuronal PPARγ knockout (KO) mice develop a more rapid and pronounced tolerance to morphine antinociception compared with wild-type (WT) controls. Moreover, in PPARγ KO mice, pioglitazone was no longer able to prevent the development of morphine tolerance. Conclusions and Implications Overall, our results demonstrate that PPARγ plays a tonic role in the modulation of morphine tolerance, and its pharmacological activation may help to reduce its development. These findings provide new information about the role of neuronal PPARγ and suggest that combining PPARγ agonists with opioid analgesics may reduce the development of tolerance and possibly attenuate the potential for opioid abuse. PMID:25048682

Effects of acute and long-term typical or atypical neuroleptics on morphine-induced behavioural effects in mice.

PubMed

Hollais, André W; Patti, Camilla L; Zanin, Karina A; Fukushiro, Daniela F; Berro, Laís F; Carvalho, Rita C; Kameda, Sonia R; Frussa-Filho, Roberto

2014-03-01

1. It has been suggested that the high prevalence of drug abuse in schizophrenics is related to chronic treatment with typical neuroleptics and dopaminergic supersensitivity that develops as a consequence. Within this context, atypical neuroleptics do not seem to induce this phenomenon. In the present study, we investigated the effects of acute administration or withdrawal from long-term administration of haloperidol and/or ziprasidone on morphine-induced open-field behaviour in mice. 2. In the first experiment, mice were given a single injection of haloperidol (1 mg/kg, i.p.) or several doses of ziprasidone (2, 4 or 6 mg/kg, i.p.) and motor activity was quantified by the open-field test. The aim of the second experiment was to verify the effects of an acute injection of haloperidol (1 mg/kg) or ziprasidone (6 mg/kg) on 20 mg/kg morphine-induced behaviours in the open-field test. In the third experiment, mice were treated with 1 mg/kg haloperidol and/or 2, 4 or 6 mg/kg ziprasidone for 20 days. Seventy-two hours after the last injection, mice were injected with 20 mg/kg, i.p., morphine and then subjected to the open-field test. Acute haloperidol or ziprasidone decreased spontaneous general activity and abolished morphine-induced locomotor stimulation. 3. Withdrawal from haloperidol or ziprasidone did not modify morphine-elicited behaviours in the open-field test. The results suggest that withdrawal from neuroleptic treatments does not contribute to the acute effect of morphine in schizophrenic patients. © 2014 Wiley Publishing Asia Pty Ltd.

Leishmania donovani amastigote component-induced colony-stimulating factor production by macrophages: modulation by morphine.

PubMed

Singal, Priya; Singh, Prati Pal

2005-02-01

The neuroimmunomodulatory effects of opiates during microbial infections are now well known; however, not much is known during leishmaniasis. Here, we report the effects of morphine on purified approximately 12-kDa component of Leishmania donovani amastigote antigen (LDAA-12)-induced colony-stimulating factor (CSF) production by mouse peritoneal macrophages (PMs) in vitro. Low concentrations (1 x 10(-9) and 1 x 10(-11) M) of morphine significantly (P < 0.05) augmented the production of CSFs, whereas high concentrations (1 x 10(-3) and 1 x 10(-5) M) inhibited CSF production. Morphine exerted a similar concentration-dependent biphasic effect on the LDAA-12-induced elaboration of granulocyte (G)-macrophage (M)-CSF (GM-CSF) and M-CSF by PMs in their conditioned medium, as quantified by using enzyme-linked immunosorbent assay. Furthermore, selective agonists of mu-(DAGO) and delta-(DPDPE) opioid receptors also, respectively, augmented and inhibited the production of CSFs. Pretreatment of PMs with naloxone (1 x 10(-5) M) significantly (P < 0.05) blocked the augmenting effect of morphine. In contrast, at 1 x 10(-5) M, naloxone lacked any effect on the inhibitory effect of morphine; however, its 100-fold higher concentration partially blocked it. This study, apparently for the first time, demonstrates that morphine, via surface opioid receptors, biphasically modulates the LDAA-12-induced CSF production by PMs, in vitro. These results thus show the implications of opiate abuse on the outcome of therapeutic interventions in areas where both visceral leishmaniasis and drug abuse are rampant.

