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Sample records for morphine sparing effect

  1. Sex Differences in the Morphine-Sparing Effects of Intraoperative Dexmedetomidine in Patient-Controlled Analgesia Following General Anesthesia

    PubMed Central

    Li, Yuan-Yuan; Ge, Dong-Jian; Li, Jin-Yu; Qi, Bin

    2016-01-01

    Abstract Previous studies have reported that intraoperative dexmedetomidine has morphine-sparing effects in patient-controlled analgesia (PCA). The present study was designed to investigate the possible sex differences in the morphine-sparing effects of intraoperative dexmedetomidine following general anesthesia. A total of 223 patients scheduled for surgeries under general anesthesia were divided into female and male groups. Each group was then subdivided into 2 subgroups that were maintained using propofol/remifentanil/dexmedetomidine (PRD) or propofol/remifentanil/saline (PRS). During the first 24 hours postsurgery, both female and male PRD patients had lower scores on a visual analog scale (VAS) (fPRS vs fPRD, P < 0.05 or P < 0.01; mPRS mPRD, P < 0.05, P < 0.01, or P < 0.001) and consumed less morphine than their controls from the PRS group (fPRS vs fPRD, P = 0.0392; mPRS vs mPRD, P = 0.0041). Interestingly, the female PRD patients had similar VAS scores (fPRD vs mPRD, P > 0.05) and consumed comparable morphine compared to the male PRD patients (fPRD vs mPRD, P = 0.4238). However, when normalized to body weight, they consumed much more morphine than male PRD patients (fPRD vs mPRD, P < 0.001), and this effect was not seen in the PRS patients. Intraoperative administration of dexmedetomidine appeared to have a stronger morphine-sparing effect in controlling postoperative acute pain in male patients than in female patients. PMID:27149500

  2. The morphine-sparing effect of propacetamol in orthopedic postoperative pain.

    PubMed

    Delbos, A; Boccard, E

    1995-05-01

    The analgesic efficacy and safety of propacetamol (Pro-Dafalgan), an injectable prodrug of acetaminophen, in combination with morphine administered by patient-controlled analgesia (PCA) were studied in 60 patients (56 men, 4 women; age 18-40 years; mean age, 26 years) after knee ligamentoplasty. Using a double-blind, randomized, parallel-group design, the effects of four (every 6 hr) intravenous injections of 2 g propacetamol (= 1 g acetaminophen) were compared with four injections of placebo (PL) in the recovery room immediately after surgery. Efficacy was assessed over 24 hr by automatic recording on the PCA device of the cumulative dose of morphine and the number of boluses requested. It was also assessed on pain scores rated on a five-point verbal scale and a visual analogue scale before administration, at 1, 2, 3, and 4 hr, and then every 2 hr until the 24th hr after administration. A five-point global efficacy scale was also administered. Any side effects were recorded throughout the duration of the study, and the ability to tolerate the drug was assessed by recording arterial pressure, cardiac and respiratory frequency, and sedation at the same assessment times as the pain scores. The 24-hr morphine consumption was significantly decreased in the propacetamol group (number of 1 mg boluses: 14.7 +/- 11.3 versus 23.2 +/- 13.8, P = 0.01; PCA usage: 26.4 +/- 12.3 mg versus 34.6 +/- 15.4 mg, P = 0.03; PCA usage + titration: 34.5 +/- 12.7 mg versus 43.1 +/- 15.9 mg, P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7541435

  3. Comparison of the morphine-sparing effect of intraoperative dexmedetomidine with and without loading dose following general anesthesia in multiple-fracture patients: A prospective, randomized, controlled clinical trial.

    PubMed

    Zhao, Jin-Ning; Kong, Min; Qi, Bin; Ge, Dong-Jian

    2016-08-01

    Intraoperative dexmedetomidine (DEX) with or without loading dose both promote morphine-sparing effect in patient-controlled analgesia on postoperative acute pain. However, the contribution of the loading dose to this effect is largely unknown, especially in long-lasting surgeries. The present study was designed to investigate the role of a loading dose of DEX in this morphine-sparing effect in multiple-fracture patients following general anesthesia.Eighty-six patients scheduled multiple-fracture surgeries under general anesthesia were allocated into 3 groups which were maintained with propofol/remifentanil/Ringer solution (PRR), propofol/remifentanil/DEX with (PRDw), or without (PRDo) DEX loading dose before induction, respectively. Time to first morphine request and 24-hour morphine consumption was monitored. Pain intensity was evaluated with visual analog scale.During the first 24 hours following surgery, patients in the PRDw/o group showed increased time to first request of postoperative morphine and decreased total morphine consumption as compared with PRR patients. There was no significant difference with respect to these parameters between patients from the PRDw and PRDo groups. More patients from the PRDw groups experienced intraoperative bradycardia when compared to those from the PRR or PRDo group.This randomized controlled trial indicates that the morphine-sparing effect of intraoperative DEX was not affected by a loading dose in long-time surgeries. PMID:27537587

  4. The hyperglycaemic effect of morphine

    PubMed Central

    Feldberg, W.; Shaligram, S. V.

    1972-01-01

    1. In the unanaesthetized cat, an injection of 0·75 mg of morphine into a lateral cerebral ventricle produced strong hyperglycaemia; on intravenous injection, 10 to 30 times larger doses were required. Other effects produced with both injections were shivering, pupillary dilatation, opening of the eyes, miaowing, periods of excitation, and analgesia. Between the periods of excitation the cat did not react to objects moving in front of its eyes and it had a vacant stare. 2. Noradrenaline, adrenaline, and 5-hydroxytryptamine (5-HT) injected intraventricularly (250 μg, twice) depressed the hyperglycaemia due to intraventricular morphine, and noradrenaline also depressed the hyperglycaemia due to intravenous morphine. Adrenaline produced the strongest and 5-HT the weakest depression. 5-HT did not depress the other effects of morphine, but the catecholamines depressed most of them; only analgesia and the vacant stare appeared to be unaffected. 3. Reserpine injected intraventricularly (0·5 mg, twice) greatly accentuated the hyperglycaemia as well as the other effects produced by intraventricular morphine, but pupillary dilatation and opening of the eyes no longer occurred; the protrusion of the nictitating membranes produced by the reserpine persisted. 4. Pentobarbitone sodium injected intraperitoneally in an anaesthetizing dose practically abolished the morphine hyperglycaemia, but injected intraventricularly in a dose of a few milligrammes, it had a two fold effect: depression followed by enhancement of the morphine hyperglycaemia. The enhancement may be due to sensitization of the effect of the adrenaline released by morphine, since adrenaline hyperglycaemia was enhanced as well. 5. Morphine did not seem to act on structures in the walls of either the lateral or third ventricle when producing its hyperglycaemic effect on intraventricular injection. The action may therefore be on more caudally situated parts of the neuro-axis, on the central grey, on structures in

  5. Morphine

    MedlinePlus

    Morphine is used to relieve moderate to severe pain. Morphine extended-release tablets and capsules are only used ... controlled by the use of other pain medications. Morphine extended-release tablets and capsules should not be ...

  6. Morphine effects on striatal transcriptome in mice

    PubMed Central

    Korostynski, Michal; Piechota, Marcin; Kaminska, Dorota; Solecki, Wojciech; Przewlocki, Ryszard

    2007-01-01

    Background Chronic opiate use produces molecular and cellular adaptations in the nervous system that lead to tolerance, physical dependence, and addiction. Genome-wide comparison of morphine-induced changes in brain transcription of mouse strains with different opioid-related phenotypes provides an opportunity to discover the relationship between gene expression and behavioral response to the drug. Results Here, we analyzed the effects of single and repeated morphine administrations in selected inbred mouse strains (129P3/J, DBA/2J, C57BL/6J, and SWR/J). Using microarray-based gene expression profiling in striatum, we found 618 (false discovery rate < 1%) morphine-responsive transcripts. Through ontologic classification, we linked particular sets of genes to biologic functions, including metabolism, transmission of nerve impulse, and cell-cell signaling. We identified numerous novel morphine-regulated genes (for instance, Olig2 and Camk1g), and a number of transcripts with strain-specific changes in expression (for instance, Hspa1a and Fzd2). Moreover, transcriptional activation of a pattern of co-expressed genes (for instance, Tsc22d3 and Nfkbia) was identified as being mediated via the glucocorticoid receptor (GR). Further studies revealed that blockade of the GR altered morphine-induced locomotor activity and development of physical dependence. Conclusion Our results indicate that there are differences between strains in the magnitude of transcriptional response to acute morphine treatment and in the degree of tolerance in gene expression observed after chronic morphine treatment. Using whole-genome transcriptional analysis of morphine effects in the striatum, we were able to reveal multiple physiological factors that may influence opioid-related phenotypes and to relate particular gene networks to this complex trait. The results also suggest the possible involvement of GR-regulated genes in mediating behavioral response to morphine. PMID:17598886

  7. Synthetic substances with morphine-like effect

    PubMed Central

    Eddy, Nathan B.; Halbach, H.; Braenden, Olav J.

    1957-01-01

    A review of effects in man of morphine-like drugs which have been brought under international narcotics control is presented in the form of individual monographs. These are based on controlled observations with quantitative data and significant reports of results obtained in medical practice. In a summarizing section, the drugs are compared with respect to effectiveness, side-effects and addiction liability. Morphine-like drugs of natural and synthetic origin now cover a wide range of potency (analgesic, antitussive), not necessarily paralleled by incidence of side-effects or addiction liability. PMID:13511135

  8. A morphine conjugate vaccine attenuates the behavioral effects of morphine in rats

    PubMed Central

    Kosten, Therese A.; Shen, Xiaoyun Y.; O'Malley, Patrick W.; Kinsey, Berma M.; Lykissa, Ernest D.; Orson, Frank M.; Kosten, Thomas R.

    2013-01-01

    Vaccines for opioid dependence may provide a treatment that would reduce or slow the distribution of the drug to brain, thus reducing the drug's reinforcing effects. We tested whether a conjugate vaccine against morphine (keyhole limpet hemocyanin-6-succinylmorphine; KLH-6-SM) administered to rats would produce antibodies and show specificity for morphine or other heroin metabolites. The functional effects of the vaccine were tested with antinociceptive and conditioned place preference (CPP) tests. Rats were either vaccinated with KLH-6-SM and received two boosts 3 and 16 weeks later or served as controls and received KLH alone. Anti-morphine antibodies were produced in vaccinated rats; levels increased and were sustained at moderate levels through 24 weeks. Antibody binding was inhibited by free morphine and other heroin metabolites as demonstrated by competitive inhibition ELISA. Vaccinated rats showed reduced morphine CPP, tested during weeks 4 to 6, and decreased antinociceptive responses to morphine, tested at week 7. Brain morphine levels, assessed using gas-chromatography coupled to mass spectrometry (GC–MS) on samples obtained at 26 weeks, were significantly lower in vaccinated rats. This suggests that morphine entry into the brain was reduced or slowed. These results provide support for KLH-6-SM as a candidate vaccine for opioid dependence. PMID:23739535

  9. 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.

  10. 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. PMID:26222257

  11. Effect of Acetaminophen Alone and in Combination with Morphine and Tramadol on the Minimum Alveolar Concentration of Isoflurane in Rats

    PubMed Central

    Chavez, Julio R.; Ibancovichi, José A.; Sanchez-Aparicio, Pedro; Acevedo-Arcique, Carlos M.; Moran-Muñoz, Rafael; Recillas-Morales, Sergio

    2015-01-01

    Background It has been observed that acetaminophen potentiates the analgesic effect of morphine and tramadol in postoperative pain management. Its capacity as an analgesic drug or in combinations thereof to reduce the minimum alveolar concentration (MAC) of inhalational anesthetics represents an objective measure of this effect during general anesthesia. In this study, the effect of acetaminophen with and without morphine or tramadol was evaluated on the isoflurane MAC. Methods Forty-eight male Wistar rats were anesthetized with isoflurane in oxygen. MACISO was determined from alveolar gas samples at the time of tail clamping without the drug, after administering acetaminophen (300 mg/kg), morphine (3 mg/kg), tramadol (10 mg/kg), acetaminophen (300 mg/kg) + morphine (3 mg/kg), and acetaminophen (300 mg/kg) + tramadol (10 mg/kg). Results The control and acetaminophen groups did not present statistically significant differences (p = 0.98). The values determined for MACISO after treatment with acetaminophen + morphine, acetaminophen + tramadol, morphine, and tramadol were 0.98% ± 0.04%, 0.99% ± 0.009%, 0.97% ± 0.02%, and 0.99% ± 0.01%, respectively. Conclusions The administration of acetaminophen did not reduce the MAC of isoflurane and did not potentiate the reduction in MACISO by morphine and tramadol in rats, and therefore does not present a sparing effect of morphine or tramadol in rats anesthetized with isoflurane. PMID:26605541

  12. The effect of different durations of morphine exposure on mesencephalic dopaminergic neurons in morphine dependent rats.

    PubMed

    Shi, Weibo; Ma, Chunling; Qi, Qian; Liu, Lizhe; Bi, Haitao; Cong, Bin; Li, Yingmin

    2015-12-01

    Mesencephalic dopaminergic neurons are heavily involved in the development of drug dependence. Thyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, plays an important role in the survival of dopaminergic neurons. Therefore, this study investigated TH changes in dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra (SN), as well as the morphine effects on dopaminergic neurons induced by different durations of morphine dependence. Models of morphine dependence were established in rats, and paraffin-embedded sections, immunohistochemistry and western blotting were used to observe the changes in the expression of TH protein. Fluoro-Jade B staining was used to detect degeneration and necrosis, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) detected the apoptosis of mesencephalic dopaminergic nerve cells. Immunohistochemistry and western blotting showed that the number of TH positive cells and the protein levels in the VTA and SN were significantly decreased in the rats with a long period of morphine dependency. With prolonged morphine exposure, the dopaminergic nerve cells in the VTA and SN showed degeneration and necrosis, while apoptotic cells were not observed. The number of VTA and SN dopaminergic nerve cells decreased with increasing periods of morphine dependence, which was most likely attributable to the degeneration and necrosis of nerve cells induced by morphine toxicity.

  13. Effect of morphine on PC12 cells with molecular radar

    NASA Astrophysics Data System (ADS)

    Shi, Chen; Yu, Xiaoli; Lu, Jiuyi; Zhang, Chunyang; Jin, Lei; Ma, Hui; Zhang, Dacheng; Chen, Die Yan

    2000-10-01

    Molecular Radar (MR) is a new method to detect biological processes in living cells at the level of molecular, it is also the newest means to get intracellular information. In this paper we study the effect of morphine on PC12 cells using MR. The results show that the effect of morphine on PC12 cells is time- and concentration-dependent. Morphine treating for short time induces the increase and fluctuation of intracellular (CA2+), while morphine treating for long time induces chromatin condensation, loss of mitochondria membrane potential apoptosis.

  14. The effect of morphine in rat small mesenteric arteries.

    PubMed

    Ozdem, Sadi S; Batu, Ozlem; Tayfun, Fatma; Yalcin, Ozlem; Meiselman, Herbert J; Baskurt, Oguz K

    2005-06-01

    We investigated the effect of morphine in phenylephrine (PE)- or KCl-precontracted rat small mesenteric arteries. Morphine (10(-6)-10(-4) M) administration caused concentration-dependent relaxation responses in small mesenteric arteries precontracted by PE or KCl. Removal of endothelium did not significantly alter the relaxation responses to morphine. The relaxant responses to morphine were partially inhibited by pre-treatment of tissues with naloxone (NAL, 10(-5) M) for 20 min. The inhibitory effect of NAL on relaxant responses to morphine in PE- or KCl-precontracted arteries did not differ significantly between endothelium-intact and endothelium-denuded preparations. Incubation of endothelium-intact or endothelium-denuded arterial segments with NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) or cyclooxygenase (COX) inhibitor indomethacin (10(-5) M) or histamine H(1)-receptor blocker diphenhydramine (10(-6) M), for 20 min did not inhibit the relaxation responses to morphine. Small mesenteric arterial segment contractions induced by stepwise addition of calcium to high KCl solution with no calcium were almost completely inhibited by morphine. These findings suggested that morphine-induced relaxation responses in isolated rat small mesenteric arteries were neither dependent on endothelium nor blocked by NOS or COX inhibition but they rather seem to depend on an interaction of morphine with calcium influx pathways. PMID:15939674

  15. Is ethnicity associated with morphine's side effects in children? morphine pharmacokinetics, analgesic response and side effects in children having tonsillectomy

    PubMed Central

    Jimenez, Nathalia; Anderson, Gail D.; Shen, Danny D.; Nielsen, Susan Searles; Farin, Federico M.; Seidel, Kristy; Lynn, Anne M.

    2012-01-01

    Objectives/Aims To examine whether morphine pharmacokinetics (PK) and/or genetic polymorphisms in opioid-related genes, underlie differences in analgesic response and side effects to morphine in Latino (L) vs non-Latino Caucasian (NL) children. Background Morphine has high interindividual variability in its analgesic response and side effects profile. Earlier studies suggest that morphine response may vary by race and ethnicity. Methods Prospective cohort study in L and NL children, 3–17 years of age comparing pain scores, occurrence of side effects, plasma morphine, morphine-6-and morphine-3-glucuronide concentrations measured after a single morphine IV bolus administration. Non-compartmental pharmacokinetic analysis and genotyping for 28 polymorphisms in 8 genes (UGT1A8, UGT2B7, ABCB1, COMT, STAT6, MC1R, OPRM1, and ARRB2) were done. Results We enrolled 68 children (33 L, 35 NL). There were no differences in pain scores or need for rescue analgesia. Statistically significant differences in the occurrence of side effects were documented: While 58% of L children experienced at least one side effect only 20% of NL did (p=0.001). Pruritus was 4 times (p=0.006) and emesis 7 times (p=0.025) more frequent in L compared to NL. PK parameters were similar between groups. None of the assessed polymorphisms mediated the association between ethnicity and side effects. Conclusions We found statistically significant differences in occurrence of side effects after morphine administration between L and NL children. Neither differences in morphine or metabolite concentrations, nor the genetic polymorphisms examined, explain these findings. Studies are needed to further investigate reasons for the increase in morphine side effects by Latino ethnicity. PMID:22486937

  16. 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

  17. 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.

  18. Effects of morphine and naloxone on feline colonic transit

    SciTech Connect

    Krevsky, B.; Libster, B.; Maurer, A.H.; Chase, B.J.; Fisher, R.S.

    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 the other opioid receptors is inferred.

  19. The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model.

    PubMed

    Wilkerson, Jenny L; Niphakis, Micah J; Grim, Travis W; Mustafa, Mohammed A; Abdullah, Rehab A; Poklis, Justin L; Dewey, William L; Akbarali, Hamid; Banks, Matthew L; Wise, Laura E; Cravatt, Benjamin F; Lichtman, Aron H

    2016-04-01

    Serious clinical liabilities associated with the prescription of opiates for pain control include constipation, respiratory depression, pruritus, tolerance, abuse, and addiction. A recognized strategy to circumvent these side effects is to combine opioids with other antinociceptive agents. The combination of opiates with the primary active constituent of cannabis (Δ(9)-tetrahydrocannabinol) produces enhanced antinociceptive actions, suggesting that cannabinoid receptor agonists can be opioid sparing. Here, we tested whether elevating the endogenous cannabinoid 2-arachidonoylglycerol through the inhibition of its primary hydrolytic enzyme monoacylglycerol lipase (MAGL), will produce opioid-sparing effects in the mouse chronic constriction injury (CCI) of the sciatic nerve model of neuropathic pain. The dose-response relationships of i.p. administration of morphine and the selective MAGL inhibitor 2,5-dioxopyrrolidin-1-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate (MJN110) were tested alone and in combination at equieffective doses for reversal of CCI-induced mechanical allodynia and thermal hyperalgesia. The respective ED50 doses (95% confidence interval) of morphine and MJN110 were 2.4 (1.9-3.0) mg/kg and 0.43 (0.23-0.79) mg/kg. Isobolographic analysis of these drugs in combination revealed synergistic antiallodynic effects. Acute antinociceptive effects of the combination of morphine and MJN110 required μ-opioid, CB1, and CB2 receptors. This combination did not reduce gastric motility or produce subjective cannabimimetic effects in the drug discrimination assay. Importantly, combinations of MJN110 and morphine given repeatedly (i.e., twice a day for 6 days) continued to produce antiallodynic effects with no evidence of tolerance. Taken together, these findings suggest that MAGL inhibition produces opiate-sparing events with diminished tolerance, constipation, and cannabimimetic side effects. PMID:26791602

  20. The Comparison of Intrathecal Morphine and IV Morphine PCA on Pain Control, Patient Satisfaction, Morphine Consumption, and Adverse Effects in Patients Undergoing Reduction Mammoplasty

    PubMed Central

    Akdağ, Osman; Kara, İnci; Yıldıran, Gokce Unal; Tosun, Zekeriya

    2015-01-01

    Background: Following breast reduction procedures, the level of postoperative pain can be severe, and sufficient pain control influences a patient's physiological, immunological, and psychological status. Objective: The aim of this study was to examine the use of intrathecal morphine (ITM) in breast reduction surgery with patient-controlled analgesia (PCA). Methods: Sixty-two female patients who underwent breast reductions with the same technique participated in this study. The study group (ITM + PCA) included 32 patients; a single shot (0.2 mg) of ITM and intravenous morphine with PCA were administered. In the control group, morphine PCA alone was intravenously administered to 30 patients. Comparisons between the groups of cumulative morphine consumption, visual analog scale scores, and patient satisfaction scores, which were the primary outcome measures, and adverse effects, which were the secondary outcome measures, were conducted. Results: The patients in the 2 groups had similar degrees of pain and satisfaction scores. The study group had lower cumulative morphine consumption (P = .001) than the PCA-only control group; there was no statistically significant difference in adverse effects between the 2 groups. Conclusion: Intrathecal morphine may effectively control pain with lower total morphine consumption following breast reduction surgery. PMID:25987940

  1. Protective effect of crocin on liver toxicity induced by morphine.

    PubMed

    Salahshoor, Mohammad Reza; Khashiadeh, Mojtaba; Roshankhah, Shiva; Kakabaraei, Seyran; Jalili, Cyrus

    2016-01-01

    Crocin, a bioactive molecule of saffron can be purely isolated from the saffron extract. It has different pharmacological effects such as antioxidant and anticancer activities. Morphine is an opioid analgesic drug. It is mainly metabolized in liver and causes devastating effects. It can increase the generation of free radicals. This study was designed to evaluate the protective role of crocin against morphine-induced toxicity in the mouse liver. In this study, various doses of crocin (12.5, 25 and 50 mg/kg) and crocin plus morphine were administered interaperitoneally once daily to 48 male mice for 20 consecutive days. These mice were randomly assigned to 8 groups of 6 each. The liver weight and histology, aspartate amino transferase, alanine aminotransferase, alkaline phosphatase (ALP) and serum nitric oxide levels were studied. The results indicated that morphine administration significantly decreased liver weight and increased the mean diameter of hepatocyte, central hepatic vein diameters, liver enzyme levels, and blood serum nitric oxide level compared to saline group (P<0.05). However, crocin administration significantly boosted liver weight and decreased the mean diameter of hepatocyte, central hepatic vein, liver enzymes and nitric oxide levels in all groups compared to the group received morphine alone (P<0.05). It seems that crocin administration could protect the liver damage induced by morphine. The antioxidant effect of crocin may be a major reason for its positive impact on liver parameters. PMID:27168751

  2. Protective effect of crocin on liver toxicity induced by morphine

    PubMed Central

    Salahshoor, Mohammad Reza; khashiadeh, Mojtaba; Roshankhah, Shiva; Kakabaraei, Seyran; Jalili, Cyrus

    2016-01-01

    Crocin, a bioactive molecule of saffron can be purely isolated from the saffron extract. It has different pharmacological effects such as antioxidant and anticancer activities. Morphine is an opioid analgesic drug. It is mainly metabolized in liver and causes devastating effects. It can increase the generation of free radicals. This study was designed to evaluate the protective role of crocin against morphine-induced toxicity in the mouse liver. In this study, various doses of crocin (12.5, 25 and 50 mg/kg) and crocin plus morphine were administered interaperitoneally once daily to 48 male mice for 20 consecutive days. These mice were randomly assigned to 8 groups of 6 each. The liver weight and histology, aspartate amino transferase, alanine aminotransferase, alkaline phosphatase (ALP) and serum nitric oxide levels were studied. The results indicated that morphine administration significantly decreased liver weight and increased the mean diameter of hepatocyte, central hepatic vein diameters, liver enzyme levels, and blood serum nitric oxide level compared to saline group (P<0.05). However, crocin administration significantly boosted liver weight and decreased the mean diameter of hepatocyte, central hepatic vein, liver enzymes and nitric oxide levels in all groups compared to the group received morphine alone (P<0.05). It seems that crocin administration could protect the liver damage induced by morphine. The antioxidant effect of crocin may be a major reason for its positive impact on liver parameters. PMID:27168751

  3. Modeling the Effects of Morphine on Simian Immunodeficiency Virus Dynamics

    PubMed Central

    Vaidya, Naveen K.; Ribeiro, Ruy M.; Perelson, Alan S.; Kumar, Anil

    2016-01-01

    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 to 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. 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. PMID:27668463

  4. Effect of linalool on morphine tolerance and dependence in mice.

    PubMed

    Hosseinzadeh, Hossein; Imenshahidi, Mohsen; Hosseini, Mohammadreza; Razavi, Bibi Marjan

    2012-09-01

    Linalool, a terpene alcohol, has been shown to interact with the opioid system and N-methyl-D-aspartate (NMDA) receptor. Therefore, the effect of linalool on morphine dependence and tolerance was studied. Dependence and tolerance were induced in mice using subcutaneous morphine injections, three times a day (50, 50 and 75 mg/kg /day) for 3 days. To evaluate the effect of agents on the induction of morphine dependence and tolerance, linalool (50, 75 and 100 mg/kg), clonidine (positive control), alpha-2 receptor agonist, (0.1 mg/kg), memantine, NMDA receptor antagonist (positive control), (30 mg/kg) and saline were injected intraperitoneally three times a day for 3 days. To determine the expression of morphine dependence and tolerance, all compounds were injected once intraperitoneally on the day of experiment. The effect of linalool and other agents on dependence were evaluated by counting the number of jumps (induced by naloxone 5 mg/kg). The tolerance was evaluated by the tail-flick test. The results showed that linalool in the induction and expression phase increased the nociception threshold. Linalool (48% and 95.6% at doses 75 and 100 mg/kg, respectively), clonidine and memantine reduced the severity of withdrawal signs in the induction and expression phases. This study indicated that linalool has a significant effect on morphine tolerance and dependence. This effect may be mediated partially through the inhibition of NMDA receptors.

  5. 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.

  6. Fangchinoline inhibited the antinociceptive effect of morphine in mice.

    PubMed

    Fang, L H; Zhang, Y H; Ku, B S

    2005-03-01

    Fangchinoline (FAN), a non-specific calcium antagonist, is a major alkaloidal component of the creeper Stephania tetrandra S. Moore (or fenfangji). It has been shown to possess antagonistic activity on morphine-induced antinociception in mice. This study was undertaken to assess the antagonistic mechanism. The results demonstrated that FAN (IP) attenuated morphine (SC)-induced antinociception in a dose-dependent manner with significant effect at doses of 30 and 60mg/kg body wt. (IP) in the tail-flick test but not the tail-pinch tests, carried out in mice. This antagonism was abolished by pretreatment with a serotonin precursor, 5-hydroxytryptophan (5-HTP, IP), but not by pretreatment with a noradrenaline precursor, L-dihydroxyphenylalanine (L-DOPA, IP) in the tail-flick test. On the other hand, the development of morphine-induced analgesic tolerance was not prevented by FAN. These results suggest that the serotonergic pathway may be involved in the antagonism of morphine-induced antinociception by FAN and, in agreement with other reports, also indicates the possible dissociation of the morphine analgesic effect from its tolerance-development mechanism. PMID:15830839

  7. 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

  8. Involvement of histaminergic system in the discriminative stimulus effects of morphine.

    PubMed

    Mori, Tomohisa; Narita, Minoru; Onodera, Kenji; Suzuki, Tsutomu

    2004-05-01

    The interactions between morphine and the histaminergic system are not yet fully clarified. More especially, the involvement of the histaminergic system in the discriminative stimulus effects of morphine has not been determined. Therefore, the effects of histamine-related compounds on the discriminative stimulus effects of morphine were examined in rats. Combination tests using histamine-related compounds with morphine were initiated in rats trained to discriminate between 3.0 mg/kg morphine and saline. Zolantidine (central histamine H2-receptor antagonist), but not pyrilamine (central histamine H1-receptor antagonist) or ranitidine (peripheral histamine H2-receptor antagonist), significantly attenuated the discriminative stimulus effects of morphine. The histamine precursor L-histidine significantly potentiated the discriminative stimulus effects of morphine. These results suggest that the discriminative stimulus effects of morphine are, at least in part, mediated through the central activation of histamine H2-receptors in rats.