The new kisspeptin derivative - kissorphin (KSO) - attenuates acute hyperlocomotion and sensitization induced by ethanol and morphine in mice.

PubMed

Gibula-Bruzda, Ewa; Marszalek-Grabska, Marta; Gawel, Kinga; Trzcinska, Roza; Silberring, Jerzy; Kotlinska, Jolanta H

2017-11-01

Kissorphin (KSO) is a new peptide derived from kisspeptin-10. This peptide possesses neuropeptide FF (NPFF)-like biological activity in vitro; NPFF, in many cases, inhibits opioid and ethanol effects in rodents. Therefore, the current study explored the influence of KSO on acute ethanol- and morphine-induced hyperactivity, and on the development and expression of locomotor sensitization induced by these drugs. In the present study, sensitization to locomotor effects was induced by repeated exposure to ethanol (2.4 g/kg, intraperitoneally [i.p.], 1 × 4 days) or morphine (10 mg/kg, subcutaneously [s.c.], 1 × 7 days). We found that KSO (1-10 nmol/300 μL, intravenously [i.v.]) did not have an impact on locomotor activity of naïve mice. However, it reduced both acute ethanol- (10 nmol/300 μL) and morphine-induced hyperactivity (3 and 10 nmol/300 μL). Pretreatment of animals with KSO (10 nmol/300 μL), before every ethanol or morphine injection during development of sensitization or before the ethanol or morphine challenge, attenuated the development, as well as the expression of locomotor sensitization to both substances. Moreover, prior administration of the NPFF receptor antagonist RF9 (10 nmol/300 μL, i.v.) inhibited the ability of KSO (10 nmol/300 μL) to reduce the expression of ethanol and morphine sensitization. KSO given alone, at all used doses, did not influence the motor coordination measured via the rotarod test. The results from this study show that KSO effectively attenuated acute and repeated effects of ethanol and morphine. Thus, KSO possesses NPFF-like anti-opioid activity in these behavioral studies. Copyright © 2017 Elsevier Inc. All rights reserved.

The α3β4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies

PubMed Central

Muldoon, P P; Jackson, K J; Perez, E; Harenza, J L; Molas, S; Rais, B; Anwar, H; Zaveri, N T; Maldonado, R; Maskos, U; McIntosh, J M; Dierssen, M; Miles, M F; Chen, X; De Biasi, M; Damaj, M I

2014-01-01

BACKGROUND AND PURPOSE Recent data have indicated that α3β4* neuronal nicotinic (n) ACh receptors may play a role in morphine dependence. Here we investigated if nACh receptors modulate morphine physical withdrawal. EXPERIMENTAL APPROACHES To assess the role of α3β4* nACh receptors in morphine withdrawal, we used a genetic correlation approach using publically available datasets within the GeneNetwork web resource, genetic knockout and pharmacological tools. Male and female European-American (n = 2772) and African-American (n = 1309) subjects from the Study of Addiction: Genetics and Environment dataset were assessed for possible associations of polymorphisms in the 15q25 gene cluster and opioid dependence. KEY RESULTS BXD recombinant mouse lines demonstrated an increased expression of α3, β4 and α5 nACh receptor mRNA in the forebrain and midbrain, which significantly correlated with increased defecation in mice undergoing morphine withdrawal. Mice overexpressing the gene cluster CHRNA5/A3/B4 exhibited increased somatic signs of withdrawal. Furthermore, α5 and β4 nACh receptor knockout mice expressed decreased somatic withdrawal signs compared with their wild-type counterparts. Moreover, selective α3β4* nACh receptor antagonists, α-conotoxin AuIB and AT-1001, attenuated somatic signs of morphine withdrawal in a dose-related manner. In addition, two human datasets revealed a protective role for variants in the CHRNA3 gene, which codes for the α3 nACh receptor subunit, in opioid dependence and withdrawal. In contrast, we found that the α4β2* nACh receptor subtype is not involved in morphine somatic withdrawal signs. CONCLUSION AND IMPLICATIONS Overall, our findings suggest an important role for the α3β4* nACh receptor subtype in morphine physical dependence. PMID:24750073

Long-term stability of morphine, codeine, and 6-acetylmorphine in real-life whole blood samples, stored at -20°C.