  9. The effect of morphine on fear extinction in rats.

    PubMed

    Morris, M D; Gebhart, G F

    1978-05-31

    Rats were trained on an appetitive discretetrial discriminated-punishment task in which they learned to suppress responding when an intense flashing light predicting punishment was present and to respond rapidly on trials when the flashing light was absent. Once animals were performing discriminatively, 0.75, 3.0, or 6.0 mg/kg of morphine (base) was administered and a fear extinction session consisting of 60 nonshocked presentations of the flashing light was given. Two saline control groups, one that received fear extinction and one that did not, were also included in the experiment. On the day following fear extinction, all rats were tested in the undrugged state on the discriminated punishment problem, but without shock. The rats receiving 3.0 and 6.0 mg/kg of morphine before the fear extinction session were suppressed by the flashing light more than the saline extinction group or the 0.75 mg/kg morphine treatment group. Moreover, the two higher dose morphine groups were suppressed as readily as the saline group that received no fear extinction. These results are attributed to the antiemotionality effects of morphine. PMID:97707

  10. Effects of morphine on glucose homeostasis in the conscious dog.

    PubMed Central

    Radosevich, P M; Williams, P E; Lacy, D B; McRae, J R; Steiner, K E; Cherrington, A D; Lacy, W W; Abumrad, N N

    1984-01-01

    This study was designed to assess the effects of morphine sulfate on glucose kinetics and on glucoregulatory hormones in conscious overnight fasted dogs. One group of experiments established a dose-response range. We studied the mechanisms of morphine-induced hyperglycemia in a second group. We also examined the effect of low dose morphine on glucose kinetics independent of changes in the endocrine pancreas by the use of somatostatin plus intraportal replacement of basal insulin and glucagon. In the dose-response group, morphine at 2 mg/h did not change plasma glucose, while morphine at 8 and 16 mg/h caused a hyperglycemic response. In the second group of experiments, morphine (16 mg/h) caused an increase in plasma glucose from a basal 99 +/- 3 to 154 +/- 13 mg/dl (P less than 0.05). Glucose production peaked at 3.9 +/- 0.7 vs. 2.5 +/- 0.2 mg/kg per min basally, while glucose clearance declined to 1.7 +/- 0.2 from 2.5 +/- 0.1 ml/kg per min (both P less than 0.05). Morphine increased epinephrine (1400 +/- 300 vs. 62 +/- 8 pg/ml), norepinephrine (335 +/- 66 vs. 113 +/- 10 pg/ml), glucagon (242 +/- 53 vs. 74 +/- 14 pg/ml), insulin (30 +/- 9 vs. 10 +/- 2 microU/ml), cortisol (11.1 +/- 3.3 vs. 0.9 +/- 0.2 micrograms/dl), and plasma beta-endorphin (88 +/- 27 vs. 23 +/- 6 pg/ml); all values P less than 0.05 compared with basal. These results show that morphine-induced hyperglycemia results from both stimulation of glucose production as well as inhibition of glucose clearance. These changes can be explained by rises in epinephrine, glucagon, and cortisol. These in turn are part of a widespread catabolic response initiated by high dose morphine that involves activation of the sympathetic nervous system, the endocrine pancreas, and the pituitary-adrenal axis. Also, we report the effect of a 2 mg/h infusion of morphine on glucose kinetics when the endocrine pancreas is clamped at basal levels. Under these conditions, morphine exerts a hypoglycemic effect (25% fall in plasma

  11. Effect of isolation on pain threshold and on different effects of morphine.

    PubMed

    Coudereau, J P; Monier, C; Bourre, J M; Frances, H

    1997-08-01

    1. The effect of three periods of isolation (8, 15 and 30 days) were studied in mice on the pain threshold and the sensitivity to morphine. 2. The pain threshold was unchanged after 8 and 15 days of isolation but increased after 30 days of isolation. 3. The analgesic effect of morphine was unchanged after 8 and 15 days of isolation but increased after 30 days of isolation. 4. The tolerance to morphine analgesia was unchanged after 8 and 15 days of isolation but increased after 30 days of isolation (morphine-induced analgesia was reduced). 5. The physical dependence on morphine induced by precipitated withdrawal was unchanged after 8 and 15 days of isolation but decreased after 30 days of isolation. 6. It is suggested that isolation may modify the metabolism the metabolism/absorption of morphine in a different way according as the treatment is unique or chronic. PMID:9380794

  12. Opiate receptor in praying mantis: effect of morphine and naloxone.

    PubMed

    Zabala, N A; Miralto, A; Maldonado, H; Nuñez, J A; Jaffe, K; Calderon, L D

    1984-05-01

    A praying mantis displays a "frightening reaction" called deimatic reaction (DR), any time that it is faced with a patterned visual stimulus that represents a potential damage for the insect. Results of the present paper show that the DR could be also elicited by an actual noxious (an electrical shock) and that this response is similar to that elicited by a potential nociceptive stimulus (a patterned visual stimulus). The DR elicited by the electric shock was used as a model for studying the analgesic effect of opiates. The mantis was placed in an apparatus that allowed us to give the insect an electrical shock and to measure the strength of its DR. During a first session the voltage threshold necessary to induce a full DR was determined, and then, the insect was injected with a certain solution. The voltage threshold was tested one, two and four hours after injection. Mantises that were injected with only distilled water showed no changes in their voltage threshold during the three tests. Injections of 300, 350 and 400 micrograms/g of morphine-HCl increased the voltage threshold in both a time-dependent and a dose related manner. A dose of 350 micrograms/g of morphine-HCl produced 50% of response inhibition after two hours of injections and is referred to as the median antinoxious dose ( AD50 ). Sixteen micrograms/g of naloxone given in conjunction with an AD50 of morphine, partially blocked the effect of morphine during the first hour and fully blocked it during the second hour. Thirty-two micrograms/g of naloxone fully blocked the morphine effect during the first and the second hour. However, more than 48 micrograms/g of naloxone alone also increased the voltage threshold in insects, similar to those described for vertebrates. PMID:6330763

  13. Evaluation of menstrual cycle effects on morphine and pentazocine analgesia

    PubMed Central

    Ribeiro-Dasilva, MC; Shinal, RM; Glover, T; Williams, RS; Staud, R; Riley, JL; Fillingim, RB

    2011-01-01

    Studies have demonstrated menstrual cycle influences on basal pain perception, but direct evidence of menstrual cycle influences on analgesic responses has not been reported in humans. Our aim was to determine whether the magnitude of morphine and pentazocine analgesia varied across the menstrual cycle. Sixty-five healthy women, 35 taking oral contraceptives (OC) and 30 normally cycling (NOC), underwent experimental pain assessment both before and after intravenous administration morphine (0.08 mg/kg) or pentazocine (0.5 mg/kg) compared to saline placebo. Both active drug and placebo were administered once during the follicular phase and once during the luteal phase. Measures of heat, ischemic and pressure pain sensitivity were obtained before and after drug administration. Change scores in pain responses were computed to determine morphine and pentazocine analgesic responses, and medication side effects were recorded. The data were analyzed using mixed-model ANOVAs. NOC women showed slightly greater heat pain sensitivity in the follicular vs. luteal phase, while the reverse pattern emerged for OC women (p=0.046). Also, OC women showed lower pressure pain thresholds compared to NOC women (p < .05). Regarding analgesic responses, NOC women showed greater morphine analgesia for ischemic pain during the follicular vs. the luteal phase (p=0.004). Likewise, side effects for morphine were significantly higher in NOC women in the follicular phase than in the luteal phase (p=0.02). These findings suggest that sex hormones may influence opioid responses; however, the effects vary across medications and pain modalities and are likely to be modest in magnitude. PMID:21239109

  14. The Effect of Acute and Chronic Morphine on Some Blood Biochemical Parameters in an Inflammatory Condition in Gonadectomized Male Rats

    PubMed Central

    Chahkandi, Mohadeseh; Askari, Nayerreh; Asadikaram, Gholamreza

    2015-01-01

    Background Opiates affect blood factors as well as pain and inflammation in a gender-dependent manner. The aim of the present study was to evaluate the effects of morphine on serum glucose, cholesterol, triglycerides, and urea in gonadectomized and inflammation conditions. Methods Animals were divided as follows: control group, carrageenan and chronic morphine recipients, acute morphine recipients, chronic morphine recipients, carrageenan recipients, acute morphine and carrageenan recipients, gonadectomized group, gonadectomized recipients of carrageenan, gonadectomized recipients of morphine, gonadectomized recipients of chronic morphine, gonadectomized recipients of carrageenan and chronic morphine, gonadectomized recipients of acute morphine and carrageenan. Findings Our results have shown that acute and chronic morphine elevates blood glucose level in the acute and chronic morphine group. Cholesterol level has shown to be increasing in the morphine and carrageenan recipient group compared with a group which merely received morphine. Triglyceride has shown to be decreasing in acute and chronic morphine recipient group compared with control group. A significant increase in serum urea was observed in acute and chronic morphine recipients compared with the carrageenan recipient group. Conclusion Morphine alters the serum glucose, cholesterol, triglyceride, and urea in the normal and inflammatory conditions differently, hence, this finding should be considered in the patients who use morphine as a relief of pain, especially in an inflammatory condition. PMID:26885349

  15. Tolerance to behavioral effects of clonidine after chronic administration of morphine.

    PubMed

    McKearney, J W

    1985-04-01

    Male rats (Buffalo strain) were studied under a procedure in which each 30th lick of a drinking tube resulted in the delivery of 0.01 ml water. The effects of clonidine HC1 (0.003-0.3 mg/kg, IP) were determined before, during and after exposure to conditions in which a morphine sulfate solution (0.5 mg/ml in 0.4% saccharin) was the only source of fluid. After either 10 or 80 days exposure to the chronic morphine regimen, rats were maintained under a repetitive cycle in which the morphine was available for 3 days and then removed for 4 days. The subjects consumed an average of 100 mg/kg/day morphine during the times it was available. The effects of clonidine were redetermined once weekly, on the 4th day after removal of the morphine solution. The effects of clonidine were also determined after morphine was removed for more prolonged periods (18-67 days). Chronic exposure to the morphine solution resulted in a 4- to 5-fold shift to the right in the dose-effect curve for clonidine (decreased responding). ED50 values returned to pre-morphine levels when rats were tested at longer post-morphine times (e.g., 18 days). Under the conditions of this experiment, chronic exposure to morphine produced marked cross-tolerance to the behavioral effects of clonidine.

  16. Analgesic Effects of Paracetamol and Morphine After Elective Laparotomy Surgeries

    PubMed Central

    Alimian, Mahzad; Pournajafian, Alireza; Kholdebarin, Alireza; Ghodraty, Mohammadreza; Rokhtabnak, Faranak; Yazdkhasti, Payman

    2014-01-01

    Background: Opioids have been traditionally used for postoperative pain control, but they have some unpleasant side effects such as respiratory depression or nausea. Some other analgesic drugs like non-steroidal anti-inflammatory drugs (NSAIDs) are also being used for pain management due to their fewer side effects. Objectives: The aim of our study was to compare the analgesic effects of paracetamol, an intravenous non-opioid analgesic and morphine infusion after elective laparotomy surgeries. Patients and Methods: This randomized clinical study was performed on 157 ASA (American Society of Anesthesiology) I-II patients, who were scheduled for elective laparotomy. These patients were managed by general anesthesia with TIVA technique in both groups and 150 patients were analyzed. Paracetamol (4 g/24 hours) in group 1 and morphine (20 mg/24 hours) in group 2 were administered by infusion pump after surgery. Postoperative pain evaluation was performed by visual analog scale (VAS) during several hours postoperatively. Meperidine was administered for patients complaining of pain with VAS > 3 and repeated if essential. Total doses of infused analgesics, were recorded following the surgery and compared. Analysis was performed on the basis of VAS findings and meperidine consumption. Results: There were no differences in demographic data between two groups. Significant difference in pain score was found between the two groups, in the first eight hours following operation (P value = 0.00), but not after 12 hours (P = 0.14) .The total dose of rescue drug (meperidine) and number of doses injected showed a meaningful difference between the two groups (P = 0.00). Also nausea, vomiting and itching showed a significant difference between the two groups and patients in morphine group, experienced higher levels of them. Conclusions: Paracetamol is not enough for postoperative pain relief in the first eight hour postoperatively, but it can reduce postoperative opioid need and is

  17. Effects of berberine on acquisition and reinstatement of morphine-induced conditioned place preference in mice

    PubMed Central

    Vahdati Hassani, Faezeh; Hashemzaei, Mahmoud; Akbari, Edris; Imenshahidi, Mohsen; Hosseinzadeh, Hossein

    2016-01-01

    Objective: It has been shown that berberine, a major component of Berberis vulgaris extract, modulates the activity of several neurotransmitter systems including dopamine (Da) and N-methyl-D-aspartate (NMDA) contributing to rewarding and reinforcing effects of morphine. Drug craving and relapsing even after a long time of abstinence therapy are the most important problems of addiction. In the present study, we investigated the alleviating effects of berberine on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP) in mice. Materials and Methods: In male NMRI mice, the acquisition of CPP was established by 40 mg/kg of morphine sulphate injection and extinguished after the extinction training and reinstated by a 10 mg/kg injection of morphine. The effects of different doses of berberine (5, 10, and 20 mg/kg) on the acquisition and reinstatement induced by morphine were evaluated in a conditioned place preference test. Results: The results showed that intraperitoneal administration of berberine (5, 10, and 20 mg/kg) did not induce conditioned appetitive or aversive effects. Injection of berberine (10 and 20 mg/kg) 2 h before the morphine administration reduced acquisition of morphine-induced CPP. In addition, same doses of berberine significantly prevented the reinstatement of morphine-induced CPP. Conclusion: These results suggest that berberine can reduce the acquisition and reinstatement of morphine-induced conditioned place preference and may be useful in treatment of morphine addiction. PMID:27222833

  18. Effects of opioids in morphine-treated pigeons trained to discriminate among morphine, the low-efficacy agonist nalbuphine, and saline.

    PubMed

    Walker, Ellen A; Picker, Mitchell J; Granger, Arthur; Dykstra, Linda A

    2004-07-01

    In opioid-dependent subjects, the low-efficacy mu agonist nalbuphine generally precipitates withdrawal or withdrawal-like stimulus effects. To provide a more complete characterization of the discriminative stimulus effects of nalbuphine in opioid-treated subjects, seven White Carneux pigeons were treated daily with 10 mg/kg morphine i.m. and trained 6 h later to discriminate among 10 mg/kg morphine, 1.0 mg/kg nalbuphine, and saline by responding on one of three different keys. When tested, morphine produced morphine-key responding and nalbuphine produced nalbuphine-key responding. Replacing the daily morphine injection with saline produced nalbuphine-key responding, and this effect was reversed by the administration of morphine. In substitution tests with other compounds, the antagonists naltrexone (i.m.) and CTAP (D-Phe-Cys-Tyr-D-Tryp-Lys-Thr-Pen-Thr-NH2) (i.c.v.) produced nalbuphine-key responding. High-efficacy agonists fentanyl and etorphine produced morphine-key responding. The intermediate-efficacy agonists buprenorphine, dezocine, and butorphanol produced a pattern of morphine-, saline-, and/or nalbuphine-key responding that differed across individual pigeons. The lower efficacy agonists nalorphine and levallorphan produced predominantly nalbuphine-key responding. The kappa agonists spiradoline and U50,488 [trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide methanesulfonate], the nonopioid d-amphetamine, and saline produced predominantly saline-key responding. Naltrexone and nalbuphine dose dependently reversed the morphine-key responding produced by the training dose of morphine. Together, these data suggest that the discriminative-stimulus effects of the low-efficacy micro agonist nalbuphine in morphine-treated pigeons are similar to those of other low-efficacy agonists, naltrexone, and the termination of daily morphine treatment.

  19. 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.

  20. Comparative effect of intraoperative propacetamol versus placebo on morphine consumption after elective reduction mammoplasty under remifentanil-based anesthesia: a randomized control trial [ISRCTN71723173].

    PubMed

    Binhas, Michèle; Decailliot, François; Rezaiguia-Delclaux, Saïda; Suen, Powen; Dumerat, Marc; François, Véronique; Combes, Xavier; Duvaldestin, Philippe

    2004-09-14

    BACKGROUND: Postoperative administration of paracetamol or its prodrug propacetamol has been shown to decrease pain with a morphine sparing effect. However, the effect of propacetamol administered intra-operatively on post-operative pain and early postoperative morphine consumption has not been clearly evaluated. In order to evaluate the effectiveness of analgesic protocols in the management of post-operative pain, a standardized anesthesia protocol without long-acting opioids is crucial. Thus, for ethical reasons, the surgical procedure under general anesthesia with remifentanil as the only intraoperative analgesic must be associated with a moderate predictable postoperative pain. METHODS: We were interested in determining the postoperative effect of propacetamol administered intraoperatively after intraoperative remifentanil. Thirty-six adult women undergoing mammoplasty with remifentanil-based anesthesia were randomly assigned to receive propacetamol 2 g or placebo one hour before the end of surgery. After remifentanil interruption and tracheal extubation in recovery room, pain was assessed and intravenous titrated morphine was given. The primary end-point was the cumulative dose of morphine administered in the recovery room. The secondary end-points were the pain score after tracheal extubation and one hour after, the delay for obtaining a Simplified Numerical Pain Scale (SNPS) less than 4, and the incidence of morphine side effects in the recovery room.For intergroup comparisons, categorical variables were compared using the chi-squared test and continuous variables were compared using the Student t test or Mann-Whitney U test, as appropriate. A p value less than 0.05 was considered as significant. RESULTS: In recovery room, morphine consumption was lower in the propacetamol group than in the placebo group (p = 0.01). Pain scores were similar in both groups after tracheal extubation and lower in the propacetamol group (p = 0.003) one hour after tracheal

  1. 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. PMID:24973610

  2. 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.

  3. 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.

  4. 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

  5. Effects of Estrogen Receptor Modulators on Morphine Induced Sensitization in Mice Memory

    PubMed Central

    Anoush, Mahdieh; Jani, Ali; Sahebgharani, Moosa; Jafari, Mohammad Reza

    2015-01-01

    Objective: In this study, the effects of estradiol valerate and raloxifenea selective estrogen receptor modulator; (SERM) on morphine induced sensitization were examined in mice memory, according to the step-down passive avoidance task. Method: The mice received morphine or estradiol and raloxifene for three days alone or in combination with morphine. After a drug free period of 5 days, the subjects received saline or morphine as pre- training treatments followed by a pre-test saline administration. The memory retrieval was evaluated using step-down passive avoidance test both on the training and test day. Results: The results illustrated that the three- day administration of morphine induced sensitization through the enhancement of memory retrieval (morphine induced sensitization in mice memory). Both the three- day administration of estradiol valerate alone and with morphine (5 mg/kg) restored memory. On the other hand, the three- day administration of raloxifene had no effect on memory retrieval alone, but declined morphine induced sensitization in mice memory. Conclusion: The results of the study indicated that there is an interaction between estrogen receptor modulators and morphine induced sensitization in mice memory. PMID:26877753

  6. Therapeutic suggestion has not effect on postoperative morphine requirements.

    PubMed

    van der Laan, W H; van Leeuwen, B L; Sebel, P S; Winograd, E; Baumann, P; Bonke, B

    1996-01-01

    This study was designed to confirm the effect of therapeutic intraoperative auditory suggestion on recovery from anesthesia, to establish the effect of preoperative suggestion, and to assess implicit memory for intraoperative information using an indirect memory task. Sixty consenting unpremedicated patients scheduled for elective gynecologic surgery were randomly divided into three equal groups: Group 1 received a tape of therapeutic suggestions preoperatively, and the story of Robinson Crusoe intraoperatively; Group 2 heard the story of Peter Pan preoperatively and therapeutic suggestions intraoperatively; Group 3 heard the Crusoe story preoperatively and the Peter Pan story intraoperatively. A standardized anesthetic technique was used with fentanyl, propofol, isoflurane, and nitrous oxide. After surgery, all patients received patient-controlled analgesia (PCA) with a standardized regimen. In the 24 h postsurgery, morphine use was recorded every 6 h and at 24 h an indirect memory test (free association) was used to test for memory of the stories. Anxiety scores were measured before surgery and at 6 and 24 h postsurgery. There were no significant differences between groups for postoperative morphine use, pain or nausea scores, anxiety scores, or days spent in hospital after surgery. Seven of 20 patients who heard the Pan story intraoperative gave a positive association with the word "Hook," whereas 2 of 20 who did not hear the story gave such an association. Indirect memory for the Pan story was established using confidence interval (CI) analysis. (The 95% CI for difference in proportion did not include zero). No indirect memory for the Crusoe story could be demonstrated. This study did not confirm previous work which suggested that positive therapeutic auditory suggestions, played intraoperatively, reduced PCA morphine requirements. In contrast, a positive implicit memory effect was found for a story presented intraoperatively.

  7. Effects of the histaminergic system on the morphine-induced conditioned place preference in mice.

    PubMed

    Suzuki, T; Takamori, K; Misawa, M; Onodera, K

    1995-03-27

    The effects of an H2 receptor antagonist, a histidine decarboxylase inhibitor and a histamine precursor on the morphine-induced place preference in mice were examined. Morphine (1-7 mg/kg) produced a place preference in a dose-dependent manner. This morphine-induced place preference was significantly antagonized by the dopamine (DA) D1 receptor antagonist SCH 23390. The histamine precursor, L-histidine, attenuated the morphine (7 mg/kg)-induced place preference. On the other hand, the histidine decarboxylase inhibitor, alpha-fluoromethylhistidine (alpha-FMH), significantly potentiated the morphine (1 mg/kg)-induced place preference. This potentiation was antagonized by SCH 23390. The H2 receptor antagonist zolantidine (0.3 mg/kg) significantly potentiated the morphine-induced place preference. Surprisingly, zolantidine (1 mg/kg) alone also produced a significant place preference. The zolantidine-induced place preference was antagonized by SCH 23390. In addition, zolantidine (1, 3 and 10 mg/kg) significantly increased DA turnover (DA ratio) in the limbic forebrain (nucleus accumbens and olfactory tubercle), implying that zolantidine may activate the mesolimbic DA system. Moreover, co-administration of zolantidine dose-dependently increased morphine (10 mg/kg)-induced DA turnover in the limbic forebrain. These results suggest that the activation of histaminergic neurons may attenuate the rewarding effect of morphine, while the inhibition of histaminergic neurons may potentiate the rewarding effect of morphine. Furthermore, potentiation of the morphine-induced rewarding effect by inhibition of histaminergic neurons may be mediated by D1 receptors. We also demonstrated that the H2 receptor antagonist zolantidine may activate the mesolimbic DA system, and as a result, zolantidine itself produces a rewarding effect and potentiates the morphine-induced rewarding effect.

  8. 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.

  9. Effect of Subchronic Intravenous Morphine Infusion and Naloxone-Precipitated Morphine Withdrawal on P-gp and Bcrp at the Rat Blood-Brain Barrier.

    PubMed

    Chaves, Catarina; Gómez-Zepeda, David; Auvity, Sylvain; Menet, Marie-Claude; Crété, Dominique; Labat, Laurence; Remião, Fernando; Cisternino, Salvatore; Declèves, Xavier

    2016-01-01

    Chronic morphine regimen increases P-glycoprotein (P-gp) and breast cancer-resistance protein (Bcrp) expressions at the rat blood–brain barrier (BBB) but what drives this effect is poorly understood. The objective of this study is to assess subchronic continuous morphine infusion and naloxone-precipitated morphine withdrawal effects on P-gp/Bcrp contents and activities at the rat BBB. Rats were treated either with (i) a continuous i.v. morphine for 120 h, (ii) escalating morphine dosing (10-40 mg/kg, i.p., 5 days), (iii) a chronic morphine regimen (10 mg/kg s.c., 5 days) followed by a withdrawal period (2 days) and treatment for 3 additional days. Animal behavior was assessed after naloxone-precipitated withdrawal (1 mg/kg, s.c.). P-gp/Bcrp expressions and activities were determined in brain microvessels by qRT-PCR, Western blot, UHPLC–MS/MS, and in situ brain perfusion of P-gp or Bcrp substrates. Results show continuous i.v. morphine did not change P-gp/Bcrp protein levels in rat brain microvessels, whereas naloxone-precipitated withdrawal after escalating or chronic morphine dose regimen increased Mdr1a and Bcrp mRNA levels by 1.4-fold and 2.4-fold, respectively. Conversely, P-gp/Bcrp protein expressions remained unchanged after naloxone administration, and brain uptake of [3H]-verapamil (P-gp) and [3H]-mitoxantrone (Bcrp) was not altered. The study concludes subchronic morphine infusion and naloxone-precipitated morphine withdrawal have poor effect on P-gp/Bcrp levels at the rat BBB.

  10. Effects of morphine on left ventricular dimensions and function in patients with previous myocardial infarction.

    PubMed

    Ryan, W F; Henning, H; Karliner, J S

    1979-12-01

    To assess the effects of morphine sulfate on left ventricular function and dimensions we administered 15 mg of this agent to 11 stable patients with previous transmural myocardial infarction. All studies were carried out in the supine position. Before morphine administration an echocardiogram was obtained, and this procedure was repeated at 15, 30, 60, 120, and 240 min after morphine. Heart rate decreased from a control value of 69 +/- 4 to 62 +/- 5 beats/min 2 h after morphine (p less than 0.01, analysis of variance); this slower heart rate persisted for 4 h after morphine. Serial measurements of blood pressure, echocardiographic ejection fraction, percent of fractional shortening, and mean normalized velocity of circumferential fiber shortening also showed no significant alterations after morphine. We conclude that in stable patients with chronic ischemic heart disease studied in the supine position, 1) morphine exerts no effect on left ventricular dimensions, an observation which does not support the concept that this agent acts in humans by producing a 'pharmacologic phlebotomy'; and 2) morphine does not alter left ventricular function at rest. Whether different results will be found in patients with increased sympathetic activity, such as occurs in the setting of an acute myocardial infarction or during an episode of acute pulmonary edema, remains to be investigated.

  11. 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

  12. Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine.

    PubMed

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

    2016-02-01

    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.

  13. Stereospecific effects of morphine on plasma opioid peptide levels and nociception in dogs

    SciTech Connect

    Adams, M.L.; Morris, D.L.; Dewey, W.L.

    1986-03-05

    ..beta..-endorphin, (met)enkephalin, and (leu)enkephalin were quantitated in canine plasma by radioimmunoassay (RIA) after extraction of the peptides on Sep Pak C18 cartridges. Plasma samples were taken one hour after a 10 mg/kg s.c. injection of (-)-morphine SO/sub 4/ or (+)-morphine HBr. Antinociception, measured by a dog tail-flick test, and morphine-induced emesis, salivation, diarrhea, and ataxia were quantitated before sampling. Control levels for each dog were taken one week earlier at the same time of day after saline injections. Antinociception, morphine signs, and opioid peptide levels in plasma were significantly increased by (-)-morphine. Antinociception increased from zero to 83.54 +/- 11.0%. The number of morphine signs increased from zero to 2.9 +/- 0.28 per dog. ..beta..-endorphin levels increased from 44.52 +/- 4.25 to 90.6 +/- 7.38 pg/ml; (met)enkephalin levels increased from 253.56 +/- 22.04 to 497.1 +/- 58.12 pg/ml; (leu)-enkephalin increased from 141.65 +/- 12.9 to 313.24 +/- 35.95 pg/ml. None of these effects were observed in the dogs that received (+)-morphine. The conclude that morphine stereospecifically inhibits nociception, induces observable signs, and increases plasma opioid peptide levels in dogs.

  14. The effects of the morphine analogue levorphanol on leukocytes

    PubMed Central

    Wurster, Nancy; Elsbach, Peter; Simon, Eric J.; Pettis, Penelope; Lebow, Sharon

    1971-01-01

    Studies on bacteria have suggested that morphine-like drugs have effects on the cell membrane. To determine the effect of this class of drugs on a mammalian cell, we selected the rabbit peritoneal exudate granulocyte, which undergoes striking membrane changes during phagocytosis. We examined the effect in vitro of the morphine analogue, levorphanol on phagocytosis and metabolism by granulocytes incubated with and without polystyrene particles or live Escherichia coli. Levorphanol (1 or 2 mmoles/liter) decreased: (a) acylation of lysolecithin or lysophosphatidylethanolamine in the medium (which is stimulated about two-fold during phagocytosis) both at rest (40%) and during phagocytosis (60%); (b) uptake of latex particles and Escherichia coli, as judged by electron microscopy; (c) killing of live Escherichia coli (10-fold); (d) 14CO2 production from glucose-1-14C during phagocytosis by at least 80%; (e) K+ content of granulocytes (35%); (f) oxidation of linoleate-1-14C by 50%, and its incorporation into triglyceride by more than 80%. However, levorphanol stimulated 2 to 3-fold the incorporation of linoleate-1-14C or palmitate-1-14C into several phospholipids. Glucose uptake, lactate production, and adenosine triphosphate (ATP) content are not affected by the drug. Thus, levorphanol does not appear to exert its effects through generalized metabolic suppression. Removal of levorphanol by twice resuspending the granulocytes completely reverses all inhibition. In line with observations on bacteria, it appears that the complex effects of levorphanol on granulocytes may be due at least in part to an effect on the cell membrane. PMID:4928264

  15. Effects of concurrent intravenous morphine sulfate and naltrexone hydrochloride on end-tidal carbon dioxide

    PubMed Central

    2012-01-01

    Background Respiratory depression, a potentially fatal side-effect of opioid-overdose, may be reversed by timely administration of an opioid antagonist, such as naloxone or naltrexone. Tampering with a formulation of morphine sulfate and sequestered naltrexone hydrochloride extended release capsules (MS-sNT) releases both the opioid morphine and the antagonist naltrexone. A study in recreational opioid-users indicated that morphine and naltrexone injected in the 25:1 ratio (duplicating the ratio of the formulation) found MS-sNT reduced morphine-induced euphoric effects vs intravenous (IV) morphine alone. In the same study, the effects of morphine + naltrexone on end-tidal carbon dioxide (EtCO2), a measure of respiratory-depression, were evaluated and these data are reported here. Methods Single-center, placebo-controlled, double-blind crossover study. Non-dependent male opioid users were randomized to receive single IV doses of placebo, 30 mg morphine alone, and 30 mg morphine + 1.2 mg naltrexone. EtCO2 was measured by noninvasive capnography. Results Significant differences in EtCO2 least-squares means across all treatments for maximal effect (Emax) and area under the effect curve (AUE0-2, AUE0-8, AUE0-24) were detected (all p ≤ 0.0011). EtCO2 Emax values for morphine + naltrexone were significantly reduced vs morphine alone (42.9 mm Hg vs 47.1 mm Hg, p < 0.0001) and were not significantly different vs placebo (41.9 mm Hg). Median time to reach maximal effect (TEmax) was delayed for morphine + naltrexone vs morphine alone (5.0 h vs 1.0 h). Conclusions Results provide preliminary evidence that the naltrexone:morphine ratio within MS-sNT is sufficient to significantly reduce EtCO2 when administered intravenously to non-dependent male recreational opioid-users. Further studies with multiple measures of respiratory-function are warranted to determine if risk of respiratory depression is also reduced by naltrexone in the tampered formulation. PMID:22420453

  16. Morphine has latent deleterious effects on the ventilatory responses to a hypoxic-hypercapnic challenge.

    PubMed

    May, Walter J; Henderson, Fraser; Gruber, Ryan B; Discala, Joseph F; Young, Alex P; Bates, James N; Palmer, Lisa A; Lewis, Stephen J

    2013-08-28

    This study explored the concept that morphine has latent deleterious actions on the ventilatory control systems that respond to a hypoxic-hypercapnic challenge. In this study, we examined the ventilatory responses elicited by hypoxic-hypercapnic challenge in conscious rats at a time when the effects of morphine (10 mg/kg) on arterial blood-gas chemistry and minute ventilation had subsided. Morphine induced pronounced changes in arterial blood-gas chemistry (e.g., an increase in pCO2, decreases in pO2 and sO2) and decreases in minute ventilation. Despite the complete resolution of the morphine-induced changes in arterial blood-gas chemistry and minute ventilation and almost complete resolution of the effects on peak inspiratory flow and peak expiratory flow, subsequent exposure to hypoxic-hypercapnic challenge elicited markedly blunted increases in minute ventilation and in peak inspiratory and expiratory flows. These findings demonstrate that (1) the changes in arterial blood-gas chemistry elicited by morphine parallel changes in minute ventilation rather than PIF and PEF, and (2) morphine has latent untoward effects on the ventilatory responses to hypoxic-hypercapnic challenge. These novel findings raise the possibility that patients deemed to have recovered from the acute ventilatory depressant effects of morphine may still be susceptible to the latent effects of this opioid analgesic. The mechanisms underlying these latent effects remain to be elucidated. PMID:25045592

  17. The antipsychotic aripiprazole selectively prevents the stimulant and rewarding effects of morphine in mice.

    PubMed

    Almeida-Santos, Ana F; Gobira, Pedro H; Souza, Diego P; Ferreira, Renata C M; Romero, Thiago R; Duarte, Igor D; Aguiar, Daniele C; Moreira, Fabricio A

    2014-11-01

    Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine D2 receptors, with a favorable pharmacological profile. Due to its unique mechanism of action, this compound has potential application as a substitutive therapy for drug addiction. Considering that distinct neural systems subserve the addictive and analgesic actions of opioids, we tested the hypothesis that aripiprazole selectively inhibit the abuse-related, but not the antinociceptive, effects of morphine. The drugs were tested in male Swiss mice for their effects on locomotion, conditioned place preference (CPP) and nociception. Morphine (20mg/kg) increased motor activity, whereas aripiprazole (0.1, 1 and 10mg/kg) did not induce any change. This antipsychotic, however, prevented morphine-induced locomotion. In the conditioning box, aripiprazole did not induce either reward or aversion. Yet, it prevented both the acquisition and the expression of morphine-induced CPP. Finally, none of the doses of this antipsychotic interfere with morphine (5mg/kg)-induced antinociception in the tail-flick test. In conclusion, aripiprazole inhibited the abuse-related effects of morphine at doses that do not interfere with basal locomotion, reward or aversion. Also, it did not alter morphine-induced antinociceptive effects. This antipsychotic should be further investigated as a possible substitutive strategy for treating certain aspects of opioid addiction.

  18. Analgesia and central side-effects: two separate dimensions of morphine response

    PubMed Central

    Droney, Joanne M; Gretton, Sophy K; Sato, Hiroe; Ross, Joy R; Branford, Ruth; Welsh, Kenneth I; Cookson, William; Riley, Julia

    2013-01-01

    Aims To present a statistical model for defining interindividual variation in response to morphine and to use this model in a preliminary hypothesis-generating multivariate genetic association study. Methods Two hundred and sixty-four cancer patients taking oral morphine were included in a prospective observational study. Pain and morphine side-effect scores were examined using principal components analysis. The resulting principal components were used in an exploratory genetic association study of single nucleotide polymorphisms across the genes coding for the three opioid receptors, OPRM1, OPRK1 and OPRD1. Associations in multivariate models, including potential clinical confounders, were explored. Results Two principal components corresponding to residual pain and central side-effects were identified. These components accounted for 42 and 18% of the variability in morphine response, respectively, were independent of each other and only mildly correlated. The genetic and clinical factors associated with these components were markedly different. Multivariate regression modelling, including clinical and genetic factors, accounted for only 12% of variability in residual pain on morphine and 3% of variability in central side-effects. Conclusions Although replication is required, this data-driven analysis suggests that pain and central side-effects on morphine may be two separate dimensions of morphine response. Larger study samples are necessary to investigate potential genetic and clinical associations comprehensively. PMID:23072578

  19. Diazepam as an adjuvant analgesic to morphine for pain due to skeletal muscle spasm.

    PubMed

    Srivastava, Manish; Walsh, Declan

    2003-01-01

    Side effects of morphine are common when it is given in titrated doses to control severe pain in advanced cancer. We describe a case of severe back pain resistant to parenteral morphine accompanied by muscle spasm, in which the addition of diazepam both had an opioid-sparing effect and provided superior symptomatic relief. Diazepam appears to have a specific role as an adjuvant analgesic for pain due to skeletal muscle spasm associated with painful vertebral metastases.

  20. Potentiating effect of morphine upon d-methamphetamine-induced hyperthermia in mice. Effects of naloxone and haloperidol.

    PubMed

    Funahashi, M; Kohda, H; Hori, O; Hayashida, H; Kimura, H

    1990-06-01

    We have examined changes in rectal temperature of mice after subcutaneous administrations of d-methamphetamine alone or methamphetamine plus morphine. Methamphetamine 5 mg/kg produced slight hyperthermia, while simultaneous administration of morphine (25-100 mg/kg), which alone produces hypothermia, potentiated markedly the increase in body temperature by methamphetamine. Methamphetamine showed a hyperthermic effect in a dose-dependent manner in the presence of morphine. The hyperthermia due to methamphetamine plus morphine was avoided by pretreatment with 10 mg/kg naloxone. When animals were pretreated with 2.5 mg/kg haloperidol, hyperthermia due to methamphetamine alone was completely abolished, while that due to methamphetamine plus morphine was still observed. These results showed that dopamine may be implicated in methamphetamine hyperthermia and a haloperidol-nonsensitive mechanism may be involved in the methamphetamine-morphine hyperthermia.

  1. Effects of voluntary exercise on hippocampal long-term potentiation in morphine-dependent rats.

    PubMed

    Miladi-Gorji, H; Rashidy-Pour, A; Fathollahi, Y; Semnanian, S; Jadidi, M

    2014-01-01

    This study was designed to examine the effect of voluntary exercise on hippocampal long-term potentiation (LTP) in morphine-dependent rats. The rats were randomly distributed into the saline-sedentary (Sal/Sed), the dependent-sedentary, the saline-exercise (Sal/Exc), and the dependent-exercise (D/Exc) groups. The Sal/Exc and the D/Exc groups were allowed to freely exercise in a running wheel for 10 days. The Sal/Sed and the morphine-sedentary groups were kept sedentary for the same extent of time. Morphine (10 mg/kg) was injected bi-daily (12 h interval) during 10 days of voluntary exercise. On day 11, 2h after the morphine injection, the in vivo LTP in the dentate gyrus of the hippocampus was examined. The theta frequency primed bursts were delivered to the perforant path for induction of LTP. Population spike (PS) amplitude and the field excitatory post-synaptic potentials (fEPSP) slope were measured as indices of increase in synaptic efficacy. Chronic morphine increased the mean basal EPSP, and augmented PS-LTP. Exercise significantly increased the mean baseline EPSP and PS responses, and augmented PS-LTP in both saline and morphine-treated groups. Moreover, the increase of PS-LTP in the morphine-exercise group was greater (22.5%), but not statistically significant, than that of the Sal/Exc group. These results may imply an additive effect between exercise and morphine on mechanisms of synaptic plasticity. Such an interaction between exercise and chronic morphine may influence cognitive functions in opiate addicts.

  2. Effects of Brugmansia arborea Extract and Its Secondary Metabolites on Morphine Tolerance and Dependence in Mice

    PubMed Central

    Mattioli, Laura; Bracci, Antonio; Titomanlio, Federica; Perfumi, Marina; De Feo, Vincenzo

    2012-01-01

    The aim of the present study was to investigate, in vivo, the effect of a Brugmansia arborea extract (BRU), chromatographic fractions (FA and FNA), and isolated alkaloids on the expression and the acquisition of morphine tolerance and dependence. Substances were acutely (for expression) or repeatedly (for acquisition) administered in mice treated with morphine twice daily for 5 or 6 days, in order to make them tolerant or dependent. Morphine tolerance was assessed using the tail-flick test at 1st and 5th days. Morphine dependence was evaluated through the manifestation of withdrawal symptoms induced by naloxone injection at 6th day. Results showed that BRU significantly reduced the expression of morphine tolerance, while it was ineffective to modulate its acquisition. Chromatographic fractions and pure alkaloids failed to reduce morphine tolerance. Conversely BRU, FA, and pure alkaloids administrations significantly attenuated both development and expression of morphine dependence. These data suggest that Brugmansia arborea Lagerh might have human therapeutic potential for treatment of opioid addiction. PMID:22454681

  3. 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

  4. Analgesic effects of dextromethorphan and morphine in patients with chronic pain.

    PubMed

    Heiskanen, Tarja; Härtel, Brita; Dahl, Marja-Liisa; Seppälä, Timo; Kalso, Eija

    2002-04-01

    N-methyl-aspartate (NMDA) receptor antagonists have been shown to improve opioid analgesia in the animal model. The cough suppressant dextromethorphan is a clinically available NMDA-receptor antagonist. In this randomised, double-blind, placebo-controlled study 20 patients with chronic pain of several years duration were given 100 mg of oral dextromethorphan or matching placebo 4 h prior to an intravenous infusion of morphine 15 mg. Pain intensity and adverse effects were assessed at 0, 4, 5 and 7 h. Dextromethorphan had no effect on morphine analgesia: the mean (+/-SEM) visual analogue scores for pain relief (VAS, 0-100 mm) at the end of the morphine infusion were 38 (+/-6) for dextromethorphan+morphine and 38 (+/-7) for placebo+morphine. VAS scores for pain intensity were comparable both at rest and at movement at all time points. The most common adverse effects reported were dizziness, nausea and sedation. There were no significant differences in either the incidence or severity of adverse effects. In conclusion, oral dextromethorphan 100 mg had no effect on pain relief by intravenous morphine 15 mg in patients with chronic pain. PMID:11972998

  5. Morphine has latent deleterious effects on the ventilatory responses to a hypoxic challenge.

    PubMed

    May, Walter J; Gruber, Ryan B; Discala, Joseph F; Puskovic, Veljko; Henderson, Fraser; Palmer, Lisa A; Lewis, Stephen J

    2013-11-01

    The aim of this study was to determine whether morphine depresses the ventilatory responses elicited by a hypoxic challenge (10% O2, 90% N2) in conscious rats at a time when the effects of morphine on arterial blood gas (ABG) chemistry, Alveolar-arterial (A-a) gradient and minute ventilation (VM) had completely subsided. In vehicle-treated rats, each episode of hypoxia stimulated ventilatory function and the responses generally subsided during each normoxic period. Morphine (5 mg/kg, i.v.) induced an array of depressant effects on ABG chemistry, A-a gradient and VM (via decreases in tidal volume). Despite resolution of these morphine-induced effects, the first episode of hypoxia elicited substantially smaller increases in VM than in vehicle-treated rats, due mainly to smaller increases in frequency of breathing. The pattern of ventilatory responses during subsequent episodes of hypoxia and normoxia changed substantially in morphine-treated rats. It is evident that morphine has latent deleterious effects on ventilatory responses elicited by hypoxic challenge. PMID:25045593

  6. Effects of morphine sulphate on pituitary-testicular morphology of rats.

    PubMed

    James, R W; Heywood, R; Crook, D

    1980-11-01

    Morphine sulphate was administered, buy s.c. injection, to male rats at 50 mg/kg/day for up to 9 weeks. Control rats were given s.c. injections of sterile water. Serum luteinising hormone (LH) and testosterone concentrations and the weight and morphology of testes, pituitary glands and secondary sex organs were examined after 4 and 9 weeks' morphine treatment and also 13 weeks after dosing stopped. Treatment with morphine decreased serum LH and testosterone concentrations and reduced secondary sex organ weights. Differential staining techniques revealed modified secretory activity of pituitary gonadotrophic cells. All stages of spermatogenesis were found in testicular sections, but quantitative reductions in spermatogenic cell populations were found among morphine-treated rats. All the observed effects were reversed within 13 weeks of drug withdrawal. These findings are discussed in relation to existing knowledge of the hormonal control of spermatogenesis in rats.

  7. Effects of daily morphine administration and deprivation on choice and demand for remifentanil and cocaine in rhesus monkeys.

    PubMed

    Wade-Galuska, Tammy; Galuska, Chad M; Winger, Gail

    2011-01-01

    Choice procedures have indicated that the relative reinforcing effectiveness of opioid drugs increases during opioid withdrawal. The demand curve, an absolute measure of reinforcer value, has not been applied to this question. The present study assessed whether mild morphine withdrawal would increase demand for or choice of remifentanil or cocaine. Four rhesus monkeys chose between remifentanil and cocaine during daily sessions. Demand curves for both drugs were subsequently obtained. The effects of daily injections of 3.2 mg/kg morphine on both choice and demand for these drugs was assayed 3 and 20.5 hr after each morphine injection, and then during a postmorphine period. Three hours following morphine injections, choice of remifentanil over cocaine decreased and demand for remifentanil--but not cocaine--became more elastic. During morphine withdrawal (20.5 hr postinjection), choice of remifentanil increased and remifentanil demand became more inelastic in 3 of 4 monkeys. Cocaine demand also became more inelastic during this period. Four to five weeks following the morphine regimen, demand for both drugs was more inelastic relative to the initial determination. The results suggest that both the relative and absolute reinforcing effectiveness of remifentanil decreased following morphine administration and increased during morphine withdrawal. The absolute reinforcing effectiveness of cocaine also increased during morphine withdrawal. In addition, extended exposure to drug self-administration and/or exposure to the morphine regimen produced long-term increases in demand for both drugs. PMID:21541117

  8. Effects of Electroacupuncture Treatment on Bone Cancer Pain Model with Morphine Tolerance

    PubMed Central

    Fan, Bifa; Yan, Longtao; Shui, Yuan

    2016-01-01

    Objective. To explore the efficacy of electroacupuncture treatment in cancer induced bone pain (CIBP) rat model with morphine tolerance and explore changes of calcitonin-gene related peptide (CGRP) expression in dorsal root ganglion (DRG). Methods. Forty SD rats were divided into five groups: sham, CIBP (B), CIBP + morphine (BM), CIBP + electroacupuncture (BE), and CIBP + morphine + electroacupuncture (BME). B, BM, BE, and BME groups were prepared CIBP model. The latter three groups then accepted morphine, electroacupuncture, and morphine combined electroacupuncture, separately, nine days consecutively (M1 to M9). Mechanical withdraw threshold (MWT) was evaluated. Results. BE group only had differences in M1, M2, and M3 compared to B group (P < 0.01). From M5, BM group showed significantly decreased MWT. Electroacupuncture could obtain analgesic effects only at early stage (M1 to M5). From M5 to M9, BME had the differences with BM group (P < 0.01). IOD value of CGRP in BM and BME was substantially less than in B group. CGRP in BME was significantly lower than that in BM group (P < 0.01). Conclusion. When used in combination with electroacupuncture, morphine could result in improving analgesic effects and reducing tolerance. CGRP may be associated with pain behaviors. PMID:27672401

  9. 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

  10. Effects of Electroacupuncture Treatment on Bone Cancer Pain Model with Morphine Tolerance

    PubMed Central

    Fan, Bifa; Yan, Longtao; Shui, Yuan

    2016-01-01

    Objective. To explore the efficacy of electroacupuncture treatment in cancer induced bone pain (CIBP) rat model with morphine tolerance and explore changes of calcitonin-gene related peptide (CGRP) expression in dorsal root ganglion (DRG). Methods. Forty SD rats were divided into five groups: sham, CIBP (B), CIBP + morphine (BM), CIBP + electroacupuncture (BE), and CIBP + morphine + electroacupuncture (BME). B, BM, BE, and BME groups were prepared CIBP model. The latter three groups then accepted morphine, electroacupuncture, and morphine combined electroacupuncture, separately, nine days consecutively (M1 to M9). Mechanical withdraw threshold (MWT) was evaluated. Results. BE group only had differences in M1, M2, and M3 compared to B group (P < 0.01). From M5, BM group showed significantly decreased MWT. Electroacupuncture could obtain analgesic effects only at early stage (M1 to M5). From M5 to M9, BME had the differences with BM group (P < 0.01). IOD value of CGRP in BM and BME was substantially less than in B group. CGRP in BME was significantly lower than that in BM group (P < 0.01). Conclusion. When used in combination with electroacupuncture, morphine could result in improving analgesic effects and reducing tolerance. CGRP may be associated with pain behaviors.

  11. Effects of Electroacupuncture Treatment on Bone Cancer Pain Model with Morphine Tolerance.

    PubMed

    Sima, Lei; Fan, Bifa; Yan, Longtao; Shui, Yuan

    2016-01-01

    Objective. To explore the efficacy of electroacupuncture treatment in cancer induced bone pain (CIBP) rat model with morphine tolerance and explore changes of calcitonin-gene related peptide (CGRP) expression in dorsal root ganglion (DRG). Methods. Forty SD rats were divided into five groups: sham, CIBP (B), CIBP + morphine (BM), CIBP + electroacupuncture (BE), and CIBP + morphine + electroacupuncture (BME). B, BM, BE, and BME groups were prepared CIBP model. The latter three groups then accepted morphine, electroacupuncture, and morphine combined electroacupuncture, separately, nine days consecutively (M1 to M9). Mechanical withdraw threshold (MWT) was evaluated. Results. BE group only had differences in M1, M2, and M3 compared to B group (P < 0.01). From M5, BM group showed significantly decreased MWT. Electroacupuncture could obtain analgesic effects only at early stage (M1 to M5). From M5 to M9, BME had the differences with BM group (P < 0.01). IOD value of CGRP in BM and BME was substantially less than in B group. CGRP in BME was significantly lower than that in BM group (P < 0.01). Conclusion. When used in combination with electroacupuncture, morphine could result in improving analgesic effects and reducing tolerance. CGRP may be associated with pain behaviors. PMID:27672401

  12. Morphine Rectal

    MedlinePlus

    Rectal morphine is used to relieve moderate to severe pain. Morphine is in a class of medications called opiate ( ... Rectal morphine comes as a suppository to insert in the rectum. It is usually inserted every 4 hours. Use ...

  13. Morphine Injection

    MedlinePlus

    Morphine injection is used to relieve moderate to severe pain. Morphine is in a class of medications called opiate ( ... Morphine injection comes as a solution (liquid) to inject intramuscularly (into a muscle) or intravenously (into a ...

  14. Differential effects of acute morphine administrations on polymorphonuclear cell metabolism in various mouse strains.

    PubMed

    Di Francesco, P; Tavazzi, B; Gaziano, R; Lazzarino, G; Casalinuovo, I A; Di Pierro, D; Garaci, E

    1998-01-01

    This paper shows that an acute morphine treatment dose-dependently alters the energetic and oxidative metabolism of polymorphonuclear leukocytes obtained from BALB/c and DBA/2 mice, while phagocytic cells from C57BL/6 were not affected. In sensitive mouse strains, i.e. BALB/c and DBA/2, morphine decreased both ATP concentration and energy charge potential. At the same time, ATP catabolic products, i.e. nucleosides (inosine+adenosine) and oxypurines (hypoxanthine+xanthine+uric acid), significantly increased, indicating an imbalance between energy production and consumption. Morphine treatment also induced malondialdehyde and superoxide anions production in leukocyte cells from sensitive mice. The opiate antagonist naloxone blocked morphine-induced modifications by the lower morphine dose. The same parameters in cells from C57BL/6 mice were not affected. These findings confirm that: i) the phagocytic cells are an important target for the in vivo effects of morphine, and ii) the genotype-dependent variation influences the immunological responsiveness to opiates.

  15. The on- and off-target effects of morphine in acute coronary syndrome: A narrative review.

    PubMed

    McCarthy, Cian P; Mullins, Kieran V; Sidhu, Sunjeet S; Schulman, Steven P; McEvoy, John W

    2016-06-01

    With potent analgesic properties, perceived hemodynamic benefits and limited alternatives, morphine is the analgesic mainstay for patients with nitrate resistant chest pain due to acute Myocardial Infarction (MI). However, observational data suggest that morphine administration during MI may have negative consequences. While vomiting, hypotension and respiratory depression are established side effects, recent reports have demonstrated attenuated and delayed oral anti-platelet agent absorption, as well as suboptimal reperfusion after MI, all of which may translate into adverse cardiovascular outcomes. These data have resulted in reduced support for morphine in recent European and U.S. clinical practice guidelines for MI; despite the absence of any prospective randomized outcomes trials addressing this question. As such, randomized trials are now necessary to confirm whether or not morphine, which is administered in up to 30% of MI cases, causes adverse clinical outcomes in these patients. However, given that placebo-controlled randomized trial designs evaluating morphine in MI are limited by an ethical requirement for appropriate analgesia, alternative investigational approaches may be necessary. In this article we review the updated evidence for morphine in MI and outline novel strategies that may facilitate future investigation of this clinical dilemma. PMID:27264228

  16. 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.

  17. Morphine Produces Immunosuppressive Effects in Nonhuman Primates at the Proteomic and Cellular Levels*

    PubMed Central

    Brown, Joseph N.; Ortiz, Gabriel M.; Angel, Thomas E.; Jacobs, Jon M.; Gritsenko, Marina; Chan, Eric Y.; Purdy, David E.; Murnane, Robert D.; Larsen, Kay; Palermo, Robert E.; Shukla, Anil K.; Clauss, Theresa R.; Katze, Michael G.; McCune, Joseph M.; Smith, Richard D.

    2012-01-01

    Morphine has long been known to have immunosuppressive properties in vivo, but the molecular and immunologic changes induced by it are incompletely understood. To explore how these changes interact with lentiviral infections in vivo, animals from two nonhuman primate species (African green monkeys and pigtailed macaques) were provided morphine and studied using a systems biology approach. Biological specimens were obtained from multiple sources (e.g. lymph node, colon, cerebrospinal fluid, and peripheral blood) before and after the administration of morphine (titrated up to a maximum dose of 5 mg/kg over a period of 20 days). Cellular immune, plasma cytokine, and proteome changes were measured and morphine-induced changes in these parameters were assessed on an interorgan, interindividual, and interspecies basis. In both species, morphine was associated with decreased levels of Ki-67+ T-cell activation but with only minimal changes in overall T-cell counts, neutrophil counts, and NK cell counts. Although changes in T-cell maturation were observed, these varied across the various tissue/fluid compartments studied. Proteomic analysis revealed a morphine-induced suppressive effect in lymph nodes, with decreased abundance of protein mediators involved in the functional categories of energy metabolism, signaling, and maintenance of cell structure. These findings have direct relevance for understanding the impact of heroin addiction and the opioids used to treat addiction as well as on the potential interplay between opioid abuse and the immunological response to an infective agent. PMID:22580588

  18. Naloxone does not reverse the inhibitory effect of morphine on luteinizing hormone secretion in prepubescent male rats.

    PubMed

    Cicero, T J; Nock, B; O'Connor, L

    1993-01-01

    Morphine and naloxone exert age-dependent effects on secretion of luteinizing hormone (LH) in the male rat. Morphine suppresses LH secretion at very early stages of development, well before puberty, whereas naloxone does not increase LH until after puberty. The mechanisms underlying these age-dependent effects of opiates on the hypothalamic-pituitary-gonadal axis in pre- and postpubertal rats are poorly understood at the present time. The purpose of the present studies was to examine one plausible explanation of these effects: that morphine and naloxone act through different receptors in the pubescent male rat than they do in adults to influence LH secretion. Specifically, we examined whether naloxone blocks the effects of morphine on LH in prepubescent and adult rats which would be anticipated if both drugs were exerting their effects on LH via the same opiate receptor. Surprisingly, we found that naloxone did not reverse the effects of morphine on serum LH levels in the prepubescent animal, although it fully reversed this effect in adults. This non-naloxone-reversible effect of morphine appeared to be specific to LH, since naloxone antagonized morphine's effects on several other hormones (e.g., prolactin and corticosterone) and completely attenuated morphine's antinociceptive activity in prepubescent rats. Additionally, naloxone precipitated a withdrawal syndrome in the prepubescent morphine-dependent animal that was quantitatively and qualitatively the same as in adults.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Different effects of L-arginine on morphine tolerance in sham and ovariectomized female mice*

    PubMed Central

    Karami, Reza; Hosseini, Mahmoud; Khodabandehloo, Fatimeh; Khatami, Leila; Taiarani, Zahra

    2011-01-01

    Objective: The roles of gonadal hormones and nitric oxide (NO) on the analgesic effects of morphine, tolerance to morphine, and their interactions have been widely investigated. In the present study, the effect of L-arginine (an NO precursor) on morphine tolerance in sham and ovariectomized (OVX) female mice was investigated. Methods: Forty mice were divided into sham and OVX groups. On the first day, a hot plate test ((55±0.2) °C; cut-off 30 s) was carried out as a base record 15 min before injection of morphine (10 mg/kg, subcutaneously (s.c.)) and was repeated every 15 min after injection. The sham group was then divided into two subgroups: sham-tolerance-L-arginine (Sham-Tol-LA) and sham-tolerance-saline (Sham-Tol-Sal) which received either L-arginine 50 mg/kg (intraperitoneally (i.p.)) or saline 10 ml/kg (i.p.), respectively, three times in a day for three consecutive days. Morphine tolerance was induced in animals by injecting 30 mg/kg morphine (s.c.) three times/day for three days. This treatment was also used for OVX subgroups. On the fifth day, the hot plate test was repeated. The analgesic effect of morphine was calculated as the maximal percent effect (MPE). The results were compared using repeated measure analysis of variance (ANOVA). Results: There was no significant difference in MPE between the OVX and sham groups. The MPEs in both the Sham-Tol-Sal and OVX-Tol-Sal groups were lower than those in both the sham and OVX groups (P<0.01). The MPE in the OVX-Tol-Sal group was greater than that in the Sham-Tol-Sal group (P<0.01). The MPE in the Sham-Tol-LA group was higher than that in the Sham-Tol-Sal group (P<0.01). However, there was no significant difference between the Sham-Tol-LA and sham groups or between the OVX-Tol-LA and OVX-Tol-Sal groups. Conclusions: The results of the present study showed that repeated administration of morphine causes tolerance to the analgesic effect of morphine. L-Arginine could prevent tolerance to morphine but its

  20. Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice.

    PubMed

    Kim, Woojin; Kim, Min Joon; Go, Donghyun; Min, Byung-Il; Na, Heung Sik; Kim, Sun Kwang

    2016-01-22

    Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA) has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat different types of pain. Here, we investigated whether treatment with a combination of these two agents has an additive effect on oxaliplatin-induced neuropathic pain in mice. To assess cold and mechanical allodynia, acetone and von Frey filament tests were used, respectively. Significant allodynia signs were observed three days after an oxaliplatin injection (6 mg/kg, i.p.). BVA (0.25, 1, and 2.5 mg/kg, s.c., ST36) or morphine (0.5, 2, and 5 mg/kg, i.p.) alone showed dose-dependent anti-allodynic effects. The combination of BVA and morphine at intermediate doses showed a greater and longer effect than either BVA or morphine alone at the highest dose. Intrathecal pretreatment with the opioidergic (naloxone, 20 μg) or 5-HT3 (MDL-72222, 15 μg) receptor antagonist, but not with α2 adrenergic (idazoxan, 10 μg) receptor antagonist, blocked this additive effect. Therefore, we suggest that the combination effect of BVA and morphine is mediated by spinal opioidergic and 5-HT3 receptors and this combination has a robust and enduring analgesic action against oxaliplatin-induced neuropathic pain.

  1. Repeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine, and cocaine.

    PubMed

    Lett, B T

    1989-01-01

    It is commonly believed that repeated exposures diminish the pleasurable effects of drugs and hence that pleasure must have only a minor role in addiction. In six experiments with rats, repeated exposures to amphetamine, morphine, or cocaine were found to enhance the drug-induced rewarding effect as measured by conditioned place preference. Thus, sensitization to the rewarding effect, rather than tolerance, was obtained. Also, cross-sensitization was obtained; exposures to amphetamine enhanced the rewarding effect of morphine and vice versa; similarly, exposures to morphine enhanced the rewarding effect of cocaine. These findings support a new theory: drugs of abuse are addictive because repeated exposures sensitize the central reward mechanism so that drug taking produces a progressively greater reinforcing effect each time it occurs.