PubMed

Høiseth, Gudrun; Fjeld, Bente; Burns, Margrete Larsen; Strand, Dag Helge; Vindenes, Vigdis

2014-06-01

Stability of drugs during storage is important in forensic toxicology. For the analytes detected after intake of heroin (6-acetylmorphine (6-AM), morphine and codeine), long-time stability in real life whole blood samples are studied in only a small number of cases. Whole blood post mortem (n=37) and whole blood samples from living persons (n=22) containing morphine and codeine as well as 6-AM in blood or urine were selected. All cases represented intake of heroin. All samples contained fluoride and were initially analysed and stored in normal conditions (-20°C) for 4-9 years. All samples were then reanalysed using the same analytical methods and the results were compared. For samples from living persons, the median change in concentration was -3.7% for morphine and -5.3% for codeine. For post mortem samples, the median change in concentration was -12% for morphine and -11% for codeine. Both for samples from living persons and post mortem samples, the decrease in the concentrations from the original analysis to reanalysis were statistically significant for morphine and codeine. Regarding 6-AM, all living samples were negative at reanalysis. For post mortem samples, four cases still tested positive for 6-AM at reanalysis with a median change in the concentrations of -81%. There was no significant change in the morphine to codeine concentration ratios neither for living nor post mortem samples. This study showed that in real life whole blood samples, the concentrations of morphine and codeine are relatively stable during long-term storage at -20°C. 6-AM on the other hand, shows a considerable decrease in concentrations that is important to consider when interpreting results from reanalyses of forensic cases. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Comparison of Intravenous Morphine with Sublingual Buprenorphine in Management of Postoperative Pain after Closed Reduction Orthopedic Surgery

PubMed Central

Soltani, Ghasem; Khorsand, Mahmood; Shamloo, Alireza Sepehri; Jarahi, Lida; Zirak, Nahid

2015-01-01

Background: Postoperative pain is a common side effect following surgery that can significantly reduce surgical quality and patient’s satisfaction. Treatment options are morphine and buprenorphine. We aimed to compare the efficacy of a single dose of intravenous morphine with sublingual buprenorphine in postoperative pain control following closed reduction surgery. Methods: This triple blind clinical trial was conducted on 90 patients referred for closed reduction orthopedic surgery. They were older than 18 years and in classes I and II of the American Society of Anesthesiologists (ASA) with an operation time of 30-90 minutes. Patients were divided into two groups of buprenorphine (4.5µg/kg sublingually) and morphine (0.2mg/kg intravenously). Baseline characteristics, vital signs, pain score, level of sedation and pharmacological side effects were recorded in the recovery room (at 0 and 30 minutes), and in the ward (at 3, 6 and 12 hours). SPSS version 19 software was used for data analysis and the significance level was set at P<0.05. Results: Ninety patients were studied, 60 males and 30 females with a mean age of 37.7±16.2 years. There was no significant difference between the two groups in terms of baseline characteristics. Pain score in the morphine group was significantly higher than the buprenorphine group with an average score of 2.5 (P<0.001). Postoperative mean heart rate in the buprenorphine group was four beats lower than the morphine group (P<0.001). Also, in the buprenorphine 48.6% and in the morphine group 86.7% of cases were conscious in recovery (P=0.001) with a higher rate of pruritus in the latter group (P=0.001). Conclusion: Sublingual buprenorphine administration before anesthesia induction in closed reduction surgery can lead to better postoperative pain control in comparison to intravenous morphine. Due to simple usage and longer postoperative sedation, sublingual buprenorphine is recommended as a suitable drug in closed reduction surgery. PMID:26550594

Comparison of Intravenous Morphine with Sublingual Buprenorphine in Management of Postoperative Pain after Closed Reduction Orthopedic Surgery.