  2. Effect of Genistein on reproductive parameter and serum nitric oxide levels in morphine-treated mice

    PubMed Central

    Jalili, Cyrus; Ahmadi, Sharareh; Roshankhah, Shiva; Salahshoor, MohammadReza

    2016-01-01

    Background: The predominant phytoestrogen in soy and derived products is the isoflavone Genistein. Genistein has antioxidant properties. Morphine is a main psychoactive chemical in opium that can increase the generation of free radicals and therefore it could adversely affects the spermatogenesis. Objective: The main goal was to investigate whether the Genistein could protect morphine adverse effects on sperm cells viability, count, motility, and testis histology and testosterone hormone and nitric oxide in blood serum. Materials and Methods: In this study, various doses of Genistein (0, 1, 2, and 3 mg/kg) and Genistein plus morphine (0, 1, 2, and 3 mg/kg) were administered interaperitoneally to 48 male mice for 30 consequent days. These mice were randomly assigned to 8 groups (n=6) and sperm parameters (sperm cells viability, count, motility and morphology), testis weight and histology, testosterone hormone (ELISA method), FSH and LH hormones (immunoradiometry) and serum nitric oxide (griess assay) were analyzed and compared. Results: The results indicated that morphine administration significantly decreased testosterone (0.03 ng/mg) LH and FSH level, histological parameters, count, viability (55.3%), morphology and motility of sperm cells (1%), testis weight (0.08 gr) and increase nitric oxide compared to saline group (p=0.00). However, administration of Genistein and Genistein plus morphine significantly boosted motility, morphology, count, viability of sperm cells, seminiferous tubules diameter, germinal thickness, testosterone, LH and FSH while decrease nitric oxide level in all groups compared to morphine group (p<0.025). Conclusion: It seems that Genistein administration could increase the quality of spermatozoa and prevent morphine- induced adverse effects on sperm parameters. PMID:27200423

  3. Effect of the co-administration of glucose with morphine on glucoregulatory hormones and causing of diabetes mellitus in rats

    PubMed Central

    Radahmadi, Maryam; Sharifi, Mohammad Reza; Amini, Masoud; Fesharaki, Mehrafarin

    2016-01-01

    Background: Morphine is related to dysregulation of serum hormone levels. In addition, addict subjects interest to sugar intake. Therefore, this study investigated the effect of co-administration of glucose with Mo on the glucoregulatory hormones and causing of diabetes mellitus in rats. Materials and Methods: Male rats were randomly divided into four groups including, control, morphine, Morphine-Glucose and diabetes groups. Morphine was undergone through doses of 10, 20, 30, 40, 50, and 60 mg/kg, respectively on days 1, 2, 3, 4, 5, and 6. Then, dose of 60 mg/kg was used repeated for 20 extra days. The Morphine-Glucose group received the same doses of morphine plus 1 g/kg glucose per day. Diabetes was induced by intraperitoneal injection of 65 mg/kg streptozotocin. At the end of experiment, the serum insulin, glucagon, growth hormone (GH), cortisol, and glucose levels were measured. The homeostasis model assessment (HOMA) indexes concluding the HOMA-insulin resistance (HOMA-IR) and HOMA-β were evaluated. Results: Morphine insignificantly induced a hyperglycemia condition and insulin resistance. Whereas, the beta-cell functions significantly (P < 0.05) decreased only in morphine group. The co-administration of glucose slightly increased the GH, and increased insulin and cortisol levels significantly (P < 0.05 and P < 0.01; respectively) in the Morphine-Glucose group. Furthermore, the co-administration of glucose with morphine could nearly modulate the morphine effects on body weight, glucose, and glucagon levels. Conclusion: It is probable that the co-administration of glucose with morphine modulate the serum glucose levels by stimulating the beta-cell functions and to increase insulin secretion. PMID:26962523

  4. Cholecystokinin receptor-1 mediates the inhibitory effects of exogenous cholecystokinin octapeptide on cellular morphine dependence

    PubMed Central

    2012-01-01

    Background Cholecystokinin octapeptide (CCK-8), the most potent endogenous anti-opioid peptide, has been shown to regulate the processes of morphine dependence. In our previous study, we found that exogenous CCK-8 attenuated naloxone induced withdrawal symptoms. To investigate the precise effect of exogenous CCK-8 and the role of cholecystokinin (CCK) 1 and/or 2 receptors in morphine dependence, a SH-SY5Y cell model was employed, in which the μ-opioid receptor, CCK1/2 receptors, and endogenous CCK are co-expressed. Results Forty-eight hours after treating SH-SY5Y cells with morphine (10 μM), naloxone (10 μM) induced a cAMP overshoot, indicating that cellular morphine dependence had been induced. The CCK receptor and endogenous CCK were up-regulated after chronic morphine exposure. The CCK2 receptor antagonist (LY-288,513) at 1–10 μM inhibited the naloxone-precipitated cAMP overshoot, but the CCK1 receptor antagonist (L-364,718) did not. Interestingly, CCK-8 (0.1-1 μM), a strong CCK receptor agonist, dose-dependently inhibited the naloxone-precipitated cAMP overshoot in SH-SY5Y cells when co-pretreated with morphine. The L-364,718 significantly blocked the inhibitory effect of exogenous CCK-8 on the cAMP overshoot at 1–10 μM, while the LY-288,513 did not. Therefore, the CCK2 receptor appears to be necessary for low concentrations of endogenous CCK to potentiate morphine dependence in SH-SY5Y cells. An additional inhibitory effect of CCK-8 at higher concentrations appears to involve the CCK1 receptor. Conclusions This study reveals the difference between exogenous CCK-8 and endogenous CCK effects on the development of morphine dependence, and provides the first evidence for the participation of the CCK1 receptor in the inhibitory effects of exogenous CCK-8 on morphine dependence. PMID:22682150

  5. Long-term behavioral effects in a rat model of prolonged postnatal morphine exposure.

    PubMed

    Craig, Michael M; Bajic, Dusica

    2015-10-01

    Prolonged morphine treatment in neonatal pediatric populations is associated with a high incidence of opioid tolerance and dependence. Despite the clinical relevance of this problem, our knowledge of long-term consequences is sparse. The main objective of this study was to investigate whether prolonged morphine administration in a neonatal rat is associated with long-term behavioral changes in adulthood. Newborn animals received either morphine (10 mg/kg) or equal volume of saline subcutaneously twice daily for the first 2 weeks of life. Morphine-treated animals underwent 10 days of morphine weaning to reduce the potential for observable physical signs of withdrawal. Animals were subjected to nonstressful testing (locomotor activity recording and a novel-object recognition test) at a young age (Postnatal Days [PDs] 27-31) or later in adulthood (PDs 55-56), as well as stressful testing (calibrated forceps test, hot plate test, and forced swim test) only in adulthood. Analysis revealed that prolonged neonatal morphine exposure resulted in decreased thermal but not mechanical threshold. Importantly, no differences were found for total locomotor activity (proxy of drug reward/reinforcement behavior), individual forced swim test behaviors (proxy of affective processing), or novel-object recognition test. Performance on the novel-object recognition test was compromised in the morphine-treated group at the young age, but the effect disappeared in adulthood. These novel results provide insight into the long-term consequences of opioid treatment during an early developmental period and suggest long-term neuroplastic differences in sensory processing related to thermal stimuli.

  6. LONG-TERM BEHAVIORAL EFFECTS IN A RAT MODEL OF PROLONGED POSTNATAL MORPHINE EXPOSURE

    PubMed Central

    Craig, Michael M.; Bajic, Dusica

    2015-01-01

    Prolonged morphine treatment in neonatal pediatric populations is associated with a high incidence of opioid tolerance and dependence. Despite the clinical relevance of this problem, our knowledge of the long-term consequences is sparse. The main objective of this study was to investigate whether prolonged morphine administration in a neonatal rat is associated with long-term behavioral changes in adulthood. Newborn animals received either morphine (10mg/kg) or equal volume of saline subcutaneously twice daily for the first 2 weeks of life. Morphine treated animals underwent 10 days of morphine weaning to reduce the potential for observable physical signs of withdrawal. Animals were subjected to non-stressful testing (locomotor activity recording and a Novel-Object Recognition test) at a young age (PD27-31) or later in adulthood (PD55-56), as well as stressful testing (calibrated forceps test, Hot Plate test, and Forced Swim test) only in adulthood. Analysis revealed that prolonged neonatal morphine exposure resulted in decreased thermal, but not mechanical threshold. Importantly, no differences were found for total locomotor activity (proxy of drug reward/reinforcement behavior), individual Forced Swim test behaviors (proxy of affective processing), or Novel-Object Recognition test. Performance on the Novel-Object Recognition test was compromised in the morphine treated group at the young age, however the effect disappeared in adulthood. These novel results provide insight into the long-term consequences of opioid treatment during an early developmental period and suggest long-term neuroplastic differences in sensory processing related to thermal stimuli. PMID:26214209

  7. Differential effects of endocannabinoid catabolic inhibitors on morphine withdrawal in mice

    PubMed Central

    Gamage, Thomas F.; Ignatowska-Jankowska, Bogna M.; Muldoon, Pretal P.; Cravatt, Benjamin F.; Damaj, M. Imad; Lichtman, Aron H.

    2014-01-01

    Background Inhibition of endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and/or monoacylglycerol lipase (MAGL) reduces somatic morphine withdrawal signs, but its effects on aversive aspects of withdrawal are unknown. The present study investigated whether Δ9-tetrahydrocannabinol (THC), the MAGL inhibitor JZL184, the FAAH inhibitor PF-3845, or the dual FAAH/MAGL inhibitor SA-57 would reduce acquisition of morphine withdrawal-induced conditioned place avoidance (CPA) and jumping. Methods Mice were implanted with placebo or 75 mg morphine pellets, 48 h later injected with naloxone or saline and placed in the conditioning apparatus, and assessed for CPA at 72 h. Subjects were also observed for jumping behavior following naloxone challenge. Results Naloxone (0.056 mg/kg) produced robust CPA in morphine-pelleted, but not placebo-pelleted, mice. Morphine pretreatment prevented the occurrence of withdrawal CPA and withdrawal jumping, while clonidine (an α2 adrenergic receptor agonist) only blocked withdrawal CPA. THC, JZL184, and SA-57 significantly reduced the percentage of mice that jumped during the conditioning session, but did not affect acquisition of withdrawal CPA. PF-3845 did not reduce morphine withdrawal CPA or jumping. Finally, neither THC nor the endocannabinoid catabolic enzyme inhibitors in non-dependent mice elicited a conditioned place preference or aversion. Conclusions These findings suggest that inhibiting endocannabinoid catabolic enzymes reduces somatic morphine withdrawal signs, but not aversive aspects as inferred in the CPA paradigm. The observation that non-dependent mice administered inhibitors of endocannabinoid degradation did not display place preferences is consistent with the idea that that endocannabinoid catabolic enzymes might be targeted therapeutically, with reduced risk of abuse. PMID:25479915

  8. Buprenorphine, methadone, and morphine treatment during pregnancy: behavioral effects on the offspring in rats.

    PubMed

    Chen, Hwei-Hsien; Chiang, Yao-Chang; Yuan, Zung Fan; Kuo, Chung-Chih; Lai, Mei-Dan; Hung, Tsai-Wei; Ho, Ing-Kang; Chen, Shao-Tsu

    2015-01-01

    Methadone and buprenorphine are widely used for treating people with opioid dependence, including pregnant women. Prenatal exposure to opioids has devastating effects on the development of human fetuses and may induce long-term physical and neurobehavioral changes during postnatal maturation. This study aimed at comparing the behavioral outcomes of young rats prenatally exposed to buprenorphine, methadone, and morphine. Pregnant Sprague-Dawley rats were administered saline, morphine, methadone, and buprenorphine during embryonic days 3-20. The cognitive function, social interaction, anxiety-like behaviors, and locomotor activity of offsprings were examined by novel object recognition test, social interaction test, light-dark transition test, elevated plus-maze, and open-field test between 6 weeks and 10 weeks of age. Prenatal exposure to methadone and buprenorphine did not affect locomotor activity, but significantly impaired novel object recognition and social interaction in both male and female offsprings in the same manner as morphine. Although prenatal exposure to methadone or buprenorphine increased anxiety-like behaviors in the light-dark transition in both male and female offsprings, the effects were less pronounced as compared to that of morphine. Methadone affected elevated plus-maze in both sex, but buprenorphine only affected the female offsprings. These findings suggest that buprenorphine and methadone maintenance therapy for pregnant women, like morphine, produced detrimental effects on cognitive function and social behaviors, whereas the offsprings of such women might have a lower risk of developing anxiety disorders.

  9. Buprenorphine, methadone, and morphine treatment during pregnancy: behavioral effects on the offspring in rats

    PubMed Central

    Chen, Hwei-Hsien; Chiang, Yao-Chang; Yuan, Zung Fan; Kuo, Chung-Chih; Lai, Mei-Dan; Hung, Tsai-Wei; Ho, Ing-kang; Chen, Shao-Tsu

    2015-01-01

    Methadone and buprenorphine are widely used for treating people with opioid dependence, including pregnant women. Prenatal exposure to opioids has devastating effects on the development of human fetuses and may induce long-term physical and neurobehavioral changes during postnatal maturation. This study aimed at comparing the behavioral outcomes of young rats prenatally exposed to buprenorphine, methadone, and morphine. Pregnant Sprague-Dawley rats were administered saline, morphine, methadone, and buprenorphine during embryonic days 3–20. The cognitive function, social interaction, anxiety-like behaviors, and locomotor activity of offsprings were examined by novel object recognition test, social interaction test, light–dark transition test, elevated plus-maze, and open-field test between 6 weeks and 10 weeks of age. Prenatal exposure to methadone and buprenorphine did not affect locomotor activity, but significantly impaired novel object recognition and social interaction in both male and female offsprings in the same manner as morphine. Although prenatal exposure to methadone or buprenorphine increased anxiety-like behaviors in the light–dark transition in both male and female offsprings, the effects were less pronounced as compared to that of morphine. Methadone affected elevated plus-maze in both sex, but buprenorphine only affected the female offsprings. These findings suggest that buprenorphine and methadone maintenance therapy for pregnant women, like morphine, produced detrimental effects on cognitive function and social behaviors, whereas the offsprings of such women might have a lower risk of developing anxiety disorders. PMID:25834439

  10. Effects of Intrathecal κ-Opioid Receptor Agonist on Morphine-Induced Itch and Antinociception in Mice.

    PubMed

    Sakakihara, Manabu; Imamachi, Noritaka; Saito, Yoji

    2016-01-01

    The μ-opioid receptor (MOR) agonist-induced itch is a significant issue associated with analgesic therapies. Research suggested that systemically administered κ-opioid receptor (KOR) agonists inhibit intrathecal morphine-induced itch in primates. However, serious adverse effects induced by systemically administered KOR agonists may restrict their usefulness in humans. We investigated the effects of intrathecal KOR agonists on intrathecal morphine-mediated itch and antinociception in mice.Mice received intrathecal injections of one of the following drugs: morphine (0.1-1.0 nmol), the selective KOR agonist TRK-820 100 pmol, the combination of morphine 0.3 nmol + TRK-820 (10-100 pmol), and 5 μL of saline. One hour after intraperitoneal administration of the selective KOR antagonist nor-binaltorphimine 1.0 μmol, the effect of TRK-820 100 pmol on intrathecal morphine 0.3 nmol-induced scratching was tested. Total numbers of scratches after intrathecal injection were analyzed. After observing scratching behavior, sedation level was evaluated subjectively. Nociceptive threshold was determined by tail immersion test with intrathecal injections of the following agents: morphine (0.1-1.0 nmol), TRK-820 (10-100 pmol), morphine 0.1 nmol + TRK-820 10 pmol, and 5 μL of saline.Intrathecal TRK-820 dose-dependently inhibited intrathecal morphine-induced scratching compared with that in the saline group. Intraperitoneal nor-binaltorphimine completely inhibited the antiscratching effect of intrathecal TRK-820 100 pmol. The combination of morphine 0.3 nmol and TRK-820 did not alter the sedation score compared with that in the morphine 0.3 nmol group. Morphine 0.1 nmol + TRK-820 10 pmol significantly produced greater thermal antinociceptive effects than morphine 0.1 nmol.We demonstrated that intrathecal KOR agonists exert antipruritic effects on intrathecal morphine-induced itch without affecting sedation. The combination of intrathecal morphine and intrathecal KOR agonists

  11. 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.

  12. Effect of nociceptin/orphanin FQ on the rewarding properties of morphine.

    PubMed

    Ciccocioppo, R; Angeletti, S; Sanna, P P; Weiss, F; Massi, M

    2000-09-15

    The present study investigated the effect of nociceptin/orphanin FQ, the endogenous ligand of the opioid receptor-like 1 (ORL1) receptor, on the rewarding properties of morphine in the place conditioning paradigm. Intracerebroventricular (i.c.v.) injections of nociceptin/orphanin FQ, 500 or 1000 (but not 250) ng/rat, abolished conditioned place preference induced by subcutaneous (s.c.) injections of morphine (3 mg/kg). These doses of nociceptin/orphanin FQ induced neither place aversion nor preference per se. The same doses did not modify the rat performance in the Morris water test, suggesting that they do not disrupt spatial learning and memory. Moreover, these doses of nociceptin/orphanin FQ did not modify the development of morphine-induced locomotor sensitization, suggesting that they do not interfere with sensitization processes to morphine. The present results confirm and extend previous reports that nociceptin/orphanin FQ is able to abolish morphine-induced conditioned place preference, and raise interest for the possible role of nociceptin/orphanin FQ and ORL1 receptors in the control of opiate abuse.

  13. Antinociceptive effects and toxicity of morphine-6-O-sulfate sodium salt in rat models of pain.

    PubMed

    Holtman, Joseph R; Crooks, Peter A; Johnson-Hardy, Jaime; Wala, Elzbieta P

    2010-12-01

    Mu-opioids (i.e. morphine, oxycodone, hydrocodone) are considered to be the primary drugs for treatment of moderate to severe acute, chronic and cancer pain. Despite their analgesic effectiveness they have several clinically significant side-effects (cognitive, motor, respiratory, cardiovascular, gastrointestinal). They also have a limited spectrum of action, being more effective for nociceptive than neuropathic pain. In an effort to identify other opioid analgesics with greater effectiveness in mixed pain states and with a better side-effect profile compared to the classical mu-opioid agonist, morphine, a relatively little-known morphine derivative, morphine-6-O-sulfate, was characterized using a range of well-established rodent pain models. The present data demonstrated that morphine-6-O-sulfate was efficacious after several routes of administration, including neuroaxial (intrathecal), parenteral (intraperitoneal) and oral in the rat. It showed potent, dose-related, analgesic activities against acute nociceptive pain (the tail flick test), neuropathic pain (chronic constriction nerve injury hyperalgesia and allodynia) and inflammatory pain (formalin test). It had a good separation based on dose (at least 10-fold) between side-effects (incoordination, hypolocomotion, inhibition of gastrointestinal motility) and analgesia in all models of pain tested. In addition, morphine-6-O-sulfate had a more favorable potency ratio for delay of gastrointestinal transit and analgesia when compared to morphine. These preclinical findings suggest that morphine-6-O-sulfate is a potential candidate for development as a novel opioid for management of nociceptive, neuropathic and mixed pain states.

  14. Effect of prenatal forced-swim stress and morphine co-administration on pentylentetrazol-induced epileptic behaviors in infant and prepubertal rats.

    PubMed

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

    2014-09-01

    Prenatal exposure to stress and morphine has complicated effects on epileptic seizure. Many reports have shown an interaction between morphine- and stress-induced behavioral changes in adult rats. In the present study, effect of prenatal forced-swim stress and morphine co-administration on pentylentetrazole (PTZ)-induced epileptic behaviors was investigated in rat offspring to address effect of the interaction between morphine and stress. Pregnant rats were divided to four groups of control-saline, control-morphine, stressed-saline and stressed-morphine. In the stressed group, the rats were placed in 25 °C water on 17-19 days of pregnancy. In the morphine/saline group, the rats received morphine/saline on the same days. In the morphine/saline-stressed group, they were exposed to stress and received morphine/saline simultaneously. On postnatal day 15 (P15), blood samples were collected to determine corticosterone (COS) level. On P15 and P25, PTZ was injected to the rest of pups to induce seizure. Then, epileptic behaviors of each rat were individually observed. Latency of tonic-colonic seizures decreased in control-morphine and stressed-saline groups while increasing in stressed-morphine rats compared to control-saline group on P15. Duration of tonic-colonic seizures significantly increased in control-morphine and stressed-saline rats compared to stressed-morphine and control-saline rats on P15, but not P25. COS levels increased in stressed-saline group but decreased in control-morphine group compared to control-saline rats. Body weight was significantly higher in morphine groups than saline treated rats. Prenatal exposure to forced-swim stress potentiated PTZ-induced seizure in the offspring rats. Co-administration of morphine attenuated effect of stress on body weight, COS levels, and epileptic behaviors.

  15. Effects of morphine glucuronides on the function of opioid receptors in human SK-N-SH cells.

    PubMed

    Baker, L; Dye, A; Ratka, A

    2000-03-01

    Morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are active metabolites of morphine. The effects of M3G and M6G on the opioid receptor transduction system has not yet been fully elucidated. Formation of cAMP after treatment with various doses of morphine, M3G, and M6G was studied. M6G and morphine, but not M3G, showed a dose dependent inhibition of cAMP accumulation. Naloxone blocked the inhibitory effect of M6G, M3G, and morphine. Pretreatment with M3G did not change the effects of morphine and M6G. The G-protein inhibitor PTX, prevented morphine, M3G, and M6G effects on cAMP. M3G and M6G vary in their ability to interact with the opioid receptor effector system. Inhibition of cAMP evoked by activation of opioid receptors and inhibitory G-proteins may play a role in the actions of M6G and M3G.

  16. The Effects of Morphine on the Production and Discrimination of Interresponse Times

    ERIC Educational Resources Information Center

    Odum, Amy L.; Ward, Ryan D.

    2004-01-01

    Recent experiments suggest that the effects of drugs of abuse on the discrimination of the passage of time may differ for experimenter-imposed and subject-produced events. The current experiment examined this suggestion by determining the effects of morphine on the discrimination of interresponse times (IRTs). Pigeons pecked a center key on a…

  17. Effect of cyanocobalamin (vitamin B12) in the induction and expression of morphine tolerance and dependence in mice.

    PubMed

    Ghazanfari, S; Imenshahidi, M; Etemad, L; Moshiri, M; Hosseinzadeh, H

    2014-03-01

    The antinociceptive effect of cyanocobalamin (Vit B12) has been reported in animal models and human studies. Our previous study showed the effect of Vit B12 on morphine tolerance. The dependence and tolerance were induced in male mice using subcutaneous morphine injections, 3 times a day (50, 50 and 75 mg/kg/day) for 3 days. Mice also received Vit B12 (100, 250 and 500 µg/kg), clonidine, memantine and saline intraperitoneally before morphine administration. On fourth day mice received only 7 mg /kg morphine just before tail-flick test. To determine the expression of morphine dependence and tolerance, all compounds were injected once intraperitoneally on the day of experiment. The tolerance was evaluated by the tail-flick test. The effect of Vit B12 and other agents on dependence were evaluated by counting the number of jumps (induced by naloxone 5 mg/kg). Co-administration of Vit B12 (100-500 µg/kg) and morphine in 3 days reduced the development of tolerance to morphine analgesic effect (8.2±0.5 and 7.83±0.5 s. vs. normal saline, 3.57±0.3 s). Repeated administration of Vit B12, also, diminished the reduced naloxane withdrawal signs of naloxone withdrawal test (100-500 µg/kg: 5±1.9 and 1.2±0.8 jumps vs. normal saline 72.6±12.2). However, Vit B12 had no effect on the expression of morphine tolerance and physical dependence. It is concluded that co-administration of Vit B12 and morphine could reduce tolerance to analgesic effect of morphine chronic administration and also reduce its withdrawal symptoms. PMID:24105105

  18. Underlying mechanism of combined effect of methamphetamine and morphine on lethality in mice and therapeutic potential of cooling.

    PubMed

    Namiki, Mizuho; Mori, Tomohisa; Sawaguchi, Toshiko; Ito, Shinobu; Suzuki, Tadashi

    2005-10-01

    An increase in polydrug abuse is a major problem worldwide. A previous study showed that coadministration of methamphetamine and morphine induced lethality in rodents and humans. However, the underlying mechanisms by which the lethality is increased by the coadministration of methamphetamine and morphine have not been fully understood. Therefore, the present study was designed to determine the mechanism of increased lethality induced by methamphetamine and morphine. Coadministered methamphetamine and morphine increased the lethality by more than 70% in BALB/c mice. Pretreatment with NMDA-receptor antagonists, such as MK-801 and 3-((R)-2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP), and benzamide [poly(ADP-ribose) polymerase (PARP) inhibitor] significantly attenuated the increased lethality induced by methamphetamine and morphine. Furthermore, the lethal effect induced by methamphetamine and morphine was completely attenuated by immediate cooling after the coadministration of methamphetamine and morphine. It has been reported that methamphetamine-induced neurotoxicity can be blocked by lowering the temperature, and this effect might be mediated by a reduction of release of free radicals. These results suggest that activation of NMDA receptors and PARP play an important role in the increased lethality induced by methamphetamine and morphine.

  19. Morphine Produces Immunosuppressive Effects in Non-human Primates at the Proteomic and Cellular Levels

    SciTech Connect

    Brown, Joseph N.; Ortiz, Gabriel M.; Angel, Thomas E.; Jacobs, Jon M.; Gritsenko, Marina A.; Chan, Eric Y.; Purdy, David E.; Murnane, Robert D.; Larsen, Kay; Palermo, Robert E.; Shukla, Anil K.; Clauss, Therese RW; Katze, Michael G.; McCune, Joseph M.; Smith, Richard D.

    2012-05-11

    Morphine has long been known to have immunosuppressive properties in vivo, but the molecular and immunologic changes induced by it are incompletely understood. As a prelude to understanding how these changes might interact with lentiviral infection in vivo, animals from two non-human primate (NHP) species [African green monkey (AGMs) and pigtailed macaque (PTs)] were provided morphine and studied using a systems biology approach. Biological specimens were obtained from multiple sources (e.g., lymph node, colon, cerebrospinal fluid (CSF), and peripheral blood) before and after the administration of morphine (titrated up to a maximum dose of 5 mg/kg over a period of 20 days). Cellular immune, plasma cytokine, and proteome changes were measured and morphine-induced changes in these parameters were assessed on an inter-organ, inter-individual, and inter-species basis. In both species, morphine was associated with decreased levels of (Ki-67+) T cell activation but with only minimal changes in overall T cell counts, neutrophil counts, and NK cells counts. While changes in T cell maturation were observed, these varied across the various tissue/fluid compartments studied. Proteomic analysis revealed a morphine-induced suppressive effect in the lymph node, with decreased abundance of protein mediators involved in the functional categories of energy metabolism, signaling, and maintenance of cell structure. These findings have relevance for understanding the impact of heroin addiction and the opioids used to treat addiction as well as on the interplay between opioid abuse and the response to infection with agents such as the human immunodeficiency virus, type 1 (HIV).

  20. Involvement of PLC-beta3 in the effect of morphine on memory retrieval in passive avoidance task.

    PubMed

    Bianchi, E; Lehmann, D; Vivoli, E; Norcini, M; Ghelardini, C

    2010-06-01

    Phospholipase C (PLC) is one signalling effector enzyme whose activity is directly modulated by opioids. Several physiological studies have implicated PLC-linked pathways in in-vivo pain regulation and opioid tolerance. Co-administration of PLC-beta(2/3) activity blocker M119 with morphine resulted in a dramatic increase in morphine-induced amnesic effect in mice, proving a role for beta subunit of PLC enzyme in these processes. Administration of morphine to mice at amnesic dose increased PLC-beta(3) activity, with respect to basal value, in the membrane-soluble material from anterior cortex and hippocampal formation in brain areas. PLC-beta(3) appears to be simultaneously implicated in both analgesic and amnesic effects induced by administration of morphine to mice suggesting a commonality in the molecular mechanisms of morphine-induced analgesia and memory impairment.

  1. Attenuation of morphine antinociceptive tolerance by a CB1 receptor agonist and an NMDA receptor antagonist: interactive effects

    PubMed Central

    Fischer, Bradford D.; Ward, Sara J.; Henry, Fredrick E.; Dykstra, Linda A.

    2009-01-01

    CB1 cannabinoid (CB1) receptor agonists and N-Methyl-d-Aspartate (NMDA) receptor antagonists attenuate the development of morphine antinociceptive tolerance. The present study used dose-addition analysis to evaluate CB1/NMDA receptor interactions on this endpoint. Chronic morphine administration (5 days, 100 mg/kg, twice daily) resulted in a 2.8-fold rightward shift in the morphine dose-effect curve. Co-administration of either the CB1 receptor agonist CP-55940 (5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol; 0.32-1.0 mg/kg) or the NMDA receptor antagonist (−)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959; 1.0-3.2 mg/kg) with morphine dose-dependently attenuated morphine tolerance. The relative potency of each drug alone was quantified using a defined level of effect (one-quarter log shift in the morphine dose-effect curve), resulting in equieffective doses of 0.42 mg/kg and 1.1 mg/kg for CP-55940 and LY235959, respectively. Subsequent experiments assessed CP-55940/LY235959 interactions using a fixed-proportion design. Co-administration of CP-55940/LY235959 mixtures (1:1, 1:3.2, or 1:10 CP-55940/LY235959) with morphine dose-dependently attenuated morphine tolerance. Isobolographic and dose-addition analysis were used to statistically compare the experimentally determined potency for each mixture (zmix) with predicted additive potency (zadd). Mixtures of 1:1 and 1:3.2 CP-55940/LY235959 produced additive effects (zadd = zmix), while the mixture of 1:10 CP-55940/LY235959 produced a supra-additive effect (zadd > zmix). These results suggest that CP-55940 and LY235959 produce additive or supra-additive attenuation of morphine antinociceptive tolerance after repeated morphine administration, depending on their relative concentrations. PMID:19699755

  2. The impact of nalmefene on side effects due to intrathecal morphine at cesarean section.

    PubMed

    Pellegrini, J E; Bailey, S L; Graves, J; Paice, J A; Shott, S; Faut-Callahan, M

    2001-06-01

    Nalmefene is a long-acting opioid antagonist that provides long-term relief from side effects of intrathecal morphine sulfate. A randomized, double-blind, placebo-controlled study was conducted to determine whether prophylactic nalmefene could decrease side effects of intrathecal morphine given during cesarean section, without affecting analgesia. Sixty parturients were given 0.25 mg of intrathecal morphine, 12.5 micrograms of fentanyl, and 11.25 to 15 mg of bupivacaine. A dose of 0.25 microgram/kg of nalmefene or placebo was given by intravenous piggyback immediately after delivery of the neonate. Nausea, vomiting, pruritus, and level of sedation were assessed for a 24-hour period using a 4-point ordinal scoring system. Pain was assessed by using a 0- to 10-point verbal analogue scale. A 5-point analgesic satisfaction survey also was completed. Subjects who received nalmefene required supplemental analgesia at a median of 6.00 hours after intrathecal morphine, compared with 14.12 hours in the placebo group (P = .037). No differences were found between the groups in the incidence of pruritus, nausea and vomiting, level of sedation, or analgesic satisfaction. We concluded that nalmefene at a dose of 0.25 microgram/kg does not decrease the incidence of side effects but increases the need for supplemental analgesics.

  3. 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.

  4. Effects of sweetening agents on morphine-induced analgesia in mice by formalin test.

    PubMed

    Nikfar, S; Abdollahi, M; Etemad, F; Sharifzadeh, M

    1997-10-01

    1. There is evidence that sweet-tasting substances such as sucrose and saccharin can interact with endogenous opioid systems. Further evidence showed that feeding mice different concentrations of sucrose and saccharin alter the latency in the tail-flick test. 2. In the current study, the effects of a 12-day regimen of different sweetening agents [sucrose (32%), saccharin (0.08%) and aspartame (0.16%)] on morphine-induced analgesia with the formalin test were investigated. 3. Male albino mice (20-27 g) were used for the experiments. Animals were given 12 days to adapt to dietary conditions. Animals were first given saline or morphine subcutaneously (1.5, 3.0, 6.0, or 9.0 mg/kg) 30 min before the observation period. The recording of the early phase started immediately and lasted for 10 min. The recording of the late response started 20 min after formalin injection and lasted for 10 min. Statistical analysis was performed by using analysis of variance followed by Newman-Keuls test, and P < or = 0.05 was considered significant. 4. Sucrose and aspartame increased morphine analgesia in the early phase, but saccharin had no effect on the early phase. On the other hand, saccharin and sucrose decreased the effect of morphine in the late phase, but aspartame increased the effect of morphine-induced analgesia. 5. In conclusion, the present data provide further evidence for an important role for dietary variables in determining the effects of exogenous opioids on pain sensitivity.

  5. Effects of imidazoline I₂ receptor ligands on morphine- and tramadol-induced antinociception in rats.

    PubMed

    Thorn, David A; Zhang, Yanan; Peng, Bi-Wen; Winter, Jerrold C; Li, Jun-Xu

    2011-11-30

    Currently available analgesics cannot meet the increasing clinical needs and new analgesics with better therapeutic profiles are in great demand. The imidazoline I₂ receptor is an emerging drug target for analgesics. However, few studies have examined the effects of selective I₂ receptor ligands on the antinociceptive activity of opioids. This study examined the antinociceptive effects of the opioids morphine (0.1-10 mg/kg) and tramadol (3.2-56 mg/kg), the nonselective I₂ receptor ligand agmatine (10-100 mg/kg), and the selective I₂ receptor ligands 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI; 1-10 mg/kg) and 2-(4, 5-dihydroimidazol-2-yl) quinoline hydrochloride (BU224; 1-10mg/kg), alone and in combination, in a warm water tail withdrawal procedure in rats. Morphine and tramadol but not agmatine, 2-BFI or BU224 increased tail withdrawal latency in a dose-related manner at 48°C water. Agmatine and 2-BFI but not BU224 dose-dependently enhanced the antinociceptive effects of morphine and tramadol, shifting the dose-effect curves of morphine and tramadol leftward. The enhancement of agmatine and 2-BFI on morphine and tramadol antinociception was prevented by BU224. These results, combined with the fact that BU224 and 2-BFI share similar behavioral effects under other conditions, suggest that BU224 has lower efficacy than 2-BFI at I₂ receptors, and that the enhancement of opioid antinociception by I₂ receptor ligands depends on their efficacies.

  6. Thymus Daenensis Extract and Essential Oils Effects on Morphine Withdrawal Signs in Mice

    PubMed Central

    Khodayar, Mohammad Javad; Taherzadeh, Esmaeil; Siahpoosh, Amir; Mansourzadeh, Zahra; Tabatabaei, Seyed Amir Hossein

    2014-01-01

    Background: Thymus species are well known medicinal plants which the previous studies suggested the involvement of the opioid system in them. Objectives: This study aimed to investigate the effects of methanolic extract and essential oil of aerial parts of Thymus daenensis (TD), an endemic aromatic medicinal plant of Iran, on morphine withdrawal syndrome in mice. Materials and Methods: Experiments were performed in two groups of five, each group treated with extracts or essential oils of TD. Dependency was induced by subcutaneous injection of morphine for three consecutive days. On the fourth day, the last dose of morphine was injected two hours prior to intraperitoneal injection of naloxone while the extract or essential oil of TD was administered 30 minutes before naloxone. A period of 20 minutes after naloxone injection was considered the critical period of the withdrawal syndrome. The number of jumps, standing, leaning, and the weight of stools were recorded as withdrawal signs. Results: The 200 mg/kg and 400 mg/kg doses of extract and all doses of essential oil decreased significantly the number of jumps, standing, leaning and the weight of stool. Administration of 100 mg/kg of extract only decreased the weight of stool and had no effect on the other factors. Conclusions: Extract and essential oil of TD attenuates morphine withdrawal behaviors in mice and may be useful in alleviating the signs and symptoms of opiate withdrawal syndrome in human. PMID:25237649

  7. 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

  8. Evidence for a role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine.

    PubMed

    Lévesque, Karine; Lamarche, Caroline; Rompré, Pierre-Paul

    2008-10-10

    This experiment was aimed at exploring the role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine. During the induction phase (Days 1, 3, 5 and 7), male Long-Evans adult rats were treated with the neurotensin antagonist SR-48692 (160, 320 or 640 microg/kg, i.p.) or its vehicle, followed by morphine (5.0 mg/kg, i.p.) or its vehicle, and their locomotor activity (ambulatory, non-ambulatory and vertical activity) was measured for 2 h. One week after the last injection, each group received a single injection of morphine (2.5 mg/kg, i.p.) and their locomotor activity was again measured for 2 h (sensitization test, day 14). Results show that SR-48692 alone did not change locomotion. Morphine stimulated locomotor activity, an effect that was stronger on day 7 than on day 1. The two higher doses of SR-48692 attenuated the acute stimulant effect of morphine and prevented the observed increase from day 1 to day 7. The sensitization test on day 14 showed that rats pre-treated with morphine alone displayed significantly stronger ambulatory and vertical activity than vehicle pre-treated rats, a sensitization effect that was attenuated by SR-48692. The present results suggest that endogenous neurotensin contributes to the acute locomotor stimulant effect of morphine and to the induction of its sensitization. PMID:18706409

  9. Effects of cholecystokinin-8 on morphine-induced spatial reference memory impairment in mice.

    PubMed

    Yang, Shengchang; Wen, Di; Dong, Mei; Li, Dong; Sun, Donglei; Ma, Chunling; Cong, Bin

    2013-11-01

    Acute and chronic exposure to opiate drugs impaired various types of memory processes. To date, there is no preventive treatment for opiate-induced memory impairment and the related mechanism is still unclear. CCK-8 is the most potent endogenous anti-opioid peptide and has been shown to exert memory-enhancing effect, but the effect of CCK-8 on morphine-induced memory impairment has not been reported. By using Morris water maze, we found that escape latency to the hidden platform in navigation test was not influenced, but performance in the probe test was seriously poor in morphine dependency mice. Amnesia induced by chronic morphine treatment was significantly alleviated by pre-treatment with CCK-8 (0.01, 0.1 and 1 μg, i.c.v.), and CCK-8 (0.1 and 1 μg, i.c.v.) treatment alone could improve performance in either navigation or probe test. Furthermore, Golgi-Cox staining analysis revealed that pre-treatment with CCK-8 (1 μg, i.c.v.) reversed spine density decreased in CA1 region of hippocampus in morphine dependency mice, and CCK-8 (1 μg, i.c.v.) alone obviously increased spine density in CA1. Our findings conclude spine density change in CA1 region of hippocampus may be the structural plasticity mechanism which is responsible for enhancing effect of CCK-8 on spatial reference memory. Therefore, CCK-8 could effectively improve memory impairment in morphine dependency mice.

  10. Carbamazepine Potentiates the Effectiveness of Morphine in a Rodent Model of Neuropathic Pain

    PubMed Central

    Due, Michael R.; Yang, Xiao-Fang; Allette, Yohance M.; Randolph, Aaron L.; Ripsch, Matthew S.; Wilson, Sarah M.; Dustrude, Erik T.; Khanna, Rajesh; White, Fletcher A.

    2014-01-01

    Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G) which may aggravate preexisting pain conditions. Accumulating evidence indicates that M3G signaling through neuronal Toll-like receptor 4 (TLR4) may be central to this proalgesic signaling event. These events are known to include elevated neuronal excitability, increased voltage-gated sodium (NaV) current, tactile allodynia and decreased opioid analgesic efficacy. Using an in vitro ratiometric-based calcium influx analysis of acutely dissociated small and medium-diameter neurons derived from lumbar dorsal root ganglion (DRG), we observed that M3G-sensitive neurons responded to lipopolysaccharide (LPS) and over 35% of these M3G/LPS-responsive cells exhibited sensitivity to capsaicin. In addition, M3G-exposed sensory neurons significantly increased excitatory activity and potentiated NaV current as measured by current and voltage clamp, when compared to baseline level measurements. The M3G-dependent excitability and potentiation of NaV current in these sensory neurons could be reversed by the addition of carbamazepine (CBZ), a known inhibitor of several NaV currents. We then compared the efficacy between CBZ and morphine as independent agents, to the combined treatment of both drugs simultaneously, in the tibial nerve injury (TNI) model of neuropathic pain. The potent anti-nociceptive effects of morphine (5 mg/kg, i.p.) were observed in TNI rodents at post-injury day (PID) 7–14 and absent at PID21–28, while administration of CBZ (10 mg/kg, i.p.) alone failed to produce anti-nociceptive effects at any time following TNI (PID 7–28). In contrast to either drug alone at PID28, the combination of morphine and CBZ completely attenuated tactile hyperalgesia in the rodent TNI model. The basis for the potentiation of morphine in combination with CBZ may be due to the effects of a latent upregulation of NaV1.7 in the DRG following TNI. Taken together, our observations demonstrate a potential

  11. 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.

  12. Effect of activity at metabotropic, as well as ionotropic (NMDA), glutamate receptors on morphine dependence.

    PubMed Central

    Fundytus, M E; Coderre, T J

    1994-01-01

    1. The contribution of various excitatory amino acid (EAA) receptors (NMDA, AMPA/kainate and metabotropic) in the brain to the development of morphine dependence was examined. This was performed by measuring the severity of the precipitated withdrawal syndrome following chronic subcutaneous (s.c.) morphine and intracerebroventricular (i.c.v.) EAA antagonist treatment. 2. Continuous subcutaneous (s.c.) treatment with morphine sulphate (36.65 mumol day-1) produced an intense and reliable naloxone-precipitated withdrawal syndrome. 3. Chronic i.c.v. treatment with antagonists selective for metabotropic and NMDA receptors, but not AMPA/kainate receptors, significantly attenuated abstinence symptoms. Conversely, EAA antagonists had very little effect on non-withdrawal behaviours. 4. These results suggest that, as well as changes elicited by activation of NMDA receptors, metabotropic receptors and intracellular changes in the phosphatidylinositol (PI) second-messenger system or the cyclic adenosine 3',5'-monophosphate (cAMP) second messenger system, to which EAA metabotropic receptors are linked, may be involved in the development of opioid dependence with chronic morphine treatment. PMID:7889275

  13. Effects of stress and. beta. -funal trexamine pretreatment on morphine analgesia and opioid binding in rats

    SciTech Connect

    Adams, J.U.; Andrews, J.S.; Hiller, J.M.; Simon, E.J.; Holtzman, S.G.

    1987-12-28

    This study was essentially an in vivo protection experiment designed to test further the hypothesis that stress induces release of endogenous opiods which then act at opioid receptors. Rats that were either subjected to restraint stress for 1 yr or unstressed were injected ICV with either saline or 2.5 ..mu..g of ..beta..-funaltrexamine (..beta..-FNA), an irreversible opioid antagonist that alkylates the mu-opioid receptor. Twenty-four hours later, subjects were tested unstressed for morphine analgesia or were sacrificed and opioid binding in brain was determined. (/sup 3/H)D-Ala/sup 2/NMePhe/sup 4/-Gly/sup 5/(ol)enkephalin (DAGO) served as a specific ligand for mu-opioid receptors, and (/sup 3/H)-bremazocine as a general ligand for all opioid receptors. Rats injected with saline while stressed were significantly less sensitive to the analgesic action of morphine 24 hr later than were their unstressed counterparts. ..beta..-FNA pretreatment attenuated morphine analgesia in an insurmountable manner. Animals pretreated with ..beta..-FNA while stressed were significantly more sensitive to the analgesic effect of morphine than were animals that received ..beta..-FNA while unstressed. ..beta..-FNA caused small and similar decreases in (/sup 3/H)-DAGO binding in brain of both stressed and unstressed animals. 35 references, 2 figures, 2 tables.

  14. Scintigraphic determination of the effect of metoclopramide and morphine on small intestinal transit time

    SciTech Connect

    Prokop, E.K.; Caride, V.J.; Winchenbach, K.; Troncale, F.J.; McCallum, R.W.

    1988-01-01

    To determine if a scintigraphic method could detect pharmacologic changes in small intestinal transit time (SITT), 10 male volunteers were studied at baseline and after intravenously administered metoclopramide (10 mg) and morphine (8 mg). Five of these volunteers were studied with the hydrogen breath test method for comparison. For each of the scintigraphic studies, the volunteers were positioned supine under a large-field-of-view gamma camera after ingesting an isosmotic lactulose solution containing 99mtechnetium-diethylenetriaminepentaacetic acid (DTPA). Data were collected and stored in a computer. Both gastric emptying and SITT were determined. SITT was 81 +/- 11 min (mean +/- S.E.M.; N = 10) during baseline studies, was decreased significantly to 50 +/- 6 min (N = 10; P less than 0.01) after metoclopramide, and was increased significantly to 161 +/- 15 min (N = 8; P less than 0.01) after morphine. Baseline mean values were 86.3 +/- 15 min (N = 15) for the hydrogen breath tests, 47 +/- 8 min (N = 5) for metoclopramide, and 183 +/- 16 min (N = 5) for morphine. For gastric emptying, there was no significant difference in percentage emptying at 1 hr for baseline and metochopramide (82 +/- 5% vs. 88 +/- 4%). Morphine prolonged gastric emptying at 1 hr to 63 +/- 8%. We conclude that the scintigraphic method for measuring SITT permits accurate investigation of the pharmacologic effects on intestinal motility and, in addition, may be a useful research and clinical method for SITT determination.

  15. Intracerebroventricular effects of histaminergic agents on morphine-induced anxiolysis in the elevated plus-maze in rats.

    PubMed

    Zarrindast, Mohammad-Reza; Rostami, Parvin; Zarei, Morteza; Roohbakhsh, Ali

    2005-11-01

    Some reports indicate that morphine can induce anxiolytic effects both in animal and in man. It has also been reported that histaminergic system can interfere with some pharmacological effects of morphine. The effects of histaminergic agents on morphine-induced anxiolysis in rats, using elevated plus-maze were investigated in the present study. Intraperitoneal injection of morphine (3, 6 and 9 mg/kg) induced antianxiety effects. Intracerebroventricular administration of histamine at the doses of (5, 10 and 20 microg/rat) also increased anxiety-related behaviours. Intracerebroventricular injection of pyrilamine, a H1 receptor antagonist (25, 50 and 100 microg/rat), increased anxiety whereas injection of ranitidine, a H2 receptor antagonist (5, 10 and 20 microg/rat) at the same site, decreased anxiety. Therefore, it seems that histamine induces anxiogenic response through activation of H2 receptors, while the response of H1 blocker may be due to release of histamine. We also evaluated the interactions between morphine and histaminergic agents. Our data show that histamine (10 microg/rat), pyrilamine (50 microg/rat) and ranitidine (5 microg/rat) did not alter the response induced by different doses of morphine (3, 6 and 9 mg/kg). Similarly, a single dose of morphine did not alter the response induced by different doses of histamine (5, 10 and 20 microg/rat), pyrilamine (25, 50 and 100 microg/rat) or ranitidine (5, 10 and 20 microg/rat). In conclusion, the histaminergic system plays an important role in the modulation of anxiety, although in our experiments, no interaction was found between the effects of histaminergic agents and morphine on anxiety-related indices in the elevated plus-maze. This may imply that morphine-induced anxiolysis probably is independent of the histaminergic system.

  16. Genetic differences in the rewarding and activating effects of morphine and ethanol.

    PubMed

    Cunningham, C L; Niehus, D R; Malott, D H; Prather, L K

    1992-01-01

    The influence of genotype on the rewarding and locomotor activating effects of morphine and ethanol was examined in the place conditioning paradigm. Two inbred mouse strains (C57BL/6J and DBA/2J) were exposed to a differential conditioning procedure in which each mouse received four pairings of a distinctive floor stimulus with IP injection of morphine (0, 2.5, 5 or 10 mg/kg) or ethanol (0, 1, 2, 3 or 4 g/kg). A different floor stimulus was paired with saline. Conditioning trials lasted 30 min and each experiment concluded with a floor preference test in the absence of drug. In accord with previous studies, morphine evoked a dose-dependent increase in activity during conditioning that was greater in C57BL/6J mice than in DBA/2J mice. In contrast, ethanol produced a dose-dependent increase in activity that was greater in DBA/2J than in C57BL/6J mice. Both strains showed conditioned place preference with morphine, but only the DBA/2J strain showed conditioned place preference with ethanol. No conditioned place aversion was seen. With both drugs, stronger place preference conditioning was obtained in DBA/2J mice, supporting the general conclusion that sensitivity to drug reward is influenced by genotype. The fact that the same genotype is more sensitive to the rewarding effects of two different drugs supports theories postulating commonality in the biological mechanisms of drug reward. Although the outcome of the ethanol study supports predictions of the psychomotor stimulant theory of addiction concerning the relationship between drug-induced activation and reward, the outcome of the morphine study does not.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Antinociceptive effect of clavulanic acid and its preventive activity against development of morphine tolerance and dependence in animal models.

    PubMed

    Hajhashemi, V; Dehdashti, Kh

    2014-01-01

    Glutamate has a key role in pain perception and also development of tolerance and dependence to morphine. It has been reported that clavulanic acid affects glutamatergic transmission via activation of glutamate transporter. Therefore the present study was aimed to evaluate the possible antinociceptive effect of clavulanic acid and its preventive activity against development of morphine tolerance and dependence in animal models. Male Swiss mice (25-30 g) were used in this study. Acetic acid-induced writhing, formalin test and hot plate method were used to assess the antinociceptive effect of clavulanic acid. Morphine (30 mg/kg, s.c.) was administered to the mice two times a day (8 AM and 4 PM) for 3 days in order to produce tolerance. To develop morphine dependence, morphine sulfate (50, 50 and 75 mg/kg) was injected at 8 and 12 AM and 16 PM respectively and for 3 consecutive days. Naloxone (5 mg/kg, i.p) was used to induce morphine withdrawal syndrome and the number of jumps and presence of ptosis, piloerection, tremor, sniffing and diarrhea were recorded and compared with control group. Clavulanic acid at doses of 10, 20 and 40 mg/kg inhibited abdominal constriction and licking behavior of acetic acid and formalin-induced pain respectively. Clavulanic acid was not able to show any antinociception in hot plate model and could not prevent development of tolerance and dependence to morphine. Clavulanic acid has considerable antinociceptive activity and further studies are needed to clarify its exact mechanism.

  18. Ameliorating effect of histamine on impairment of cued fear extinction induced by morphine withdrawal in histidine decarboxylase gene knockout mice

    PubMed Central

    Gong, Ying-xia; Shou, Wen-ting; Feng, Bo; Zhang, Wei-ping; Wang, Hui-juan; Ohtsu, Hiroshi; Chen, Zhong

    2010-01-01

    Aim: Histamine plays an important role in morphine addiction and memory-dependent behavior. However, little is known about the effect of histamine on the impairment of memory after morphine withdrawal. This study was designed to investigate the effect of histamine on memory impairment induced by morphine withdrawal in histidine decarboxylase knockout (HDC-KO) and wild-type (WT) mice. Methods: WT and HDC-KO mice were given subcutaneous morphine or saline twice daily for 5 consecutive days. The mice received a cued or contextual fear conditioning session 7 days after the last injection. During subsequent days, mice received 4 cued or contextual extinction sessions (one session per day). Western blot was used to assess extracellular signal-regulated kinase (ERK) phosphorylation in the amygdala and hippocampus. Results: Morphine withdrawal did not affect the acquisition of cued or contextual fear responses. It impaired cued but not contextual fear extinction. The acquisition of cued and contextual fear responses was accelerated in HDC-KO mice. Histamine deficiency aggravated the impairment of cued fear extinction induced by morphine withdrawal, whereas histamine (icv, 5 μg/mouse) reversed this effect. Morphine withdrawal decreased ERK phosphorylation in the amygdala after cued fear extinction, especially in HDC-KO mice. Conclusion: These results suggest that morphine withdrawal specifically impairs cued fear extinction and histamine ameliorates this impairment. Its action might be mediated by the modulation of ERK phosphorylation in the amygdala. Histamine should be explored for possible roles in the prevention or treatment of morphine abuse and relapse. PMID:21052083

  19. Effects of Fentanyl and Morphine on Shivering During Spinal Anesthesia in Patients Undergoing Endovenous Ablation of Varicose Veins

    PubMed Central

    Onk, Didem; Ayazoğlu, Tülin Akarsu; Kuyrukluyıldız, Ufuk; Aksüt, Mehmet; Bedir, Zehra; Küpeli, İlke; Onk, Oruç Alper; Alagöl, Ayşin

    2016-01-01

    Background We sought to investigate the effect of morphine and fentanyl on shivering when used adjunctively with bupivacaine during spinal anesthesia in patients undergoing varicose vein surgery on an outpatient basis. Material/Methods The study included a total of 90 patients, aged 25–45 years, ASA I–II, scheduled to undergo endovenous laser ablation under spinal anesthesia for lower extremity venous insufficiency/varicose vein disease. Patients were randomly allocated into 3 groups: Group M (morphine group) received 5 mg 0.5% hyperbaric bupivacaine + 0.1 mg morphine, Group F (fentanyl group) received 5 mg 0.5% hyperbaric bupivacaine + 25 μg fentanyl, and Group C (control group) received 5 mg 0.5% hyperbaric bupivacaine + physiologic saline. The level of sensory blockade was assessed with pin-prick test and the level of motor blockade was assessed with Bromage scale at 5-min intervals. Shivering grade and time to first postoperative analgesic requirement was recorded. Results Level and time of sensory block showed a slight but insignificant increase in the Morphine Group and Fentanyl Group. Time of postoperative analgesic requirement was significantly longer in patients who received morphine (p<0.05). Shivering was significantly less common in patients who received morphine and fentanyl than in patients who are in the Control Group (p<0.02). Conclusions Morphine or fentanyl may be used as adjunctives to spinal anesthesia to prevent shivering in patients undergoing venous surgery. PMID:26871238

  20. Effects of Fentanyl and Morphine on Shivering During Spinal Anesthesia in Patients Undergoing Endovenous Ablation of Varicose Veins.

    PubMed

    Onk, Didem; Akarsu Ayazoğlu, Tülin; Kuyrukluyıldız, Ufuk; Aksüt, Mehmet; Bedir, Zehra; Küpeli, İlke; Onk, Oruç Alper; Alagöl, Ayşin

    2016-01-01

    BACKGROUND We sought to investigate the effect of morphine and fentanyl on shivering when used adjunctively with bupivacaine during spinal anesthesia in patients undergoing varicose vein surgery on an outpatient basis. MATERIAL AND METHODS The study included a total of 90 patients, aged 25-45 years, ASA I-II, scheduled to undergo endovenous laser ablation under spinal anesthesia for lower extremity venous insufficiency/varicose vein disease. Patients were randomly allocated into 3 groups: Group M (morphine group) received 5 mg 0.5% hyperbaric bupivacaine + 0.1 mg morphine, Group F (fentanyl group) received 5 mg 0.5% hyperbaric bupivacaine + 25 µg fentanyl, and Group C (control group) received 5 mg 0.5% hyperbaric bupivacaine + physiologic saline. The level of sensory blockade was assessed with pin-prick test and the level of motor blockade was assessed with Bromage scale at 5-min intervals. Shivering grade and time to first postoperative analgesic requirement was recorded. RESULTS Level and time of sensory block showed a slight but insignificant increase in the Morphine Group and Fentanyl Group. Time of postoperative analgesic requirement was significantly longer in patients who received morphine (p<0.05). Shivering was significantly less common in patients who received morphine and fentanyl than in patients who are in the Control Group (p<0.02). CONCLUSIONS Morphine or fentanyl may be used as adjunctives to spinal anesthesia to prevent shivering in patients undergoing venous surgery. PMID:26871238

  1. Effects of footshock stress and morphine on natural killer lymphocytes in rats: studies of tolerance and cross-tolerance.

    PubMed

    Shavit, Y; Terman, G W; Lewis, J W; Zane, C J; Gale, R P; Liebeskind, J C

    1986-05-01

    Exposure to a form of footshock stress known to cause opioid-mediated analgesia suppresses the cytotoxic activity of natural killer (NK) cells in rats. This suppression is blocked by the opioid antagonist, naltrexone and is mimicked by morphine administration, suggesting mediation by opioid receptors. Supporting this hypothesis, we now report that the morphine-induced suppression of NK activity shows tolerance after 14 daily injections. The NK-suppressive effect of stress, however, shows neither tolerance with repetition nor cross-tolerance in morphine-tolerant rats.

  2. Effect of MS-153, a glutamate transporter activator, on the conditioned rewarding effects of morphine, methamphetamine and cocaine in mice.

    PubMed

    Nakagawa, Takayuki; Fujio, Mayumi; Ozawa, Tohru; Minami, Masabumi; Satoh, Masamichi

    2005-01-30

    There is a body of evidence implying the involvement of the glutamatergic system in the conditioned rewarding effects of drugs of abuse. It is recognized that the release of extracellular glutamate from nerve terminals is counterbalanced by the functions of neuronal and glial glutamate transporters. In the present study, we investigated the effects of (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), a glutamate transporter activator, on the induction of the conditioned place preference to morphine, methamphetamine and cocaine in mice. In the conditioned place preference paradigm, mice were conditioned with repeated subcutaneous injections of morphine (5 mg/kg), methamphetamine (2 mg/kg) or cocaine (8 mg/kg) in combination with or without MS-153 (3 and 10 mg/kg). Co-administration of MS-153 at a dose of 10 mg/kg, but not 3 mg/kg, significantly attenuated the induction of conditioned place preference to morphine, methamphetamine and cocaine. However, MS-153 itself produced neither conditioned place preference nor aversion. On the other hand, co-administration of MS-153 (10 mg/kg) did not alter the acute locomotor activation elicited by a single injection of morphine, methamphetamine and cocaine. These results suggest that MS-153, a glutamate transporter activator, has an inhibitory effect on the conditioned rewarding effects of morphine, methamphetamine and cocaine without affecting their acute locomotor responses.

  3. Effect of filtration on morphine and particle content of injections prepared from slow-release oral morphine tablets

    PubMed Central

    2009-01-01

    Background Injections of mixtures prepared from crushed tablets contain insoluble particles which can cause embolisms and other complications. Although many particles can be removed by filtration, many injecting drug users do not filter due to availability, cost or performance of filters, and also due to concerns that some of the dose will be lost. Methods Injection solutions were prepared from slow-release morphine tablets (MS Contin®) replicating methods used by injecting drug users. Contaminating particles were counted by microscopy and morphine content analysed by liquid chromatography before and after filtration. Results Unfiltered tablet extracts contained tens of millions of particles with a range in sizes from < 5 μm to > 400 μm. Cigarette filters removed most of the larger particles (> 50 μm) but the smaller particles remained. Commercial syringe filters (0.45 and 0.22 μm) produced a dramatic reduction in particles but tended to block unless used after a cigarette filter. Morphine was retained by all filters but could be recovered by following the filtration with one or two 1 ml washes. The combined use of a cigarette filter then 0.22 μm filter, with rinses, enabled recovery of 90% of the extracted morphine in a solution which was essentially free of tablet-derived particles. Conclusions Apart from overdose and addiction itself, the harmful consequences of injecting morphine tablets come from the insoluble particles from the tablets and microbial contamination. These harmful components can be substantially reduced by passing the injection through a sterilizing (0.22 μm) filter. To prevent the filter from blocking, a preliminary coarse filter (such as a cigarette filter) should be used first. The filters retain some of the dose, but this can be recovered by following filtration with one or two rinses with 1 ml water. Although filtration can reduce the non-pharmacological harmful consequences of injecting tablets, this remains an unsafe practice due

  4. Analgesic effect of paracetamol combined with low-dose morphine versus morphine alone on patients with biliary colic: a double blind, randomized controlled trial

    PubMed Central

    Farnia, Mohammad Reza; Babaei, Rasoul; Shirani, Farzaneh; Momeni, Mehdi; Hajimaghsoudi, Majid; Vahidi, Elnaz; Saeedi, Morteza

    2016-01-01

    BACKGROUND: Numerous drugs have been proposed to alleviate pain in patients with biliary colic, especially opioids, but still there is a tendency to use less narcotics because of their side effects and the unwillingness of some patients. The present study aimed to compare the analgesic effect of paracetamol combined with low-dose morphine versus morphine alone in patients with biliary colic. METHODS: A randomized double-blind controlled trial was performed in 98 patients with biliary colic, recruited from two emergency departments from August 2012 to August 2013. Eleven patients were excluded and the remaining were randomized into two groups: group A received 0.05 mg/kg morphine+1 000 mg paracetamol in 100 mL normal saline and group B received 0.1 mg/kg morphine+normal saline (100 mL) as placebo. Pain scores were recorded using visual analogue scale (VAS) at baseline and 15 and 30 minutes after drug administration. Adverse effects and the need for rescue medication (0.75 µg/kg intravenous fentanyl) were also reported within 60 minutes of drug administration. RESULTS: Before the infusion, the mean±SD VAS scores were 8.73±1.57 in group A and 8.53±1.99 in group B. At 15 minutes after drug administration, the mean±SD VAS scores were 2.16±1.90 in group A vs. 2.51±1.86 in group B; mean difference was –0.35, and 95%CI –1.15 to 0.45 (P=0.38). At 30 minutes the mean±SD VAS scores were 1.66±1.59 in group A vs. 2.14±1.79 in group B; mean difference was –0.48, and 95%CI –1.20 to 0.24 (P=0.19). The mean pain scores in the two groups at 15 and 30 minutes demonstrated no significant difference. CONCLUSION: Paracetamol combined with low-dose morphine may be effective for pain management in patients with biliary colic. PMID:27006734

  5. A Methanol Extract of Brugmansia arborea Affects the Reinforcing and Motor Effects of Morphine and Cocaine in Mice

    PubMed Central

    Bracci, Antonio; Daza-Losada, Manuel; Aguilar, Maria; Miñarro, José; Rodríguez-Arias, Marta

    2013-01-01

    Previous reports have shown that several of the effects of morphine, including the development of tolerance and physical withdrawal symptoms, are reduced by extracts of Brugmansia arborea (L.) Lagerheim (Solanaceae) (B. arborea). In the present study we evaluate the action of the methanol extract of B. arborea (7.5–60 mg/kg) on the motor and reinforcing effects of morphine (20 and 40 mg/kg) and cocaine (25 mg/kg) using the conditioned place preference (CPP) procedure. At the doses employed, B. arborea did not affect motor activity or induce any effect on CPP. The extract partially counteracted morphine-induced motor activity and completely blocked the CPP induced by 20 mg/kg morphine. On the other hand, B. arborea blocked cocaine-induced hyperactivity but did not block cocaine-induced CPP. Reinstatement of extinguished preference with a priming dose of morphine or cocaine was also inhibited by B. arborea. The complex mechanism of action of B. arborea, which affects the dopaminergic and the cholinergic systems, seems to provide a neurobiological substrate for the effects observed. Considered as a whole, these results point to B. arborea as a useful tool for the treatment of morphine or cocaine abuse. PMID:23533488

  6. Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect

    PubMed Central

    2012-01-01

    This study demonstrated that cyclomethyline (2) and the corresponding enantiomers (R)-(−)-2 and (S)-(+)-2, displaying α2C-adrenoreceptor (AR) agonism/α2A-AR antagonism, similarly to allyphenyline (1) and its enantiomers, significantly decreased the naloxone-precipitated withdrawal symptoms in mice at very low doses. It also highlighted that such positive effects on morphine dependence can even be improved by additional serotoninergic 5-HT1A receptor (5-HT1A-R) activation. Indeed, 1 or the single (S)-(+)-1, 2, or both its enantiomers, all behaving as α2C-AR agonists/α2A-AR antagonists/5-HT1A-R agonists, alone and at the same low dose, improved morphine withdrawal syndrome and exerted a potent antidepressant-like effect. Therefore, considering the elevated comorbidity between opiate abuse and depressed mood and the benefit of these multifunctional compounds to both disorders, it is possible that they prove more efficacious and less toxic than a cocktail of drugs in managing opioid addiction. PMID:24900506

  7. Additive effect of combined application of magnesium and MK-801 on analgesic action of morphine.

    PubMed

    Bujalska-Zadrożny, Magdalena; Duda, Kamila

    2014-01-01

    As previously reported, magnesium ions (Mg(2+)) administered in relatively low doses markedly potentiated opioid analgesia in neuropathic pain, in which the effectiveness of opioids is limited. Considering that Mg(2+) behaves like an N-methyl-D-aspartate receptor antagonist, the effect of this ion on the analgesic action of morphine was compared with that of MK-801. Acute pain was evoked by mechanical or thermal stimuli, whereas neuropathic hyperalgesia was induced by streptozotocin (STZ) administration. Magnesium sulphate (40 mg/kg i.p.) or MK-801 (0.05 mg/kg s.c.) administered alone did not modify the nociceptive threshold to acute stimuli or the streptozotocin hyperalgesia but significantly augmented the analgesic action of morphine (5 mg/kg i.p.). Furthermore, if these drugs (i.e. magnesium sulphate and MK-801) were applied concomitantly, a clear additive effect on the analgesic action of morphine occurred in both models of pain. Possible explanations of these observations are discussed. PMID:24577345

  8. Effects of the Persian Carum copticum fruit extracts on morphine withdrawal syndrome in mice

    PubMed Central

    Ghannadi, A.; Hajhashemi, V.; Abrishami, R.