PubMed

Soltani, Ghasem; Khorsand, Mahmood; Shamloo, Alireza Sepehri; Jarahi, Lida; Zirak, Nahid

2015-10-01

Postoperative pain is a common side effect following surgery that can significantly reduce surgical quality and patient's satisfaction. Treatment options are morphine and buprenorphine. We aimed to compare the efficacy of a single dose of intravenous morphine with sublingual buprenorphine in postoperative pain control following closed reduction surgery. This triple blind clinical trial was conducted on 90 patients referred for closed reduction orthopedic surgery. They were older than 18 years and in classes I and II of the American Society of Anesthesiologists (ASA) with an operation time of 30-90 minutes. Patients were divided into two groups of buprenorphine (4.5µg/kg sublingually) and morphine (0.2mg/kg intravenously). Baseline characteristics, vital signs, pain score, level of sedation and pharmacological side effects were recorded in the recovery room (at 0 and 30 minutes), and in the ward (at 3, 6 and 12 hours). SPSS version 19 software was used for data analysis and the significance level was set at P<0.05. Ninety patients were studied, 60 males and 30 females with a mean age of 37.7±16.2 years. There was no significant difference between the two groups in terms of baseline characteristics. Pain score in the morphine group was significantly higher than the buprenorphine group with an average score of 2.5 (P<0.001). Postoperative mean heart rate in the buprenorphine group was four beats lower than the morphine group (P<0.001). Also, in the buprenorphine 48.6% and in the morphine group 86.7% of cases were conscious in recovery (P=0.001) with a higher rate of pruritus in the latter group (P=0.001). Sublingual buprenorphine administration before anesthesia induction in closed reduction surgery can lead to better postoperative pain control in comparison to intravenous morphine. Due to simple usage and longer postoperative sedation, sublingual buprenorphine is recommended as a suitable drug in closed reduction surgery.

Pharmacokinetic evaluation of a sprinkle-dose regimen of a once-daily, extended-release morphine formulation.

PubMed

Eliot, Lise; Butler, Jackie; Devane, John; Loewen, Gordon

2002-02-01

Morphine sulfate extended-release (MSER) uses a drug-delivery technology that allows once-daily dosing. It is possible to open the MSER capsule and sprinkle the contents on soft food, a potentially useful alternative to the intact capsule in patients who have difficulty swallowing. This study compared the bioavailability of MSER and its metabolites morphine-3-glucuronide and morphine-6-glucuronide after administration of MSER in a sprinkle-dose regimen relative to an intact capsule swallowed whole. This was a randomized, open-label, single-dose, crossover study, with a 7-day washout period between the 2 dosing days. Healthy volunteers were randomized to receive an intact 60-mg MSER capsule swallowed whole or the contents of a 60-mg MSER capsule sprinkled on applesauce. Blood samples were collected and analyzed for concentrations of morphine and its active glucuronide metabolites. Pharmacokinetic (PK) parameters were calculated and bioequivalence assessed. Bioequivalence was concluded if the 90% CIs of the ratio of log-transformed values for maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were within 80% to 125%. Of 30 subjects enrolled, 28 completed the study and were eligible for PK evaluation. Two subjects were withdrawn for reasons unrelated to study treatment. The plasma concentration-time profiles of morphine and its metabolites were superimposable after administration of the 2 regimens. Cmax and total systemic exposure-based on AUC from time 0 to the last quantifiable concentration (AUC(last)) and AUC from time 0 to infinity (AUC(infinity))-were comparable between treatments. The 90% CIs for morphine AUC(last), AUC, and Cmax ratios were 98 to 109, 96 to 106, and 95 to 117, respectively. Similar 90% CIs were obtained for the morphine metabolites. In this study in healthy volunteers, sprinkling the entire contents of an MSER capsule onto applesauce and swallowing without chewing was bioequivalent to swallowing an intact MSER capsule.

Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial.

PubMed

Kubica, Jacek; Adamski, Piotr; Ostrowska, Małgorzata; Sikora, Joanna; Kubica, Julia Maria; Sroka, Wiktor Dariusz; Stankowska, Katarzyna; Buszko, Katarzyna; Navarese, Eliano Pio; Jilma, Bernd; Siller-Matula, Jolanta Maria; Marszałł, Michał Piotr; Rość, Danuta; Koziński, Marek

2016-01-14

The currently available data indicate a drug-drug interaction between morphine and oral P2Y12 receptor inhibitors, when administered together. The aim of this trial was to assess the influence of infused morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with acute myocardial infarction. In a single-centre, randomized, double-blind trial, patients were assigned in a 1:1 ratio to receive intravenously either morphine (5 mg) or placebo, followed by a 180 mg loading dose of ticagrelor. Pharmacokinetics was determined with liquid chromatography tandem mass spectrometry and ticagrelor antiplatelet effects were measured with up to three different platelet function tests: vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode aggregometry and VerifyNow. The pharmacokinetic and pharmacodynamic assessment was performed in 70 patients (35 in each study group). Morphine lowered the total exposure to ticagrelor and its active metabolite by 36% (AUC(0-12): 6307 vs. 9791 ng h/mL; P = 0.003), and 37% (AUC(0-12): 1503 vs. 2388 ng h/mL; P = 0.008), respectively, with a concomitant delay in maximal plasma concentration of ticagrelor (4 vs. 2 h; P = 0.004). Multiple regression analysis showed that lower AUC(0-12) values for ticagrelor were independently associated with the administration of morphine (P = 0.004) and the presence of ST-segment elevation myocardial infarction (P = 0.014). All three methods of platelet reactivity assessment showed a stronger antiplatelet effect in the placebo group and a greater prevalence of high platelet reactivity in patients receiving morphine. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction. ClinicalTrials.gov Identifier: NCT02217878. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

Subcellular plasticity of the corticotropin-releasing factor receptor in dendrites of the mouse bed nucleus of the stria terminalis following chronic opiate exposure.

PubMed

Jaferi, A; Lane, D A; Pickel, V M

2009-09-29

Chronic opiate administration alters the expression levels of the stress-responsive peptide, corticotropin-releasing factor (CRF), in the bed nucleus of the stria terminalis (BNST). This brain region contains CRF receptors that drive drug-seeking behavior exacerbated by stress. We used electron microscopy to quantitatively compare immunolabeling of the corticotropin-releasing factor receptor (CRFr) and CRF in the anterolateral bed nucleus of the stria terminalis (BSTal) of mice injected with saline or morphine in escalating doses for 14 days. We also compared the results with those in non-injected control mice. The tissue was processed for CRFr immunogold and CRF immunoperoxidase labeling. The non-injected controls had a significantly lower plasmalemmal density of CRFr immunogold particles in dendrites compared with mice receiving saline, but not those receiving morphine, injections. Compared with saline, however, mice receiving chronic morphine showed a significantly lower plasmalemmal, and greater cytoplasmic, density of CRFr immunogold in dendrites. Within the cytoplasmic compartment of somata and dendrites of the BSTal, the proportion of CRFr gold particles associated with mitochondria was three times as great in mice receiving morphine compared with saline. This subcellular distribution is consistent with morphine,- and CRFr-associated modulation of intracellular calcium release or oxidative stress. The between-group changes occurred without effect on the total number of dendritic CRFr immunogold particles, suggesting that chronic morphine enhances internalization or decreases delivery of the CRFr to the plasma membrane, a trafficking effect that is also affected by the stress of daily injections. In contrast, saline and morphine treatment groups showed no significant differences in the total number of CRF-immunoreactive axon terminals, or the frequency with which these terminals contacted CRFr-containing dendrites. This suggests that morphine does not influence axonal availability of CRF in the BSTal. The results have important implications for drug-associated adaptations in brain stress systems that may contribute to the motivation to continue drug use during dependence.