    2012-01-01

    Carum copticum from Apiaceae family has several biological effects including analgesic, anti-inflammatory, anxiolytic and antispasmodic activities. This study was designed to evaluate its effect on suppression of naloxone-induced morphine withdrawal signs. Hydroalcoholic and polyphenolic extracts were prepared according to the standard methods. Male mice (25-30 g) were made dependent by subcutaneous injection of increasing doses (30-90 mg/kg) of morphine. Withdrawal syndrome was elicited by naloxone (5 mg/kg, i.p.) and number of jumpings and also presence of ptosis, hyperventilation, piloerection, tremor and diarrhea were evaluated during a 30 min period started immediately after naloxone injection. The hydroalcoholic extract at doses of 1 and 2 g/kg and the polyphenolic extract at doses of 0.5, 1 and 2 g/kg significantly (P<0.05) inhibited jumpings. Both extracts inhibited tremor significantly (P<0.01). Also the maximum applied dose of the extracts significantly (P<0.05) reduced ptosis. These results clearly show that Carum copticum is effective in suppression of morphine withdrawal and further studies are needed to find out the responsible constituents and also the mechanism of their actions. PMID:23181090

  9. Effects of the Persian Carum copticum fruit extracts on morphine withdrawal syndrome in mice.

    PubMed

    Ghannadi, A; Hajhashemi, V; Abrishami, R

    2012-07-01

    Carum copticum from Apiaceae family has several biological effects including analgesic, anti-inflammatory, anxiolytic and antispasmodic activities. This study was designed to evaluate its effect on suppression of naloxone-induced morphine withdrawal signs. Hydroalcoholic and polyphenolic extracts were prepared according to the standard methods. Male mice (25-30 g) were made dependent by subcutaneous injection of increasing doses (30-90 mg/kg) of morphine. Withdrawal syndrome was elicited by naloxone (5 mg/kg, i.p.) and number of jumpings and also presence of ptosis, hyperventilation, piloerection, tremor and diarrhea were evaluated during a 30 min period started immediately after naloxone injection. The hydroalcoholic extract at doses of 1 and 2 g/kg and the polyphenolic extract at doses of 0.5, 1 and 2 g/kg significantly (P<0.05) inhibited jumpings. Both extracts inhibited tremor significantly (P<0.01). Also the maximum applied dose of the extracts significantly (P<0.05) reduced ptosis. These results clearly show that Carum copticum is effective in suppression of morphine withdrawal and further studies are needed to find out the responsible constituents and also the mechanism of their actions.

  10. Effects of ketoprofen, morphine, and kappa opioids on pain-related depression of nesting in mice.

    PubMed

    Negus, S Stevens; Neddenriep, Bradley; Altarifi, Ahmad A; Carroll, F Ivy; Leitl, Michael D; Miller, Laurence L

    2015-06-01

    Pain-related functional impairment and behavioral depression are diagnostic indicators of pain and targets for its treatment. Nesting is an innate behavior in mice that may be sensitive to pain manipulations and responsive to analgesics. The goal of this study was to develop and validate a procedure for evaluation of pain-related depression of nesting in mice. Male ICR mice were individually housed and tested in their home cages. On test days, a 5- × 5-cm Nestlet was subdivided into 6 pieces, the pieces were evenly distributed on the cage floor, and Nestlet consolidation was quantified during 100-minute sessions. Baseline nesting was stable within and between subjects, and nesting was depressed by 2 commonly used inflammatory pain stimuli (intraperitoneal injection of dilute acid; intraplantar injection of complete Freund adjuvant). Pain-related depression of nesting was alleviated by drugs from 2 classes of clinically effective analgesics (the nonsteroidal anti-inflammatory drug ketoprofen and the μ-opioid receptor agonist morphine) but not by a drug from a class that has failed to yield effective analgesics (the centrally acting kappa opioid agonist U69,593). Neither ketoprofen nor morphine alleviated depression of nesting by U69,593, which suggests that ketoprofen and morphine effects were selective for pain-related depression of nesting. In contrast to ketoprofen and morphine, the kappa opioid receptor antagonist JDTic blocked depression of nesting by U69,593 but not by acid or complete Freund adjuvant. These results support utility of this procedure to assess expression and treatment of pain-related depression in mice.

  11. Effects of repeated morphine administration on copulation and on the hypothalamic-pituitary-gonadal axis of male rats.

    PubMed

    Tokunaga, Y; Muraki, T; Hosoya, E

    1977-02-01

    Adult male rats were administered morphine twice a day for 45 days and the effects of morphine on the copulation rate, the weight of various organs, and on the hypothalamic-pituitary-gonadal axis were examined. Morphine administered rats showed a loss of weight, hypertrophy of the adrenals, decreased weight of accessory sex organs, low sperm count, and decreased copulation rate. The contents of the luteinizing hormone releasing hormone in the hypothalamus and the luteinizing hormone in the pituitary remained unchanged. Serum luteinizing hormone and testosterone levels decreased, but serum follicle-stimulating hormone levels increased. These results suggest that morphine inhibits the hypothalamic-pituitary-gonadal axis and causes a diminution in the number of fertilizations of the partner females.

  12. The Postoperative Analgesic Effect of Morphine and Paracetamol in the Patients Undergoing Laparotomy, Using PCA Method

    PubMed Central

    Yaghoubi, Siamak; Pourfallah, Reza; Barikani, Ameneh; Kayalha, Hamid

    2014-01-01

    Objective: postoperative pain increases the activity of the sympathetic system, causes hypermetabolic conditions, retains salt and water, increases glucose, fatty acid lactate and oxygen consumption, weakens the immunity system which delays wound healing. Our object was comparison of the analgesic effect of morphine and paracetamol in the patients undergoing laparotomy, using PCA method. Method: Seventy patients who had undergone laparotomy were studied using double blind randomized clinical trial (35 patients received morphine and 35 paracetamol) in the Shahid Rajaee Center and Velayat Hospital (Qazvin, Iran). People using opioids, painkillers and sedatives regularly and in large doses and patients with a history of lung or liver problems did not participate in this project. The parameters of the severity of pain and nausea (VAS), hemodynamic changes (BP and HR), pruritus, arterial oxygen desaturation and patient satisfaction (VAS) of both groups were measured by a third party (trained colleague). The data was analyzed using SPSS 16 statistical software then descriptive results were extracted and ultimately the groups were compared using the following statistical tests: student’s T-test, chi 2 and Fisher’s exact test (P<0.05). Findings: The mean age of the participants was 45±12.5 years. Women constituted 24.3% of the patients and men 75.7%. The average pain severity for morphine and paracetamol groups (VAS) was 5.3±2.2and 6.37±1.7 after2 hours and reached 1.91±1.3 and 2.49±1.3 after 8 hours (after the operation) respectively. There was a significant difference between the groups after 2 and 4 hours in terms of pain severity (after 2 hours P=0.007 and after 4 hours P=0.047). However there was no significant difference between the average pain severity of the studied groups (after 6 hours P=0.4 and 8 hours P=0.08). After 8 hours, the average nausea severity was the minimum in both groups being 1.71±1.6 and 1.43±1.1 in morphine and paracetamol groups

  13. Effects of Oral Morphine on the Larvae, Pupae and Imago Development in Drosophila Melanogaster

    PubMed Central

    Tekieh, Elaheh; Kazemi, Masoomeh; Dehghani, Leila; Bahramyian, Sina; Sadogi, Mehrangiz; Zardooz, Homeira; Fakhanik-Babaei, Javad; Sahraei, Hedayat

    2011-01-01

    Objective: Previous studies, focusing on the effects of abused drugs, have used mice or rats as the main animal models; the present study tries to introduce a simple animal model. For this propose, we investigated the effects of oral morphine consumption by parents on the development of larvae, pupae and imago in Drosophila Melanogaster (D. Melanogaster). Materials and Methods: In this experimental study, twenty male and 20 female D. Melanogaster pupae were housed in test tubes with banana (5 pupae /tube).). Male and female groups each were divided into three experimental group and one control group, which were maintained at 25℃. Morphine (0.2, 0.02, 0.002 mg/ml) was added into the test tubes of the experimental groups. The control group maintained at morphine-free test tube. The male and female groups with the same treatment were coupled and then female fertilization, egg deposit, larval, pupae and imago stages were studied macro and microscopically. The SPSS software (version 9.01) was used for statistical evaluations. Results: In the experimental groups, in the larvae stage, both increase and decrease of length and surface area in the pupae stage were observed. The number of larvae pupae, and imago was reduced in the experimental groups. Conclusion: The study showed that oral morphine consumption by parents may affect the development of larvae, pupation and imago stages in D. Melanogaster. The results also showed that D. Melanogaster may be a reliable animal model to study on the concerns about abused drugs especially those with opioids. PMID:23508520

  14. The effect of morphine consumption on plasma corticosteron concentration and placenta development in pregnant rats

    PubMed Central

    Kazemi, Masoomeh; Sahraei, Hedayat; Azarnia, Mahnaz; Dehghani, Leila; Bahadoran, Hossein; Tekieh, Elaheh

    2011-01-01

    Background: Previous studies have shown that morphine consumption during pregnancy may delay embryo development or cause abnormal nervous system function. Objective: The present study focused on the effect of maternal morphine consumption on development of placenta and blood corticosteron concentration in addictive pregnant mothers. Materials and Methods: 24 female rats, 170-200g weight, were used. The experimental groups after pregnancy received an oral dose of 0.05 mg/ml of morphine by tap water while the control group received only tap water. On 10th and 14th day of pregnancy, rats were anesthetized and placenta removed surgically, 1ml blood was collected from each pregnant mother from retro-orbital sinus, the concentration of blood corticosteron was determined by corticosteron Elisa kit after centrifugation. The fixed tissue was processed, sectioned and stained with hematoxylin and eosin. Placenta was studied microscopically according to the thickness of layers, area of blood cisterns, and the number of cells. Results: Comparing the plasma corticosteron concentration of the treatment and the control groups, not only a severe increase in the treatment group was detected, but also the thickness of maternal and embryonic portions of the placenta at day 10th and 14th of gestation was different significantly (p≤0.05). Furthermore, an increase in number of cells in maternal and embryonic portion of placenta and a decrease in blood cistern area were demonstrated in both the experimental and the control groups. Conclusion: The effects of morphine, including an increase in blood concentration of corticosteron, in dependent pregnant mothers were seen. Development of placenta in the experimental group was delayed. PMID:25587250

  15. Morphine intake and the effects of naltrexone and buprenorphine on the acquisition of methamphetamine intake.

    PubMed

    Eastwood, E C; Phillips, T J

    2014-02-01

    Some common genetic factors appear to influence risk for drug dependence across multiple drugs of abuse. In previous research, mice that were selectively bred for higher amounts of methamphetamine consumption, using a two-bottle choice methamphetamine drinking procedure, were found to be less sensitive to the locomotor stimulant effects of morphine and of the more selective μ-opioid receptor agonist fentanyl, compared to mice that were bred for low methamphetamine consumption. This suggested that μ-opioid receptor-mediated pathways may influence genetic risk for methamphetamine consumption. We hypothesized that these differences in opioid sensitivity would impact opioid intake in the methamphetamine drinking lines and that drugs with μ-opioid receptor activity would impact methamphetamine intake. Consumption of morphine was examined in 2, two-bottle choice studies, one that compared morphine to quinine consumption and another that used a saccharin fading procedure. Next, naltrexone (0, 0.5, 1, 2, 5, 10 and 20 mg/kg), a μ-opioid receptor antagonist, and buprenorphine (0, 1, 2 or 4 mg/kg), a μ-opioid receptor partial agonist, were each examined for their effects on the acquisition of methamphetamine consumption. Low methamphetamine drinking mice consumed more morphine compared to high methamphetamine drinking mice. Naltrexone did not alter methamphetamine consumption in either selected line; however, buprenorphine reduced methamphetamine intake in the high methamphetamine drinking line. These data show that greater sensitivity to opioids is associated with greater opioid intake and warrant further investigation of drugs with μ-opioid receptor-specific agonist activity in genetically determined differences in methamphetamine consumption.

  16. 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.

  17. The effect of pituitary adenylate cyclase-activating polypeptide on elevated plus maze behavior and hypothermia induced by morphine withdrawal.

    PubMed

    Lipták, Nándor; Dochnal, Roberta; Babits, Anikó; Csabafi, Krisztina; Szakács, Júlia; Tóth, Gábor; Szabó, Gyula

    2012-02-01

    The aim of the present investigation was to study the effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on morphine withdrawal-induced behavioral changes and hypothermia in male CFLP mice. Elevated plus maze (EPM) and jump tests were used to assess naloxone-precipitated morphine withdrawal-induced behavior responses. Different doses of subcutaneous (s.c.) naloxone, (0.1 and 0.2 mg/kg, respectively) were used to precipitate the emotional and psychical aspects of withdrawal on EPM and 1 mg/kg (s.c.) was used to induce the somatic withdrawal signs such as jumping, and the changes in body temperature. In our EPM studies, naloxone proved to be anxiolytic in mice treated with morphine. Chronic intracerebroventricular (i.c.v.) administration of PACAP alone had no significant effect on withdrawal-induced anxiolysis and total activity at doses of 500 ng and 1 μg. At dose of 500 ng, however, PACAP significantly counteracted the reduced motor activity in the EPM test in mice treated with morphine and diminished the hypothermia and shortened jump latency induced by naloxone in mice treated with morphine. These findings indicate that anxiolytic-like behavior may be mediated via a PACAP-involved pathway and PACAP may play an important role in chronic morphine withdrawal-induced hypothermia as well.

  18. Effects of intracerebroventricular administration of ultra low doses of histaminergic drugs on morphine state-dependent memory of passive avoidance in mice.

    PubMed

    Khalilzadeh, Azita; Zarrindast, Mohammad-Reza; Djahanguiri, Bijan

    2006-01-01

    The effects of intracerebroventricular (i.c.v.) administration of ultra low doses (ULDs) of histamine, clobenpropit and pyrilamine are studied on morphine state-dependent (STD) memory in mice. Although pre-test administration of different doses of histamine and clobenpropit showed no effect on impairment of memory induced by pre-training morphine, when the above drugs were co-administered with morphine, they inhibited the restoration of memory by morphine. These effects were opposite to microgram doses of the same drugs.

  19. Long-Term Effects of Neonatal Morphine Infusion on Pain Sensitivity: Follow-Up of a Randomized Controlled Trial.

    PubMed

    Valkenburg, Abraham J; van den Bosch, Gerbrich E; de Graaf, Joke; van Lingen, Richard A; Weisglas-Kuperus, Nynke; van Rosmalen, Joost; Groot Jebbink, Liesbeth J M; Tibboel, Dick; van Dijk, Monique

    2015-09-01

    Short-term and long-term effects of neonatal pain and its analgesic treatment have been topics of translational research over the years. This study aimed to identify the long-term effects of continuous morphine infusion in the neonatal period on thermal pain sensitivity, the incidence of chronic pain, and neurological functioning. Eighty-nine of the 150 participants of a neonatal randomized controlled trial on continuous morphine infusion versus placebo during mechanical ventilation underwent quantitative sensory testing and neurological examination at the age of 8 or 9 years. Forty-three children from the morphine group and 46 children from the placebo group participated in this follow-up study. Thermal detection and pain thresholds were compared with data from 28 healthy controls. Multivariate analyses revealed no statistically significant differences in thermal detection thresholds and pain thresholds between the morphine and placebo groups. The incidence of chronic pain was comparable between both groups. The neurological examination was normal in 29 (76%) of the children in the morphine group and 25 (61%) of the children in the control group (P = .14). We found that neonatal continuous morphine infusion (10 μg/kg/h) has no adverse effects on thermal detection and pain thresholds, the incidence of chronic pain, or overall neurological functioning 8 to 9 years later. Perspective: This unique long-term follow-up study shows that neonatal continuous morphine infusion (10 μg/kg/h) has no long-term adverse effects on thermal detection and pain thresholds or overall neurological functioning. These findings will help clinicians to find the most adequate and safe analgesic dosing regimens for neonates and infants.

  20. Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain.

    PubMed

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Heegaard, Anne-Marie; Kreilgaard, Mads; Lund, Trine Meldgaard

    2016-01-20

    Despite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacological interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of morphine and gabapentin in range of different dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7mg/kg), gabapentin (10, 30 and 100mg/kg) or their combination (9 combinations in total) were evaluated in the rat plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response ranged between 26 and 58% for the synergistic doses. The finding of dose-dependent synergistic effects highlights that choosing the right dose-dose combination is of importance in postoperative pain therapy. Our results indicate benefit of high doses of gabapentin as adjuvant to morphine. If these findings translate to humans, they might have important implications for the treatment of pain in postoperative patients.

  1. Corticosteroid-Sparing Effect of Chromoglycate Sodium and Nedocromil

    PubMed Central

    Capristo, A. F.; Alfaro, C.; Maiello, N.

    1994-01-01

    The most appropiate management for bronchial asthma is the control of airway inflammation. Corticosteroids are the most effective anti-inflammatory drugs available, but they have a number of side effects; most of these are dose-dependent. In children, asthma control should be accomplished with low steroid doses possibly given by inhalation. In a double-bind placebo-controlled crossover study a group of children with mild to moderate asthma received NED 16 mg/day or BDP 400 μg/day. Values for FEV1, PEF, symptoms use ofbronchodilators overlapped, whereas bronchial hyper-responsiveness assessed by histamine bronchoprovocation challenge was better with BDP than NED. In another case, one boy with high bronchial hyper-reactivity assessed by provocation test with hypertonic solution, experienced a significant improvement only after 2 weeks of therapy with Deflazacort (2 mg/Kg/day) followed by 4 months on combined treatment with NED (16 mg/day) and BDP (300 μ/day). Authors conclude that NED could have a steroidsparing effect over long-term use. PMID:18475599

  2. Effects of the fruit essential oil of Cuminum cyminum Linn. (Apiaceae) on acquisition and expression of morphine tolerance and dependence in mice.

    PubMed

    Haghparast, Abbas; Shams, Jamal; Khatibi, Ali; Alizadeh, Amir-Mohammad; Kamalinejad, Mohammad

    2008-08-01

    The problem of morphine tolerance and dependence is a universal phenomenon threatening social health everywhere the world. The major objective of this paper was to investigate the effects of fruit essential oil (FEO) of Cuminum cyminum on acquisition and expression of morphine tolerance and dependence in mice. Animals were rendered dependent on morphine using the well-established method in which was morphine (50, 50, 75 mg/kg; s.c.) injected three times daily for 3 days. In experimental groups, administration of FEO (0.001, 0.01, 0.1, 0.5, 1 and 2%; 5 ml/kg; i.p.) or Tween-80 (5 ml/kg; i.p.) was performed 60 min prior to each morphine injection (for acquisition) or the last injection of morphine on test day (for expression). Morphine tolerance was measured by tail-flick before and after administration of a single dose of morphine (50 mg/kg; s.c.) in test day (4th day). Morphine dependence was also evaluated by counting the number of jumps after injection of naloxone (5 mg/kg; i.p.) on the test day. The results showed that Cumin FEO, only at the dose of 2%, significantly attenuated the development of morphine tolerance (P<0.01) and dependence (P<0.05) while it could be significantly effective on expression of morphine tolerance (1 and 2%) and dependence (0.5, 1 and 2%) in a dose-dependent manner. Solely Cumin FEO injection (0.001-2%) did not show any analgesic effect. In conclusion, the essential oil of Cuminum cyminum seems to ameliorate the morphine tolerance and dependence in mice.

  3. Withdrawal from repeated administration of morphine alters histamine-induced anxiogenic effects produced by intra-ventral hippocampal microinjection.

    PubMed

    Zarrindast, Mohammad-Reza; Khodarahmi, Parvin; Rezayof, Ameneh; Oryan, Shahrbano

    2010-06-01

    In the present study, the influence of withdrawal from repeated administration of morphine on intra-ventral hippocampal microinjection of histamine-induced anxiety-like behavior was investigated in male Wistar rats. Three days subcutaneous administration of morphine (5-10 mg/kg) followed by five days free of the drug decreased the percentage open arm time and the percentage open arm entries. Intra-ventral hippocampal administration of histamine (2.5-7.5 microg/rat) decreased percentage open arm time and percentage open arm entries. Intra-ventral hippocampal histamine-induced anxiogenic effect was reversed in animals that had previously received the three days morphine (7.5 mg/kg) followed by five days free of the drug. Intra-ventral hippocampal administration of pyrilamine (5-20 microg/rat) or ranitidine (10-40 microg/rat) decreased percentage open arm time and percentage open arm entries. Pyrilamine- or ranitidine-induced anxiogenic effect was not changed in animals that had previously received the three days morphine (7.5 mg/kg) followed by five days free of the drug. Intra-ventral hippocampal injections of clobenpropit increased percentage open arm time. The percentage open arm time and percentage open arm entries were decreased in the morphine-treated animals compared with non-morphine-treated controls. Percentage open arm entries and locomotor activity was reduced with some doses of clobenpropit. It can be concluded that the histamine system is involved in anxiety-like behavior, and repeated injections of morphine followed by five days free of the drugs interact with histamine receptor mechanism.

  4. Antinociceptive effect of clavulanic acid and its preventive activity against development of morphine tolerance and dependence in animal models

    PubMed Central

    Hajhashemi, V.; Dehdashti, Kh.

    2014-01-01

    Glutamate has a key role in pain perception and also development of tolerance and dependence to morphine. It has been reported that clavulanic acid affects glutamatergic transmission via activation of glutamate transporter. Therefore the present study was aimed to evaluate the possible antinociceptive effect of clavulanic acid and its preventive activity against development of morphine tolerance and dependence in animal models. Male Swiss mice (25-30 g) were used in this study. Acetic acid-induced writhing, formalin test and hot plate method were used to assess the antinociceptive effect of clavulanic acid. Morphine (30 mg/kg, s.c.) was administered to the mice two times a day (8 AM and 4 PM) for 3 days in order to produce tolerance. To develop morphine dependence, morphine sulfate (50, 50 and 75 mg/kg) was injected at 8 and 12 AM and 16 PM respectively and for 3 consecutive days. Naloxone (5 mg/kg, i.p) was used to induce morphine withdrawal syndrome and the number of jumps and presence of ptosis, piloerection, tremor, sniffing and diarrhea were recorded and compared with control group. Clavulanic acid at doses of 10, 20 and 40 mg/kg inhibited abdominal constriction and licking behavior of acetic acid and formalin-induced pain respectively. Clavulanic acid was not able to show any antinociception in hot plate model and could not prevent development of tolerance and dependence to morphine. Clavulanic acid has considerable antinociceptive activity and further studies are needed to clarify its exact mechanism. PMID:25657803

  5. The bone-sparing effects of estrogen and WNT16 are independent of each other

    PubMed Central

    Movérare-Skrtic, Sofia; Wu, Jianyao; Henning, Petra; Gustafsson, Karin L.; Sjögren, Klara; Windahl, Sara H.; Koskela, Antti; Tuukkanen, Juha; Börjesson, Anna E.; Lagerquist, Marie K.; Lerner, Ulf H.; Zhang, Fu-Ping; Gustafsson, Jan-Åke; Poutanen, Matti; Ohlsson, Claes

    2015-01-01

    Wingless-type MMTV integration site family (WNT)16 is a key regulator of bone mass with high expression in cortical bone, and Wnt16−/− mice have reduced cortical bone mass. As Wnt16 expression is enhanced by estradiol treatment, we hypothesized that the bone-sparing effect of estrogen in females is WNT16-dependent. This hypothesis was tested in mechanistic studies using two genetically modified mouse models with either constantly high osteoblastic Wnt16 expression or no Wnt16 expression. We developed a mouse model with osteoblast-specific Wnt16 overexpression (Obl-Wnt16). These mice had several-fold elevated Wnt16 expression in both trabecular and cortical bone compared with wild type (WT) mice. Obl-Wnt16 mice displayed increased total body bone mineral density (BMD), surprisingly caused mainly by a substantial increase in trabecular bone mass, resulting in improved bone strength of vertebrae L3. Ovariectomy (ovx) reduced the total body BMD and the trabecular bone mass to the same degree in Obl-Wnt16 mice and WT mice, suggesting that the bone-sparing effect of estrogen is WNT16-independent. However, these bone parameters were similar in ovx Obl-Wnt16 mice and sham operated WT mice. The role of WNT16 for the bone-sparing effect of estrogen was also evaluated in Wnt16−/− mice. Treatment with estradiol increased the trabecular and cortical bone mass to a similar extent in both Wnt16−/− and WT mice. In conclusion, the bone-sparing effects of estrogen and WNT16 are independent of each other. Furthermore, loss of endogenous WNT16 results specifically in cortical bone loss, whereas overexpression of WNT16 surprisingly increases mainly trabecular bone mass. WNT16-targeted therapies might be useful for treatment of postmenopausal trabecular bone loss. PMID:26627248

  6. Interactive effects of morphine and ionizing radiation on the latency of tail-withdrawal from warm water in the rat

    SciTech Connect

    Burghardt, W.F.; Hunt, W.A.

    1984-04-01

    The analgesic effect of morphine was enhanced in rats exposed to ionizing radiation (250-5000) in a dose-dependent manner. This was indicated by an increase in the latency of tail-withdrawal from warm water, compared with animals receiving morphine alone. Radiation alone had no effect on latencies or on gross behavior. The enhancing effect of radiation was strongest at 24 hours after irradiation and was partially reversible with naloxone, an opiate antagonist, at a dose of 2 mg/kg, i.m. No changes in survival time after irradiation were noted between animals receiving morphine and those receiving saline injections. The results of this study suggest that the effect of narcotic analgesics to relieve pain in casualties on a nuclear battlefield may be enhanced depending on the postirradiation interval.

  7. Morphine-6-glucuronide: analgesic effects and receptor binding profile in rats

    SciTech Connect

    Abbott, F.V.; Palmour, R.M.

    1988-01-01

    The antinociceptive effects of morphine-6-glucuronide (M6G) were examined in two animal models of pain, the tail immersion test (reflex withdrawal to noxious heat) and the formalin test (behavioral response to minor tissue injury). In the tail immersion test, M6G produced and increase in withdrawal latency that rose rapidly between 0.01 and 0.025 ug ICV or 1 and 2 mg/kg SC. A further increase occurred at doses greater than 0.2 ug ICV or 4 mg/kg SC and was associated with marked catelepsy and cyanosis. Naloxone, 0.1 mg/kg SC, shifted the lower component of the dose-effect relation by a factor of 24. In the formalin test, 0.01 ug M6G ICV produced hyperalgesia, while between 0.05 and 0.2 ug ICV, antinociception increased rapidly without toxicity. The dose effect relations for hyperalgesia and antinociception were shifted to the right by factors of 20- and 3-fold, respectively. By comparison, ICV morphine was 60 (formalin test) to 145-200 (tail immersion test) times less potent than M6G. At sub-nanomolar concentrations, M6G enhanced the binding of (/sup 3/H)-etorphine, (/sup 3/H)-dihydromorphine and (/sup 3/H)-naloxone to rat brain membrane receptors by 20-40%. At higher concentrations, M6G displaced each ligand from binding sites, with K/sub i/ values of about 30 nM, as compared to morphine K/sub i/ values of about 3 nM.

  8. 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.

  9. 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.

  10. Development of tolerance to the effects of morphine on luteinizing hormone secretion as a function of castration in the male rat.

    PubMed

    Cicero, T J; Meyer, E R; Schmoeker, P F

    1982-12-01

    The effects of morphine on the secretion of luteinizing hormone (LH) were examined in male rats at intervals after castration. We found that morphine was extremely effective in suppressing serum LH levels in animals that had been castrated for periods of less than 7 days, but was considerably less potent in long-term castrates (13 + days). For example, the dose of morphine producing the half-maximal suppression of serum LH levels in 3-day castrates was 1.5 mg/kg, whereas in 31-day castrates the ED50 was 13.8 mg/kg. This insensitivity to morphine satisfied the two pharmacological criteria for tolerance: a parallel shift to the right in the morphine dose-response curve and a reduced effect of the drug at the same brain concentration. Hence, castration appeared to render male rats, never exposed to opiates, tolerant to the effects of morphine. Corresponding to the development of tolerance to morphine, 31-day castrates were also less responsive to the LH-depressing effects of testosterone than were 3-day castrates or sham-operated controls. In marked contrast to these results, castration did not significantly affect naloxone-induced increases in serum LH levels. The tolerance observed to morphine in the long-term castrated rat was selective to LH secretion because long- and short-term castrates and sham-operated controls were equally responsive to the antinociceptive effects of morphine (in fact, at a dose of 8 mg/kg long-term castrates were more sensitive to morphine than short-term castrates or sham-operated controls) and there was no apparent shift in the LD50. The mechanisms underlying the development of tolerance to morphine in castrated male rats are not clear at the present time. PMID:7143239

  11. The analgesic effect of Carum copticum extract and morphine on phasic pain in mice.

    PubMed

    Dashti-Rahmatabadi, Mohammad Hossein; Hejazian, Seyed Hassan; Morshedi, Abbas; Rafati, Ali

    2007-01-19

    Pain is a universal complaint, which needs further investigations for new pain relieving agents. Carum copticum (L.) Sprague ex Turrill is a plant in Umbelliferae family, which is mentioned to have some therapeutic effects on headache and joint pains in Iranian traditional literature, but there are not enough scientific reports to prove its effects on pain. So, we conducted to design an experimental clinical trial study to assess and compare the analgesic effect of ethanolic extract of Carum copticum fruit with morphine by using a tail-flick analgesiometer device. Our results indicate that the test drug produced significant increase in tail-flick latency (TFL) during 2h post-drug administration (p<0.05). The peak of the effect was observed at 45min after drug injection, which was comparable to that of 1mg/kg morphine (i.p.). Positive results in this type of analgesiometric test indicate that the antinociceptive action may be of the opoid type. The present study supports the claims of Iranian traditional medicine showing that Carum copticum extract possesses a clear-cut analgesic effect. However, further investigations are required to evaluate the efficacy and safety of this herbal medication in man.

  12. Olfactory repeated discrimination reversal in rats: effects of chlordiazepoxide, dizocilpine, and morphine.

    PubMed

    Galizio, Mark; Miller, Laurence; Ferguson, Adam; McKinney, Patrick; Pitts, Raymond C

    2006-10-01

    Effects of a benzodiazepine (chlordiazepoxide), an N-methyl-D-aspartate receptor antagonist (dizocilpine), and an opiate agonist (morphine) were studied with a procedure designed to assess effects of drugs and other manipulations on nonspatial learning in rats. In each session, rats were exposed to 2 different 2-choice odor-discrimination problems with food reinforcement for correct responses. One problem (performance discrimination) remained the same throughout the study. That is, 1 odor was always correct (S+) and the other was never correct (S-). For the other problem (reversal discrimination), stimuli changed every session. Six different odors were used to program the reversal discrimination; on any given session, S+ was a stimulus that had served as S- the last time it had appeared, S- was a stimulus that had been S+ on its last appearance. Thus, in each session, learning a discrimination reversal could be studied along with the performance of a comparable, but previously learned, discrimination. Chlordiazepoxide interfered with reversal learning at doses that had no effect on the performance discrimination. Morphine and dizocilpine also impaired reversal learning but only at doses that also affected performance of the well-learned performance discrimination.

  13. Administration of lithium and magnesium chloride inhibited tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice.

    PubMed

    Ghasemi, Abbas; Saberi, Mohammad; Ghasemi, Mehdi; Shafaroodi, Hamed; Moezi, Leila; Bahremand, Arash; Montaser-Kouhsari, Laleh; Ziai, Pouya; Dehpour, Ahmad Reza

    2010-12-01

    Although morphine has an anticonvulsant effect in several animal models of seizures, its potential clinical application in epilepsy may be hindered by its adverse effects like opioid tolerance. The present study evaluated the development of tolerance to the anticonvulsant effect of morphine in a model of clonic seizures induced with pentylenetetrazole (PTZ) in male Swiss mice. We also examined whether administration of either lithium chloride (LiCl) or magnesium chloride (MgCl(2)) was able to prevent the probable tolerance. Our data demonstrated that the anticonvulsant effect of a potent dose of morphine (1mg/kg) was abolished in chronic morphine-treated mice (mice administered the same dose of morphine intraperitoneally twice daily for 4 days). Four days of pretreatment with low and noneffective doses of MgCl(2) (2 and 5mg/kg) and LiCl (5mg/kg) inhibited the development of tolerance to the anticonvulsant effect of morphine (1mg/kg, ip). Moreover, a single acute injection of the aforementioned agents at the same doses reversed the expression of tolerance to the anticonvulsant effects of morphine (1mg/kg, ip). Chronic 17-day treatment with LiCl (600 mg/L in drinking water) also inhibited the development of tolerance to the anticonvulsant effects of 1mg/kg morphine. These results demonstrate that the anticonvulsant effect of morphine is subject to tolerance after repeated administration. Both development and expression of tolerance are inhibited by either LiCl or MgCl(2). As both LiCl and MgCl(2) can modulate the function of N-methyl-d-aspartate (NMDA) receptors, we discuss how NMDA receptor functioning might be involved in the effects of LiCl and MgCl(2) on the development of tolerance to the anticonvulsant effect of morphine.

  14. The blockade of GABAA receptors attenuates the inhibitory effect of orexin type 1 receptors antagonist on morphine withdrawal syndrome in rats.

    PubMed

    Davoudi, Mahnaz; Azizi, Hossein; Mirnajafi-Zadeh, Javad; Semnanian, Saeed

    2016-03-23

    The aim of present study was to investigate the involvement of orexin-A neuropeptide in naloxone-induced morphine withdrawal syndrome via modulating neurons bearing GABAA receptors. The locus coeruleus (LC) is a sensitive site for expression of the somatic aspects of morphine withdrawal. Intra-LC microinjection of GABAA receptor agonist attenuates morphine withdrawal signs in rats. Here we studied the influence of LC orexin type 1 receptors blockade by SB-334867 in presence of bicuculline, a GABAA receptor antagonist, on naloxone-induced morphine withdrawal syndrome. Adult male Wistar rats, weighing 250-300 g, were rendered dependent on morphine by subcutaneous (s.c.) injection of increasing morphine doses (6, 16, 26, 36, 46, 56 and 66 mg/kg, 2 ml/kg) at set intervals of 24 h for 7 days. On 8th day, naloxone (3 mg/kg, s.c.) was injected and the somatic signs of morphine withdrawal were evaluated. Intra-LC microinjections (0.2 μl) of either bicuculline (15 μM) or SB-334867 (3 mM) or a combination of both chemicals were done immediately before naloxone injection. Intra-LC microinjection of bicuculline (15 μM) had no significant effect on morphine withdrawal signs, whereas intra-LC microinjection of SB-334867 considerably attenuated morphine withdrawal signs. However, the effect of SB-334867 in attenuating naloxone-induced morphine withdrawal signs was blocked in presence of bicuculline. This finding, for the first time, indicated that orexin-A may participate in expression of naloxone-induced morphine withdrawal syndrome partly through decreasing the activity of neurons bearing GABAA receptors.

  15. The effects of lamotrigine on the acquisition and expression of morphine-induced place preference in mice.

    PubMed

    Tehrani, S Pournaghash; Daryaafzoon, M; Bakhtiarian, A; Ejtemaeemehr, S; Sahraei, H

    2009-01-01

    The purpose of the present study is to determine the effects of the anticonvulsant drug, lamotrigine, on the acquisition and expression of morphine-induced place preference in mice. Lamotrigine prevents the release of glutamate from presynaptic neurons and inhibits action potential in postsynaptic area by inhibiting presynaptic sodium and calcium channels. Because of such properties, lamotrigine is used for reducing craving for and use of cocaine, alcohol and abused inhalant. So, to determine the effects of lamotrigine on opiates; specifically morphine, 180 male Swiss-Webster mice (20-35 g) were used in this study. Conditioned place preference, was assessed using a biased place conditioning paradigm. In a pilot study the effects of various doses of morphine (2.5, 5 and 10 mg kg(-1)), alone, or in combination with lamotrigine (1, 5 and 25 mg kg(-1)) on the place conditioning paradigm were examined. Animals were injected with the aforementioned doses of lamotrigine 60 min either prior to each morphine injections (acquisition) or prior to the start of the expression on the test day (expression). Administration of different doses of morphine (2.5, 5 and 10 mg kg(-1)) induced conditioned place preference whereas the administration of different doses of lamotrigine (1, 5 and 25 mg kg(-1)) failed to induce place preference. Acquisition and expression of morphine-induced CPP were reduced by lamotrigine at doses of 1, 5 and 25 mg kg(-1) and 5 and 25 mg kg(-1), respectively. Physiological mechanisms of action of lamotrigine and its potential therapeutic use in the treatment of drug-dependence are discussed.

  16. 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.

  17. The Effect of Oral Morphine on Pain-Related Brain Activation - An Experimental Functional Magnetic Resonance Imaging Study.

    PubMed

    Hansen, Tine Maria; Olesen, Anne Estrup; Graversen, Carina; Drewes, Asbjørn Mohr; Frøkjaer, Jens Brøndum

    2015-11-01

    Knowledge about cerebral mechanisms underlying pain perception and effect of analgesic drugs is important for developing methods for diagnosis and treatment of pain. The aim was to explore altered brain activation before and after morphine treatment using functional magnetic resonance imaging recorded during experimental painful heat stimulation. Functional magnetic resonance imaging data were recorded and analysed in 20 healthy volunteers (13 men and 7 women, 24.9 ± 2.6 years) in a randomized, double-blind, placebo-controlled, cross-over study. Painful stimulations were applied to the right forearm using a contact heat evoked potential stimulator (CHEPS) before and after treatment with 30 mg oral morphine and placebo. CHEPS stimulations before treatment induced activation in the anterior cingulate cortex, secondary somatosensory cortex/insula, thalamus and cerebellum (n = 16, p < 0.05). In response to morphine treatment, the spatial extent of these pain-specific areas decreased (n = 20). Reduced pain-induced activation was seen in the right insula, anterior cingulate cortex and inferior parietal cortex after morphine treatment compared to before treatment (n = 16, p < 0.05), and sensory ratings of pain perception were significantly reduced after morphine treatment (p = 0.02). No effect on pain-induced brain activation was seen after placebo treatment compared to before treatment (n = 12, p > 0.05). In conclusion, heat stimulation activated areas in the 'pain matrix' and a clinically relevant dose of orally administered morphine revealed significant changes in brain areas where opioidergic pathways are predominant. The method may be useful to investigate the mechanisms of analgesics.

  18. Effects of treadmill running exercise during the adolescent period of life on behavioral deficits in juvenile rats induced by prenatal morphine exposure.

    PubMed

    Ahmadalipour, Ali; Rashidy-Pour, Ali

    2015-02-01

    Prenatal exposure to morphine throughout pregnancy results in an array of prolonged or permanent neurochemical and behavioral deficits, including deficits in learning and memory in children of addicted mothers. This study investigated the effects of forced exercise on behavioral deficits of pups born to mothers addicted to morphine in rats. After mating and ensuring of pregnancy of female Wistar rats, they were divided into morphine or saline groups and in the second half of pregnancy (on days 11-18 of gestation) were injected subcutaneously with morphine or saline, respectively. Pups were weaned at postnatal day (PND) 21 and trained at mild intensity on a treadmill 20 days. On PND 41-47, the behavioral responses were studied. Light/dark (L/D) box and elevated plus maze (EPM) apparatus were used for investigation of anxiety, shuttle box and forced swimming tests were used to assess passive avoidance learning and memory and depression behavior, respectively. The results showed that prenatal morphine exposure caused reductions in time spent in light compartment of L/D box and EPM open arm, while postnatal exercise reversed these effects. We also found that prenatal morphine exposure caused a reduction in step through latency in passive avoidance memory test and exercise counteracted with this effect. Performance in the forced swimming test did not affected by prenatal morphine exposure or postnatal exercise. Exercise seems to be one of the strategies in reduction of behavioral deficits of children born to addicted mothers to morphine.

  19. Molecular Mechanisms Underlying the Enhanced Analgesic Effect of Oxycodone Compared to Morphine in Chemotherapy-Induced Neuropathic Pain

    PubMed Central

    Thibault, Karine; Calvino, Bernard; Rivals, Isabelle; Marchand, Fabien; Dubacq, Sophie; McMahon, Stephen B.; Pezet, Sophie

    2014-01-01

    Oxycodone is a μ-opioid receptor agonist, used for the treatment of a large variety of painful disorders. Several studies have reported that oxycodone is a more potent pain reliever than morphine, and that it improves the quality of life of patients. However, the neurobiological mechanisms underlying the therapeutic action of these two opioids are only partially understood. The aim of this study was to define the molecular changes underlying the long-lasting analgesic effects of oxycodone and morphine in an animal model of peripheral neuropathy induced by a chemotherapic agent, vincristine. Using a behavioural approach, we show that oxycodone maintains an optimal analgesic effect after chronic treatment, whereas the effect of morphine dies down. In addition, using DNA microarray technology on dorsal root ganglia, we provide evidence that the long-term analgesic effect of oxycodone is due to an up-regulation in GABAB receptor expression in sensory neurons. These receptors are transported to their central terminals within the dorsal horn, and subsequently reinforce a presynaptic inhibition, since only the long-lasting (and not acute) anti-hyperalgesic effect of oxycodone was abolished by intrathecal administration of a GABAB receptor antagonist; in contrast, the morphine effect was unaffected. Our study demonstrates that the GABAB receptor is functionally required for the alleviating effect of oxycodone in neuropathic pain condition, thus providing new insight into the molecular mechanisms underlying the sustained analgesic action of oxycodone. PMID:24618941

  20. Effect of ketamine, pentobarbital, and morphine on Tc-99m-DISIDA hepatobiliary kinetics

    SciTech Connect

    Durakovic, A.; Dubois, A.

    1985-05-01

    The purpose of this study was to evaluate hapatobiliary kinetics of Tc-99m-DISIDA in dogs after administration of anesthetic sedative or narcotic agents. Four groups of six male Beagle dogs were studied as a non-treated control group and after parenteral administration of ketamine (30 mg/kg IM), pentobarbital (25 mg/kg IV) or morphine (1 mg/kg IV). Each animal was injected with 4 mCi Tc-99m-DISIDA and hepatobiliary scintigraphic studies were obtained using a gamma camera with parallel hole multipurpose collimator and an A/sup 3/ MDS computer. The authors determined; peak activity of Tc-99m-DISIDA in the liver, visualization and peak activity of gallbladder, and intestinal visualization of Tc-99m-DISIDA. Total bilirubin, LDH, SGOT and SGPT were not modified significantly after any drug compared to control. The results showed that two commonly used anesthetics and sedatives (ketamine and pentobarbital) have dramatic and opposite effects on extrahepatic biliary kinetics. Furthermore, ketamine, but not pentobarbital, significantly accelerates intrahepatic biliary kinetics. Finally, as expected, morphine delayed extrahepatic biliary kinetics. Thus, studies of biliary kinetics should be interpreted with caution when measurements are made after administration of anesthetic, sedative or narcotic agents.

  1. [Analgesic and opioid-sparing effects of intravenous paracetamol in the early period after aortocoronary bypass surgery].

    PubMed

    Eremenko, A A; Kuslieva, E V

    2008-01-01

    The study was to evaluate the analgesic and opioid-sparing effect of intravenous paracetamol injections in cardiosurgical patients in the early postoperative period. Adequate analgesia within the first 12-18 hours of the early postoperative period is very important for a good prognosis of the further course of pain syndrome and for the reduction of a risk for its progression to its chronic form. In early studies, propacetamol lowered morphine use after orthopedic and gynecological operations. The efficacy of paracetamol used in cardiac surgery has been little studied and the results of the studies are conflicting. The randomized, blind, placebo-controlled study included patients after aortocoronary bypass surgery, of them 22 patients received paracetamol and 23 had placebo. The test drug (perfalgan 100 ml or placebo) was intravenously injected 30 min before extubation and then every 6 hours within succeeding 18 hours. The intensity of the pain syndrome was rated by a 5-score verbal scale every 2 hours. With pain score of 2 or more, promedol was intramuscularly administered in a dose of 10 mg. Inspiratory volume was recorded before extubation and the first administration of a drug just after extubation and then every 2 hours. The baseline indices did not differ in both groups. Throughout the observation, the inspiratory volume was lower in the paracetamol group than in the placebo group; however, there was a statistically significant difference (p = 0.012) in the reduction in the manifestations of the pain syndrome (by 81%) only just after tracheal extubation. During this period, inspiratory volume values were higher in the paracetamol group; however, a statistically significant (39%) difference between the groups in the mean values was obtained only during and 2 hours after extubation. In the perfalgan group, the mean total use of promedol was 36% less than in the placebo-group, which was statistically significant (p = 0.019). The early postoperative use of

  2. Discriminative stimulus effects of morphine and oxycodone in the absence and presence of acetic acid in male and female C57Bl/6 mice.

    PubMed

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

    2015-08-01

    The use of prescription opioids for clinical management of pain remains problematic because of concerns about addiction associated with opioid use. Another difficulty in pain management is the increasing evidence for sex differences in pain behavior and opioid-induced behavioral effects. However, few studies have documented the abuse potential of prescription opioids as a function of pain in rodents, with significant gaps in the literature pertaining to sex differences in the interaction between pain and opioid effects. The present study evaluated the effects of an experimentally induced acute pain state (acetic acid injections) on the potency of morphine and oxycodone to produce discriminative stimulus effects in male and female C57Bl/6 mice trained to discriminate 3.2 mg/kg morphine from saline. Acetic acid injections attenuated the stimulus potency of morphine by 2.2-fold but not the stimulus potency of oxycodone in male mice. Acetic acid injections did not alter the discriminative stimulus effects of either morphine or oxycodone in female mice. The antinociceptive effects of the 2 opioids were evaluated using the acetic acid-induced stretching test. For antinociceptive effects, morphine was 2.0-fold less potent relative to oxycodone in male mice, whereas morphine and oxycodone were equipotent in female mice. Taken together, these results indicate that acetic acid-induced acute pain differentially modulates the discriminative stimulus effects of morphine in male and female mice and that this change may be related to the variable antinociceptive effectiveness of these opioids across sexes.

  3. Changes in locomotor-activity patterns as a measure of spontaneous morphine withdrawal: no effect of clonidine.

    PubMed

    van der Laan, J W; de Groot, G

    1988-10-01

    The anti-withdrawal action of clonidine was studied in a model of spontaneous morphine withdrawal in rats. After withdrawal the behaviour of the animals was registered continuously for several days. In the initial phase of induction of dependence the locomotor activity was enhanced during daytime. Partial tolerance to this increase developed in the course of 3 weeks. In morphine withdrawn animals the activity decreased strongly at night, and this effect was maximal on the second night after removal of morphine. After four nights the nightly activity was restored. Treatment with clonidine (100 micrograms/kg s.c. twice daily) changed neither the observed decrease in nightly locomotor activity nor other withdrawal symptoms such as a decrease in food intake and loss of body weight. In non-dependent animals clonidine induced a biphasic effect in locomotor activity, i.e. a decrease in the first few hours of the night and an increase in the second part of the night. The latter can be interpreted as a rebound phenomenon occurring after only three injections. It was concluded that clonidine was not effective as an anti-withdrawal compound in a model for spontaneous morphine abstinence. The low incidence of symptoms relating to a hyperactive sympathetic system during spontaneous withdrawal may be an explanation for the absence of an effect of clonidine.

  4. Effects of Daily Morphine Administration and Deprivation on Choice and Demand for Remifentanil and Cocaine in Rhesus Monkeys

    ERIC Educational Resources Information Center

    Wade-Galuska, Tammy; Galuska, Chad M.; Winger, Gail

    2011-01-01

    Choice procedures have indicated that the relative reinforcing effectiveness of opioid drugs increases during opioid withdrawal. The demand curve, an absolute measure of reinforcer value, has not been applied to this question. The present study assessed whether mild morphine withdrawal would increase demand for or choice of remifentanil or…

  5. [Effects of propranolol on acquisition and retrieval of morphine- induced conditioned place preference memories in ICR mice].

    PubMed

    Mao, Yu; Yang, Shang-Chuan; Liu, Chang; Ma, Yuan-Ye; Hu, Xin-Tian

    2011-12-01

    To interfere with the drug-cue memory processes of addicts such as reconsolidation by the administration of the β-adrenergic receptor (β-AR) of norepinephrine (NE) antagonist propranolol (PRO) has become a potential therapy in the future to decrease or inhibit relapse. However, the relationship between PRO and the acquisition or retrieval of morphine-cue memory is not clear. This study examined the effects of PRO on the acquisition and retrieval of memories in morphine-induced conditioned place preference (CPP) mice model. We found that during memory acquisition period, PRO had no effects on the expression and extinction of morphine-CPP, which suggests that the β-AR was irrelevant to the CPP memory acquisition. However, during memory retrieval period, although PRO did not affect the expression of CPP, but it delayed the occurrence of CPP extinction, which indicates that PRO has an inhibit effect on CPP memory extinction, and β-AR plays an important role in modulating the extinction of morphine-CPP. Our study further improved the relationship between drug addiction and β-AR, and proposed a new theory to help developing potential therapy to cure addiction and other neuropsychiatric disorders.

  6. [Effects of propranolol on acquisition and retrieval of morphine- induced conditioned place preference memories in ICR mice].

    PubMed

    Mao, Yu; Yang, Shang-Chuan; Liu, Chang; Ma, Yuan-Ye; Hu, Xin-Tian

    2011-12-01

    To interfere with the drug-cue memory processes of addicts such as reconsolidation by the administration of the β-adrenergic receptor (β-AR) of norepinephrine (NE) antagonist propranolol (PRO) has become a potential therapy in the future to decrease or inhibit relapse. However, the relationship between PRO and the acquisition or retrieval of morphine-cue memory is not clear. This study examined the effects of PRO on the acquisition and retrieval of memories in morphine-induced conditioned place preference (CPP) mice model. We found that during memory acquisition period, PRO had no effects on the expression and extinction of morphine-CPP, which suggests that the β-AR was irrelevant to the CPP memory acquisition. However, during memory retrieval period, although PRO did not affect the expression of CPP, but it delayed the occurrence of CPP extinction, which indicates that PRO has an inhibit effect on CPP memory extinction, and β-AR plays an important role in modulating the extinction of morphine-CPP. Our study further improved the relationship between drug addiction and β-AR, and proposed a new theory to help developing potential therapy to cure addiction and other neuropsychiatric disorders. PMID:22184028

  7. The magnitude and duration of the analgesic effect of morphine, butorphanol, and buprenorphine in rats and mice.

    PubMed

    Gades, N M; Danneman, P J; Wixson, S K; Tolley, E A

    2000-03-01

    This study was designed to determine the magnitude and duration of the analgesic effect of three commonly used opioids: buprenorphine (0.5 mg/kg for rats; 2.0 mg/kg for mice), butorphanol (2.0 mg/kg for rats; 5.0 mg/kg for mice), and morphine (10 mg/kg for rats and mice). We used two standard tests, the hot plate and tail flick assays, to measure opioid analgesia in 62 male, 200 to 300 g Sprague-Dawley rats and 61 male, 25 to 35 g ICR mice. We obtained five baseline measurements then administered the drugs subcutaneously. Morphine gave the highest analgesic effect and was intermediate in duration (2 to 3 h in rats and mice) of analgesia. Butorphanol provided the lowest level of and shortest (1 to 2 h in rats and mice) analgesia. Buprenorphine had an intermediate analgesic effect and the longest duration (6 to 8 h in rats and 3 to 5 h in mice). In light of our results, we recommend the use of morphine (with frequent redosing) for severe pain, butorphanol for mild pain of short duration, and buprenorphine for mild to moderate pain of increased duration. The dosing intervals suggested by our study are 2 to 3 h for morphine in both rats and mice, 1 to 2 h for butorphanol in both rats and mice; and 6 to 8 h in rats and 3 to 5 h in mice for buprenorphine. PMID:11487232

  8. Effect of premedication with diazepam, morphine or nalbuphine on gastrointestinal motility after surgery.

    PubMed

    Shah, M; Rosen, M; Vickers, M D

    1984-11-01

    Premedication with nalbuphine and morphine delayed gastric emptying in the period after operation, but oral diazepam did not. All three drugs delayed co-ordinated intestinal motility, although nalbuphine did so for less than half as long as morphine. This property of nalbuphine, if confirmed, could make it a valuable analgesic drug in the period after operation. PMID:6487444

  9. Development of tolerance to the antinociceptive effect of systemic morphine at the lumbar spinal cord level: a c-Fos study in the rat.

    PubMed

    Le Guen, S; Catheline, G; Besson, J M

    1998-11-30

    The development of tolerance to the antinociceptive effects of morphine was investigated in rats using carrageenin-induced spinal c-Fos expression. We took advantage of this technique to especially study, at the cellular level, in freely moving animals, the development of tolerance based on the visualization of dorsal horn spinal cord neurons which play a major role in nociceptive processes. Two hours after intraplantar injection of carrageenin (6 mg/150 microliter of saline), c-Fos-like immunoreactivity (FLI) was observed predominantly in the superficial and deep laminae of the dorsal horn in segments L4 and L5 of the spinal cord. In naive rats, acute intravenous morphine (3 mg/kg, i.v.) reduced the number of superficial and deep FLI neurons; 49% and 59% reduction respectively (p<0.0001 for both). In morphine-pretreated rats (daily administration of subcutaneous morphine: 1, 3, 5, 10, 20 or 40 mg/kg once a day for 4 days), antinociceptive tolerance tested on day 5 by acute morphine (3 mg/kg, i.v.) was manifest in those groups pretreated with the highest doses of morphine (10, 20 or 40 mg/kg). From regression analysis, it appeared that tolerance to the antinociceptive effect of morphine developed progressively as a function of the chronic morphine dose used on neurons involved in spinal nociceptive processes (superficial and deep dorsal horn neurons). Similarly, in rats pretreated with 10 mg/kg of morphine over 1, 2, 3 or 4 days, tolerance progressively developed, for both spinal neuronal populations, as a function of the duration of the pretreatment. These results are discussed in the context of the several possible sites of action of morphine.

  10. SU-E-J-59: Effective Adaptive DMLC Gated Radiotherapy with OAR Sparing

    SciTech Connect

    Chen, Y; Wu, H; Zhou, Z; Sandison, MinGeorge

    2014-06-01

    Purpose: Patient respiratory motion degrades the effectiveness of cancer radiation treatment. Advanced respiratory gating delivers radiation dose accurately yet with elongated treatment time. The goal of this research is to propose a novel adaptive dMLC dynamic gating with high delivery efficiency and precision. Methods: The dose delivery of dMLC is aided by simultaneous tracking of tumor and organ at risk (OAR). The leaf opening/closing will follow the motion trajectory of the tumor while sparing the OAR. The treatment beam turns on only when there is no overlapping between OAR and tumor in BEV. A variety of evaluation metrics were considered and calculated, including duty cycle, beam toggling rate, and direct irradiation avoidance to OAR, under various combinations of different tumor margins and the distance between the centers of the tumor and OAR in BEV (expressed as dx). Results: Retrospective simulation was performed to investigate the feasibility and superiority of this technique using four groups of synchronized tumor and OAR motion data. The simulation results indicate that the tumor and OAR motion patterns and their relative positions are the dominant influential factors. The duty cycle can be greater than 96.71% yet can be as low as 6.69% depending different motion groups. This proposed technique provides good OAR protection, especially for such cases with low duty cycle for which as high as 77.71% maximal direct irradiation to OAR can be spared. Increasing dx improves the duty cycle (treatment efficiency) and provides better OAR volume sparing, whereas, that of the tumor margins has the opposite influence. Conclusion: This real-time adaptive dMLC gated radiation treatment with synchronous tumor and OAR tracking has inherent accurate dose delivery to tumor with reduced treatment time. In addition, the OAR protection capability make it an outstanding potential treatment strategy for mobile tumors.

  11. The Effect of the iBEAM Evo Carbon Fiber Tabletop on Skin Sparing

    SciTech Connect

    Simpson, John B. Godwin, Guy A.

    2011-10-01

    Replicating the attenuation properties of the treatment tabletop are of primary importance for accurate treatment planning; however, the effect of the tabletop on the skin-sparing properties of x-rays can be overlooked. Under some conditions, the reaction of skin to the radiation can be so serious as to be the dose-limiting organ for radiotherapy treatment. Hence, an understanding of the magnitude of the reduction in skin sparing is important. Because of the development of image-guided radiotherapy, modern tabletops have been developed without the use of metal supports that otherwise provided the necessary level of rigidity. Rigidity is instead provided by compressed foam within a carbon-fiber shell, which, although it provides artefact-free imaging and high levels of rigidity, has an adverse affect on the dose in the build-up region. Representative of this type is the iBEAM evo tabletop, whose effect on the skin dose was determined at 6-MV, 10-MV, and 18-MV x-rays. Skin dose was found to increase by 60-70% owing to the tabletop, with the effect increasing with field size and decreasing with energy. By considering an endpoint of erythema, a radiobiological advantage of selecting 10 MV over 6 MV for applicable treatments was demonstrated.