Simultaneous analysis of gemfibrozil, morphine, and its two active metabolites in different mouse brain structures using solid-phase extraction with ultra-high performance liquid chromatography and tandem mass spectrometry with a deuterated internal standard.

PubMed

Yang, Zizhao; Wang, Lu; Xu, Mingcheng; Gu, Jingkai; Yu, Lushan; Zeng, Su

2016-06-01

A rapid and sensitive bioassay was established and validated to simultaneously determine gemfibrozil, morphine, morphine-3β-glucuronide, and morphine-6β-glucuronide in mouse cerebrum, epencephalon, and hippocampus based on ultra-high performance liquid chromatography and tandem mass spectrometry. The deuterated internal standard, M6G-d3, was mixed with the prepared samples at 10 ng/mL as the final concentration. The samples were transferred into the C18 solid-phase extraction columns with gradient elution for solid-phase extraction. The mobile phase consisted of methanol and 0.05% formic acid (pH 3.2). Multiple reaction monitoring has been applied to analyze gemfibrozil (m/z 249.0 → 121.0) in anion mode, and M6G-d3 (m/z 465.1 → 289.1), morphine (m/z 286.0 → 200.9), and M3G and M6G (m/z 462.1 → 286.1) in the positive ion mode. The method has a linear calibration range from 0.05 to 10 ng for gemfibrozil, morphine, and M3G and M6G with correlation coefficients >0.993. The lower limit of quantitation for all four analytes was 0.05 ng/mL, relative standard deviation of intra- and interday precision was less than 10.5%, and the relative error of accuracy was from -8.2 to 8.3% at low, medium, and high concentrations for all the analytes. In conclusion, gemfibrozil can influence the morphine antinociception after coronary heart disease induced chronic angina by the change in one of morphine metabolites', M3G, distribution in mouse brain. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pharmacokinetics of Oral and Intravenous Paracetamol (Acetaminophen) When Co-Administered with Intravenous Morphine in Healthy Adult Subjects.

PubMed

Raffa, Robert B; Pawasauskas, Jayne; Pergolizzi, Joseph V; Lu, Luke; Chen, Yin; Wu, Sutan; Jarrett, Brant; Fain, Randi; Hill, Lawrence; Devarakonda, Krishna

2018-03-01

Several features favor paracetamol (acetaminophen) administration by the intravenous rather than the oral route in the postoperative setting. This study compared the pharmacokinetics and bioavailability of oral and intravenous paracetamol when given with or without an opioid, morphine. In this randomized, single-blind, parallel, repeat-dose study in healthy adults, subjects received four repeat doses of oral or intravenous 1000 mg paracetamol at 6-h intervals, and morphine infusions (0.125 mg/kg) at the 2nd and 3rd intervals. Comparisons of plasma pharmacokinetic profiles were conducted before, during, and after opioid co-administrations. Twenty-two subjects were included in the pharmacokinetic analysis. Observed paracetamol peak concentration (C max ) and area under the plasma concentration-time curve over the dosing interval (AUC 0-6 ) were reduced when oral paracetamol was co-administered with morphine (reduced from 11.6 to 7.25 µg/mL and from 31.00 to 25.51 µg·h/mL, respectively), followed by an abruptly increased C max and AUC 0-6 upon discontinuation of morphine (to 13.5 µg/mL and 52.38 µg·h/mL, respectively). There was also a significantly prolonged mean time to peak plasma concentration (T max ) after the 4th dose of oral paracetamol (2.84 h) compared to the 1st dose (1.48 h). However, pharmacokinetic parameters of paracetamol were not impacted when intravenous paracetamol was co-administered with morphine. Morphine co-administration significantly impacted the pharmacokinetics of oral but not intravenous paracetamol. The abrupt release of accumulated paracetamol at the end of morphine-mediated gastrointestinal inhibition following oral but not intravenous administration of paracetamol suggests that intravenous paracetamol provides a better option for the management of postoperative pain. CLINICALTRIALS. NCT02848729.

Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion.

PubMed

Dahan, Albert; Romberg, Raymonda; Teppema, Luc; Sarton, Elise; Bijl, Hans; Olofsen, Erik

2004-11-01

To study the influence of morphine on chemical control of breathing relative to the analgesic properties of morphine, the authors quantified morphine-induced analgesia and respiratory depression in a single group of healthy volunteers. Both respiratory and pain measurements were performed over single 24-h time spans. Eight subjects (four men, four women) received a 90-s intravenous morphine infusion; eight others (four men, four women) received a 90-s placebo infusion. At regular time intervals, respiratory variables (breathing at a fixed end-tidal partial pressure of carbon dioxide of 50 mmHg and the isocapnic acute hypoxic response), pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 24 h. Population pharmacokinetic (sigmoid Emax)-pharmacodynamic models were applied to the respiratory and pain data. The models are characterized by potency parameters, shape parameters (gamma), and blood-effect site equilibration half-lives. All collected data were analyzed simultaneously using the statistical program NONMEM. Placebo had no systematic effect on analgesic or respiratory variables. Morphine potency parameter and blood-effect site equilibration half-life did not differ significantly among the three measured effect parameters (P > 0.01). The integrated NONMEM analysis yielded a potency parameter of 32 +/- 1.4 nm (typical value +/- SE) and a blood-effect site equilibration half-life of 4.4 +/- 0.3 h. Parameter gamma was 1 for hypercapnic and hypoxic breathing but 2.4 +/- 0.7 for analgesia (P < 0.01). Our data indicate that systems involved in morphine-induced analgesia and respiratory depression share important pharmacodynamic characteristics. This suggests similarities in central mu-opioid analgesic and respiratory pathways (e.g., similarities in mu-opioid receptors and G proteins). The clinical implication of this study is that after morphine administration, despite lack of good pain relief, moderate to severe respiratory depression remains possible.

New protopine alkaloids from Aristolochia constricta reduce morphine withdrawal in vitro.

PubMed

Capasso, A; De Tommasi, N; Rastrelli, L; De Simone, F

2000-12-01

The present study examines the effect of four new protopine alkaloids (1-4) isolated and purified from the aerial parts of Aristolochia constricta (Aristolichiaceae) on morphine withdrawal in vitro. The results of our experiments indicate that the pure compounds (1-4) significantly and in a concentration-dependent manner reduced the morphine withdrawal. The results of the present study suggest that these new protopine alkaloids may be potential anti-addictive agents.

Protective effect of vilva juice on glycoconjugate levels in experimentally induced constipation in rats.

PubMed

Padmini, R; Sabitha, K E; Devi, C S Shyamala

2004-10-01

Efficacy of vilva, a polyherbal formulation was evaluated in morphine induced constipated rats. Vilva juice, at a dose of 1.5 ml/100 g body wt was given orally for a period of 7 days. Morphine sulfate was injected to induce constipation on 8th day, 45 min before the experiments. Protein bound glycoconjungates were estimated in intestinal tissue. Altered levels of glycoconjugates were maintained at near normalcy when pretreated with vilva juice in morphine induced rats. Histological changes were observed in the colon tissue. The damage to crypts of Liberkunn in constipated rats were found to be reduced in vilva pretreated rats. Vilva, thus, offered significant protection against morphine induced constipation by way of augmenting mucus secretion.

The interaction of tetrahydroisoquinoline derivatives with antinociceptive action of morphine and oxotremorine in mice.

PubMed

Vetulani, J; Pavone, F; Przewłocka, B; Borghi, V; Nalepa, I

2003-11-01

To extend our earlier data on synergistic action of tetrahydroisoquinolines and morphine, we have investigated the analgesic effects of 1,2,3,4-tetrahydroisoquinoline (TIQ) and its 1-methyl-(1-MeTIQ) and N-methyl (N-MeTIQ) analogs on analgesia induced by morphine and oxotremorine. 1-MeTIQ and N-MeTIQ induced a moderate, delayed and prolonged analgesic action measured in the tail-flick test in CD-1 mice; 1-MeTIQ and TIQ prolonged the opiate (morphine, 2.5 mg/kg i.p.) analgesia while TIQ and N-TIQ potentiated cholinergic (oxotremorine, 0.02 mg/kg i.p.) analgesia. The involvement of the opioid and noradrenergic systems in this effect is discussed.

Ibogaine interferes with motivational and somatic effects of naloxone-precipitated withdrawal from acutely administered morphine.

PubMed

Parke, Linda A; Burton, Page; McDonald, Robert V; Kim, Joseph A; Siegel, Shepard

2002-02-01

It has been reported that ibogaine interferes with somatic withdrawal reactions in rats chronically treated with morphine. The present experiments demonstrated that ibogaine also interferes with motivational withdrawal reactions and somatic withdrawal reactions in rats treated with morphine on only two occasions. On each of two conditioning trials, naloxone was administered 24 h following an injection of morphine. Four hours prior to each naloxone administration, rats were injected with either ibogaine or saline. In two experiments, ibogaine interfered with naloxone-precipitated withdrawal. In Experiment 1, ibogaine-treated rats displayed a weaker aversion to the withdrawal-paired chamber, and in Experiment 2, ibogaine-treated rats displayed fewer somatic withdrawal reactions than did saline treated rats.

The effect of intraoperative dexmedetomidine on postoperative analgesia and sedation in pediatric patients undergoing tonsillectomy and adenoidectomy.

PubMed

Olutoye, Olutoyin A; Glover, Chris D; Diefenderfer, John W; McGilberry, Michael; Wyatt, Matthew M; Larrier, Deidre R; Friedman, Ellen M; Watcha, Mehernoor F

2010-08-01

The immediate postoperative period after tonsillectomy and adenoidectomy, one of the most common pediatric surgical procedures, is often difficult. These children frequently have severe pain but postoperative airway edema along with increased sensitivity to the respiratory-depressant effects of opioids may result in obstructive symptoms and hypoxemia. Opioid consumption may be reduced by nonsteroidal antiinflammatory drugs, but these drugs may be associated with increased bleeding after this operation. Dexmedetomidine has mild analgesic properties, causes sedation without respiratory depression, and does not have an effect on coagulation. We designed a prospective, double-blind, randomized controlled study to determine the effects of intraoperative dexmedetomidine on postoperative recovery including pain, sedation, and hemodynamics in pediatric patients undergoing tonsillectomy and adenoidectomy. One hundred nine patients were randomized to receive a single intraoperative dose of dexmedetomidine 0.75 microg/kg, dexmedetomidine 1 microg/kg, morphine 50 microg/kg, or morphine 100 microg/kg over 10 minutes after endotracheal intubation. There were no significant differences among the 4 groups in patient demographics, ASA physical status, postoperative opioid requirements, sedation scores, duration of oxygen supplementation in the postanesthetic care unit, and time to discharge readiness. The median time to first postoperative rescue analgesic was similar in patients receiving dexmedetomidine 1 microg/kg and morphine 100 microg/kg, but significantly longer compared with patients receiving dexmedetomidine 0.75 microg/kg or morphine 50 microg/kg (P < 0.01). In addition, the number of patients requiring >1 rescue analgesic dose was significantly higher in the dexmedetomidine 0.75 microg/kg group compared with the dexmedetomidine 1 microg/kg and morphine 100 microg/kg groups, but not the morphine 50 microg/kg group. Patients receiving dexmedetomidine had significantly slower heart rates in the first 30 minutes after surgery compared with those receiving morphine (P < 0.05). There was no significant difference in sedation scores among the groups. The total postoperative rescue opioid requirements were similar in tonsillectomy patients receiving intraoperative dexmedetomidine or morphine. However, the use of dexmedetomidine 1 microg/kg and morphine 100 microg/kg had the advantages of an increased time to first analgesic and a reduced need for additional rescue analgesia doses, without increasing discharge times.