  12. Specific blockade of morphine- and cocaine-induced reinforcing effects in conditioned place preference by nitrous oxide in mice.

    PubMed

    Benturquia, N; Le Guen, S; Canestrelli, C; Lagente, V; Apiou, G; Roques, B P; Noble, F

    2007-11-01

    Nitrous oxide (N(2)O), a pharmacological active gas and an antagonist of N-methyl-D-aspartic acid receptors, has been reported to be effective in the treatment of alcohol and tobacco withdrawal syndrome. However, the neurobiological bases of N(2)O effects are unknown. The aim of the present studies was to examine the effect of N(2)O on acquisition and expression of morphine- (10 mg/kg; s.c.) and cocaine- (20 mg/kg; i.p.) induced conditioned place preference (CPP) in mice. Unbiased place conditioning method was used. Mice were exposed to N(2)O during the conditioning phase (acquisition of CPP) or during postconditioning phase (expression of CPP). The same protocol was used to evaluate the impact of N(2)O on locomotor activity, two-trial recognition task (memory), spontaneous alternation, sucrose consumption (anhedonic state), forced swim (depressive state) and elevated O-maze tests (anxiety state). In all these tests, mice were treated with morphine (10 mg/kg, s.c.) the first day, the following day mice were given saline. This sequence alternated during the next 4 days. Control animals received saline every day. The behavior of animals was evaluated on day 8. N(2)O did not induce CPP but impaired the acquisition of morphine-induced CPP and blocked the expression of cocaine- and morphine-induced CPP. The effects of the gas were long lasting and persist 4 days following the exposure. Moreover no behavioral modifications in tests usually used to investigated emotional state as compared with control mice were observed in animals exposed to N(2)O, ruling out an effect of this gas on attention, anxiety, depression, locomotion and anhedonia. These studies raise the possibility that N(2)O could have a clinical benefit in the management of morphine and cocaine addiction.

  13. Withania somnifera root extract prolongs analgesia and suppresses hyperalgesia in mice treated with morphine.

    PubMed

    Orrù, Alessandro; Marchese, Giorgio; Casu, Gianluca; Casu, Maria Antonietta; Kasture, Sanjay; Cottiglia, Filippo; Acquas, Elio; Mascia, Maria Paola; Anzani, Nicola; Ruiu, Stefania

    2014-04-15

    Previous studies demonstrated that Withania somnifera Dunal (WS), a safe medicinal plant, prevents the development of tolerance to the analgesic effect of morphine. In the present study, we investigated whether WS extract (WSE) (100 mg/kg, i.p.) may also modulate the analgesic effect induced by acute morphine administration (2.5, 5, 10 mg/kg, s.c.) in the tail-flick and in the hot plate tests, and if it may prevent the development of 2.5 mg/kg morphine-induced rebound hyperalgesia in the low intensity tail-flick test. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor-binding assay, the affinity of WSE for opioid (μ, δ, k), cannabinoid (CB1, CB2), glutamatergic (NMDA), GABAergic (GABAA, GABAB), serotoninergic (5HT2A) and adrenergic (α2) receptors. The results demonstrated that (i) WSE alone failed to alter basal nociceptive threshold in both tests, (ii) WSE pre-treatment significantly protracted the antinociceptive effect induced by 5 and 10 mg/kg of morphine only in tail-flick test, (iii) WSE pre-treatment prevented morphine-induced hyperalgesia in the low intensity tail-flick test, and (iv) WSE exhibited a high affinity for the GABAA and moderate affinity for GABAB, NMDA and δ opioid receptors. WSE prolongs morphine-induced analgesia and suppresses the development of morphine-induced rebound hyperalgesia probably through involvement of GABAA, GABAB, NMDA and δ opioid receptors. This study suggests the therapeutic potential of WSE as a valuable adjuvant agent in opioid-sparing therapies.

  14. Effect of Nebulized Morphine on Dyspnea of Mustard Gas-Exposed Patients: A Double-Blind Randomized Clinical Trial Study

    PubMed Central

    Shohrati, Majid; Ghanei, Mostafa; Harandi, Asghar Amini; Foroghi, Soniya; Harandi, Ali Amini

    2012-01-01

    Background. Dyspnea is one of the main complaints in a group of COPD patients due to exposure to sulfur mustard (SM) and is refractory to conventional therapies. We designed this study to evaluate effectiveness of nebulized morphine in such patients. Materials and Methods. In a double-blind clinical trial study, 40 patients with documented history of exposure to SM were allocated to two groups: group 1 who received 1 mg morphine sulfate diluted by 4 cc normal saline 0.5% using nebulizer once daily for 5 days and group 2 serving as control who received normal saline as placebo. They were visited by pulmonologist 7 times per day to check symptoms and signs and adverse events. Different parameters including patient-scored peak expiratory flow using pick flow meter, visual analogue scale (VAS) for dyspnea, global quality of life and cough, and number of respiratory rate, night time awaking for dyspnea and cough have been assessed. Results. The scores of VAS for dyspnea, cough and quality of life and also respiratory rate, heart rate, and night time awaking due to dyspnea and night time awaking due to cough improved significantly after morphine nebulization without any major adverse events. Also pick expiratory flow has been improved significantly after nebulization in each day. Conclusion. Our results showed the clinical benefit of nebulized morphine on respiratory complaints of patients due to exposure to SM without significant side effects. PMID:22530119

  15. Effect of nebulized morphine on dyspnea of mustard gas-exposed patients: a double-blind randomized clinical trial study.

    PubMed

    Shohrati, Majid; Ghanei, Mostafa; Harandi, Asghar Amini; Foroghi, Soniya; Harandi, Ali Amini

    2012-01-01

    Background. Dyspnea is one of the main complaints in a group of COPD patients due to exposure to sulfur mustard (SM) and is refractory to conventional therapies. We designed this study to evaluate effectiveness of nebulized morphine in such patients. Materials and Methods. In a double-blind clinical trial study, 40 patients with documented history of exposure to SM were allocated to two groups: group 1 who received 1 mg morphine sulfate diluted by 4 cc normal saline 0.5% using nebulizer once daily for 5 days and group 2 serving as control who received normal saline as placebo. They were visited by pulmonologist 7 times per day to check symptoms and signs and adverse events. Different parameters including patient-scored peak expiratory flow using pick flow meter, visual analogue scale (VAS) for dyspnea, global quality of life and cough, and number of respiratory rate, night time awaking for dyspnea and cough have been assessed. Results. The scores of VAS for dyspnea, cough and quality of life and also respiratory rate, heart rate, and night time awaking due to dyspnea and night time awaking due to cough improved significantly after morphine nebulization without any major adverse events. Also pick expiratory flow has been improved significantly after nebulization in each day. Conclusion. Our results showed the clinical benefit of nebulized morphine on respiratory complaints of patients due to exposure to SM without significant side effects. PMID:22530119

  16. Individual differences in the psychomotor effects of morphine are predicted by reactivity to novelty and influenced by corticosterone secretion.

    PubMed

    Deroche, V; Piazza, P V; Le Moal, M; Simon, H

    1993-10-01

    Clinical observations show that individual vulnerability to the reinforcing properties of drugs plays an important part in the subsequent development of addition. In animals, individual vulnerability to psychostimulants has been found to be predicted by their locomotor response to novelty as well as their corticosterone response. Rats with a high locomotor response to novelty (High Responders or HR) relative to Low Responders (LR), show a higher sensitivity to both the psychomotor and reinforcing effects of psychostimulants and a longer lasting corticosterone secretion in response to stress. In this study, we addressed two main questions. First, does the locomotor response to novelty also predict the psychomotor effects of morphine? Second, do differences in corticosterone secretion underlie individual differences in the stimulant effects of morphine? We compared the locomotor response to morphine (2 mg/kg s.c.) in: (i) HR and LR rats with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) HR and LR rats in which stress-induced corticosterone secretion was suppressed by adrenalectomy but basal levels of corticosterone were maintained by implantation of subcutaneous corticosterone pellets. In animals with an intact HPA axis, HR rats showed a higher locomotor response than did LRs to morphine. In animals in which corticosterone secretion was suppressed, the enhanced locomotor response of the HRs to morphine fell to that observed in the LRs. In conclusion our data show that, (1) individual reactivity to novelty can predict individual vulnerability to the psychomotor effects of opioids, and (2) stress-induced corticosterone secretion may play a role in determining individual differences in sensitivity to these drugs.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8221119

  17. Working Memory in the Odor Span Task: Effects of Chlordiazepoxide, Dizocilpine (MK801), Morphine and Scopolamine

    PubMed Central

    Galizio, Mark; Deal, Melissa; Hawkey, Andrew; April, Brooke

    2012-01-01

    Rationale A number of tasks are used to assess working memory in rodents, but the Odor Span task (OST) is unique in studying performance as a function of the number of stimuli to remember. Objectives The purpose of the present study was to better characterize the behavioral pharmacology of the OST by exploring the effects of several amnestic agents including an NMDA antagonist (dizocilpine), a positive GABA-A modulator (chlordiazepoxide), an anticholinergic compound (scopolamine) and as a negative control, an opiate receptor agonist (morphine). Methods Rats were trained to perform on the OST which is a non-match-to-sample procedure with an incrementing number of sample odors to remember as the session progresses. Trials with a simple odor discrimination task (SD) were interspersed to provide a control for effects unrelated to memory load. Results All four drugs disrupted performances on the OST task in a dose-dependent fashion, but only the NMDA antagonist dizocilpine produced impairments that were clearly dependent on the number of stimuli to remember. Dizocilpine impaired OST performance at a dose (0.1 mg/kg) that did not affect SD and that impairment depended on memory-load. Chlordiazepoxide (3.0 mg/kg) also produced amnestic effects that were manifest by shorter memory spans and runs of correct responding. In contrast, morphine and scopolamine impaired OST accuracy only at doses that also disrupted SD (18.0 and 0.3 mg/kg, respectively). Conclusions These results provide evidence of NMDA and benzodiazepine modulation of working memory as assessed by the OST. PMID:22918519

  18. Dual Inhibition of Endocannabinoid Catabolic Enzymes Produces Enhanced Antiwithdrawal Effects in Morphine-Dependent Mice

    PubMed Central

    Ramesh, Divya; Gamage, Thomas F; Vanuytsel, Tim; Owens, Robert A; Abdullah, Rehab A; Niphakis, Micah J; Shea-Donohue, Terez; Cravatt, Benjamin F; Lichtman, Aron H

    2013-01-01

    Inhibition of the endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) attenuates naloxone-precipitated opioid withdrawal signs in mice via activation of CB1 receptors. Complete FAAH inhibition blocks only a subset of withdrawal signs, whereas complete MAGL inhibition elicits enhanced antiwithdrawal efficacy, but is accompanied with some cannabimimetic side effects. Thus, the primary objective of the present study was to determine whether combined, full FAAH inhibition and partial MAGL represents an optimal strategy to reduce opioid withdrawal. To test this hypothesis, we examined whether combined administration of high-dose of the FAAH inhibitor PF-3845 and low-dose of the MAGL inhibitor JZL184, as well as the novel dual FAAH-MAGL inhibitor SA-57, which is 100-fold more potent in inhibiting FAAH than MAGL, would prevent spontaneous withdrawal in morphine-dependent mice, a model with greater face validity than precipitating withdrawal with μ-opioid receptor antagonists. Strikingly, a combination of low-dose JZL184 and high-dose PF-3845 as well as the dual inhibitor SA-57 reduced all abrupt withdrawal signs (ie, platform jumping, paw flutters, head shakes, diarrhea, and total body weight loss), but did not elicit any cannabimimetic side effects. In addition, JZL184 or PF-3845 blocked naloxone-precipitated hypersecretion in morphine-dependent small intestinal tissue. Collectively, these results are the first to show that endocannabinoid catabolic enzyme inhibitors reduce abrupt withdrawal in morpine-dependent mice and are effective in a novel in vitro model of opioid withdrawal. More generally, these findings support the idea that joint MAGL and FAAH inhibition represents a promising approach for the treatment of opioid dependence. PMID:23303065

  19. Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia

    PubMed Central

    Hutchinson, Mark R.; Northcutt, Alexis L.; Chao, Lindsey W.; Kearney, Jeffrey J.; Zhang, Yingning; Berkelhammer, Debra L.; Loram, Lisa C.; Rozeske, Robert R.; Bland, Sondra T.; Maier, Steven F.; Gleeson, Todd T.; Watkins, Linda R.

    2008-01-01

    Recent data suggest that opioids can activate immune-like cells of the central nervous system (glia). This opioid-induced glial activation is associated with decreased analgesia, owing to the release of proinflammatory mediators. Here we examine in rats whether the putative microglial inhibitor, minocycline, may affect morphine-induced respiratory depression and/or morphine-induced reward (conditioned place preference). Systemic co-administration of minocycline significantly attenuated morphine-induced reductions in tidal volume, minute volume, inspiratory force and expiratory force, but did not affect morphine-induced reductions in respiratory rate. Minocycline attenuation of respiratory depression was also paralleled with significant attenuation by minocycline of morphine-induced reductions in blood oxygen saturation. Minocycline also attenuated morphine conditioned place preference. Minocycline did not simply reduce all actions of morphine, as morphine analgesia was significantly potentiated by minocycline co-administration. Lastly, morphine dose-dependently increased cyclooxygenase-1 gene expression in a rat microglial cell line, an effect that was dose-dependently blocked by minocycline. Together, these data support that morphine can directly activate microglia in a minocycline-suppressible manner and suggest a pivotal role for minocycline-sensitive processes in the mechanisms of morphine-induced respiration depression, reward, and pain modulation. PMID:18706994

  20. Effects of repeated exposure to morphine in adolescent and adult male C57BL/6J mice: age-dependent differences in locomotor stimulation, sensitization, and body weight loss

    PubMed Central

    Koek, Wouter

    2013-01-01

    Rationale Given evidence for age-related differences in the effects of drugs of abuse, surprisingly few preclinical studies have explored effects of opioids in adolescents (versus adults). Objectives This study compared the motor stimulating and ataxic effects of repeatedly-administered morphine in adolescent, late-adolescent, and adult mice. Methods Mice were treated with saline or morphine (10–100 mg/kg, i.p.) once per day for 4 days, and morphine (3.2–56 mg/kg)-induced locomotion was assessed 3 days or 5 weeks later. Different mice were treated repeatedly with morphine and ataxia was measured. Results Acute administration of morphine increased locomotion more in adolescents than in adults. Repeated morphine enhanced morphine-induced locomotion, assessed 3 days later, to a similar extent in each age group (minimum effective dose: 17.8 mg/kg). This sensitization was still evident 5 weeks later when the adolescents had become adult, but was smaller and occurred at a higher dose (56 mg/kg). In animals treated repeatedly with morphine as adults, sensitization was no longer apparent 5 weeks later. Intermittent morphine was at least 10-fold less potent to produce body weight loss in adolescents than in adults. Repeated morphine did not alter morphine-induced ataxia at any age. Conclusions Compared with adults, adolescents were more sensitive to the acute locomotor stimulating effects of morphine and to its long-lasting locomotor sensitizing effects, consistent with overactivity of dopamine systems during adolescence. In contrast, adolescents were less sensitive than adults to body weight loss induced by intermittent morphine, an effect indicative of morphine withdrawal in adult rodents. PMID:24096538

  1. Steroid-sparing effect and toxicity of dapsone treatment in giant cell arteritis

    PubMed Central

    Ly, Kim Heang; Dalmay, François; Gondran, Guillaume; Palat, Sylvain; Bezanahary, Holy; Cypierre, Anne; Fauchais, Anne-Laure; Liozon, Eric

    2016-01-01

    Abstract Although a glucocorticoid (GC)-sparing strategy is needed for patients with giant cell arteritis (GCA) suffering from refractory disease or serious treatment-related complications, evidence of efficacy in this setting of immunosuppressive drugs and biotherapies is lacking. Herein, we evaluated the GC-sparing effects and tolerability of addition of dapsone (DDS) to prednisone therapy in patients with GCA. We retrospectively assessed data on 18 GCA patients who received DDS as a first-line treatment (DDS-1 group) and 52 patients who received it as a second- or third-line treatment for refractory GCA, with or without excessive GC-related toxicity (DDS-2 group). Of these 70 patients, 63 belonged to an inception cohort of 478 patients, whereas the remaining 7 were referred to our department for resistant GCA. In all, 52 patients were assessable for DDS efficacy. The baseline characteristics of the DDS-1 patients were similar to those of 395 GCA patients (control group) who received prednisone alone. DDS-1 patients had a more sustained decrease in GC dose with a lower mean prednisone dose at 12 months, and they comprised higher proportions who achieved GC withdrawal within the first year, who stopped prednisone treatment, and who recovered from GCA (P < 0.001 for each variable). Patients in the DDS-2 group achieved a mean rate of prednisone reduction of 65% and a prednisone dose reduction of 16.9 ± 13.3 mg/d. The monthly decreases in the prednisone dose were 2.4 and 1.25 mg in DDS-1 and DDS-2 patients, respectively. DDS-induced side effects were recorded in 44 (64%) assessable patients. These side effects led to lowering of the DDS dose by 25 mg/d in 11 (16%) patients and permanent cessation of DDS in 14 patients (20%), due to allergic skin rash in 7, agranulocytosis in 2, icteric hepatitis in 2, and excessive hemolysis in 2 patients. DDS is a potent GC-sparing agent in GCA that should be evaluated in prospective studies. However, DDS use should

  2. Morphine-Induced Analgesic Tolerance Effect on Gene Expression of the NMDA Receptor Subunit 1 in Rat Striatum and Prefrontal Cortex

    PubMed Central

    Ahmadi, Shamseddin; Rafieenia, Fatemeh; Rostamzadeh, Jalal

    2016-01-01

    Introduction: Morphine is a potent analgesic but its continual use results in analgesic tolerance. Mechanisms of this tolerance remain to be clarified. However, changes in the functions of μ-opioid and N-Methyl-D-aspartate (NMDA) receptors have been proposed in morphine tolerance. We examined changes in gene expression of the NMDA receptor subunit 1 (NR1) at mRNA levels in rat striatum and prefrontal cortex (PFC) after induction of morphine tolerance. Methods: Morphine (10 mg/kg, IP) was injected in male Wistar rats for 7 consecutive days (intervention group), but control rats received just normal saline (1 mL/kg, IP). We used a hotplate test of analgesia to assess induction of tolerance to analgesic effects of morphine on days 1 and 8 of injections. Later, two groups of rats were sacrificed one day after 7 days of injections, their whole brains removed, and the striatum and PFC immediately dissected. Then, the NR1 gene expression was examined with a semi-quantitative RT-PCR method. Results: The results showed that long-term morphine a administration induces tolerance to analgesic effect of the opioid, as revealed by a significant decrease in morphine-induced analgesia on day 8 compared to day 1 of the injections (P<0.001). The results also showed that the NR1 gene expression at mRNA level in rats tolerant to morphine was significantly increased in the striatum (P<0.01) but decreased in the PFC (P<0.001). Conclusion: Therefore, changes in the NR1 gene expression in rat striatum and PFC have a region-specific association with morphine-induced analgesic tolerance. PMID:27563417

  3. Social influences on morphine sensitization in adolescent rats.

    PubMed

    Hofford, Rebecca S; Schul, Destri L; Wellman, Paul J; Eitan, Shoshana

    2012-05-01

    Given that social influences are among the strongest predictors of adolescents' drug use, this study examines the effects of social interactions on morphine sensitization in both adolescent and adult rats. Rats treated with morphine (twice daily, 6 days, 2.5-10 mg/kg, subcutaneously, s.c.) or saline were group-housed in two different conditions. Thus, four experimental groups were examined for each age group: (1) morphine-treated rats housed physically and visually separate from saline-injected rats ('morphine only'); (2) morphine-treated rats housed together with saline-injected rats ('morphine cage-mates'); (3) saline-injected rats housed together with morphine-treated rats ('saline cage-mates'); and (4) saline-injected rats housed physically and visually separate from morphine-treated rats ('saline only'). Starting 9 days following the last morphine injection, rats were individually examined once daily for 5 consecutive days for their locomotor response to 2.5 mg/kg of morphine. For both age groups, there were no significant differences in morphine-induced hyper-locomotion between saline cage-mates and saline only rats. Morphine only rats exhibited morphine locomotor sensitization as compared to both the saline only and saline cage-mates rats. Notably, a significant difference was observed between the adolescent morphine cage-mates and morphine only rats. The adolescent morphine cage-mates did not exhibit the enhanced locomotor response as compared to the saline only and saline cage-mate rats. A trend of reduced morphine locomotor sensitization was observed in the adult morphine cage-mates as compared to morphine only but it did not reach statistical significance. Thus, this study demonstrates social influences on morphine sensitization which are more prevalent in adolescents as compared to adults.

  4. Time course of morphine's effects on adult hippocampal subgranular zone reveals preferential inhibition of cells in S phase of the cell cycle and a subpopulation of immature neurons.

    PubMed

    Arguello, A A; Harburg, G C; Schonborn, J R; Mandyam, C D; Yamaguchi, M; Eisch, A J

    2008-11-11

    Opiates, such as morphine, decrease neurogenesis in the adult hippocampal subgranular zone (SGZ), raising the possibility that decreased neurogenesis contributes to opiate-induced cognitive deficits. However, there is an incomplete understanding of how alterations in cell cycle progression and progenitor maturation contribute to this decrease. The present study examined how morphine regulates progenitor cell cycle, cell death and immature SGZ neurons (experiment 1) as well as the progression of SGZ progenitors through key stages of maturation (experiment 2). In experiment 1, mice received sham or morphine pellets (s.c., 0 and 48 h) and bromodeoxyuridine (BrdU) 2 h prior to sacrifice (24, 72 or 96 h). Morphine decreased both the number of S phase and total cycling cells, as there were fewer cells immunoreactive (IR) for the S phase marker BrdU and the cell cycle marker Ki67. The percentage of Ki67-IR cells that were BrdU-IR was decreased after 24 but not 96 h of morphine, suggesting a disproportionate effect on S phase cells relative to all cycling cells at this time point. Cell death (activated caspase-3 counts) was increased after 24 but not 96 h. In experiment 2, nestin-green fluorescent protein (GFP) mice given BrdU 1 day prior to morphine or sham surgery (0 and 48 h, sacrifice 96 h) had fewer Ki67-IR cells, but no change in BrdU-IR cell number, suggesting that this population of BrdU-IR cells was less sensitive to morphine. Interestingly, examination of key stages of progenitor cell maturation revealed that morphine increased the percent of BrdU-IR cells that were type 2b and decreased the percent that were immature neurons. These data suggest that chronic morphine decreases SGZ neurogenesis by inhibiting dividing cells, particularly those in S phase, and progenitor cell progression to a more mature neuronal stage.

  5. Effects of maternal oral administration of morphine sulfate on developing rat fetal cerebrum: a morphometrical evaluation.

    PubMed

    Sadraie, Seyed Homayoon; Kaka, Gholam Reza; Sahraei, Hedayat; Dashtnavard, Hosein; Bahadoran, Hosein; Mofid, Mahmood; Nasab, Hossein Mahdavi; Jafari, Fatemeh

    2008-12-15

    Intrauterine morphine exposure is a risk factor for neurological and behavioral deficit in children, although the precise underlying biological correlate for this is unclear. Female pregnant rats were orally treated with 0.1 mg/ml of morphine solution on the 21st day of gestation. Pregnant rats were killed on the 21st day of gestation and their fetuses were taken out and evaluated for growth and cerebral development. The fetuses were fixed and followed by dehydration through graded ethanol solutions and were then embedded and their heads were coronally sectioned through the frontal cerebral cortex. Quantitative computer-assisted morphometric study was done on the frontal cerebral cortex (FCC) which consists of cortical plate (CP), intermediate (migratory) zone (IZ) and matrix (proliferative) zone (MZ) in the rat embryos. The results showed that morphine exposure caused a significant reduction of fetal weight and crown-to-rump length in morphine exposure group. The present study showed that animals with intrauterine morphine exposure, induced by a period of reduced placental blood flow during the second week of pregnancy, demonstrate reduced both cortical thickness and the numbers of neurons in the developing fetal frontal cerebral cortex (FCC). Histomorphometric evaluation revealed that the thickness of the CP was significantly decreased in the morphine-exposed embryos. In addition, neuronal counting showed that cell proliferation in the CP was suppressed after morphine administration and that the migration of neurons from the matrix zone (MZ) to the cortex was decelerated. In conclusion, these results showed that morphine exposure during the second week of pregnancy could affect brain development in a way, which could lead to neurological and behavioral deficits in the postnatal animal.

  6. 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

  7. Changes in the antitumour effect of some cytostatic agents applied under conditions of morphine-induced hyperthermia.

    PubMed

    Ovtcharov, R; Mircheva, Y; Yakimova, K; Stoichkov, Y

    1987-01-01

    The effect of the cytostatic agents bleomycetin, vincristine and methotrexate on the growth of the Lewis lung carcinoma was investigated under conditions of normothermia and morphine-induced hyperthermia. Morphine was administered 1, 3, 5, 7, 9 and 11 days after the tumour transplantation (in a single of 20 mg/kg), 75 min prior to the administration of bleomycetin (in a single dose of 2 mg/kg), vincristine (in a single dose of 0.3 mg/kg) and methotrexate (in a single dose of 5 mg/kg). The therapeutic effect was assessed on the 24th hour after the end of the treatment through determining the tumour growth inhibition. The administration of morphine to mice was found to be accompanied by the development of a hyperthermal reaction, with a maximum between the 90th and 120th min after the treatment, the change in the rectal temperature of the animals being of the order of 2.2 +/- 0.14 degrees C. Hyperthermia potentiates the effect of the antitumour antibiotic bleomycetin which, unlike bleomycin, does not manifest a threshold effect of interaction with the hyperthermia. Temperatures of the order of 40 degrees C are found to result in sensitization of the relatively resistant cells of the Lewis lung carcinoma to the antitumour effect of vincristine. Hyperthermia did not affect the activity of methotrexate. The analysis of the data obtained suggests that morphine-induced hyperthermia is a convenient model in mice for testing the behaviour of the cytostatic agents under conditions of increased temperature.

  8. Modification of the analgesic effect and the effect on body temperature of morphine and fentanyl, included in liposomal suspensions.

    PubMed

    Yakimova, K; Todorov, D; Mihaylova, S; Bantounova, I; Stanoeva, L

    1986-01-01

    The analgesic and thermomodulating effect of the powerful narcotic analgesics morphine and phentanyl, included in liposomal suspensions, was tested in experiments on rats and rabbits. The aim of the experiments was to determine the changes taking place in these effects of the above analgesics, using as their carriers small neutral liposomes formed by phosphatidylcholine (egg lecithin) and cholesterol in molar ratio 7:2. The liposomes were obtained by applying the classical method of A. Bangham (1968), with subsequent ultrasoundtreatment. The changes in the body temperature of the rats and rabbits were traced in dynamics by means of electrothermometry. The analgesic activity was also investigated in dynamics, using two methods: thermal stimulation ("tail flick" test) and mechanical pressure (after Randall-Selitto, 1957). Incorporation of morphin and Fentanyl in liposomal suspensions was found to result in a tendency towards intensification and statistically significant prolongation of their thermomodulating and analgesic effects, compared with these effects of the free preparations. The pharmacological investigations carried out reveal considerable possibilities for a clinically favourable modification of the effects of the narcotic analgesics by means of their incorporation in liposomal carriers.

  9. Differential effects of gram-positive and gram-negative bacterial products on morphine induced inhibition of phagocytosis

    PubMed Central

    Jana, Ninkovic; Vidhu, Anand; Raini, Dutta; Zhang, Li; Saluja, Anuj; Meng, Jingjing; Lisa, Koodie; Santanu, Banerjee; Sabita, Roy

    2016-01-01

    Opioid drug abusers have a greater susceptibility to gram positive (Gram (+)) bacterial infections. However, the mechanism underlying opioid modulation of Gram (+) versus Gram (−) bacterial clearance has not been investigated. In this study, we show that opioid treatment resulted in reduced phagocytosis of Gram (+), when compared to Gram (−) bacteria. We further established that LPS priming of chronic morphine treated macrophages leads to potentiated phagocytosis and killing of both Gram (+) and Gram (−) bacteria in a P-38 MAP kinase dependent signaling pathway. In contrast, LTA priming lead to inhibition of both phagocytosis and bacterial killing. This study demonstrates for the first time the differential effects of TLR4 and TLR2 agonists on morphine induced inhibition of phagocytosis. Our results suggest that the incidence and severity of secondary infections with Gram (+) bacteria would be higher in opioid abusers. PMID:26891899

  10. Effect of long-term exposure of SH-SY5Y cells to morphine: a whole cell proteomic analysis

    PubMed Central

    Neasta, Jérémie; Uttenweiler-Joseph, Sandrine; Chaoui, Karima; Monsarrat, Bernard; Meunier, Jean-Claude; Moulédous, Lionel

    2006-01-01

    Background Opiate addiction reflects plastic changes that endurably alter synaptic transmission within relevant neuronal circuits. The biochemical mechanisms of these adaptations remain largely unknown and proteomics-based approaches could lead to a broad characterization of the molecular events underlying adaptations to chronic drug exposure. Results Thus, we have started proteomic analyses of the effects of chronic morphine exposure in a recombinant human neuroblastoma SH-SY5Y clone that stably overexpresses the μ-opioid receptor. Cells were treated with morphine for 6, 24 and 72 hours, the proteins were separated by 2-D gel electrophoresis and stained with Coomassie blue, and the protein map was compared with that obtained from untreated cells. Spots showing a statistically significant variation were selected for identification using mass spectrometric analyses. Conclusion A total of 45 proteins were identified, including proteins involved in cellular metabolism, cytoskeleton organization, vesicular trafficking, transcriptional and translational regulation, and cell signaling. PMID:17184524

  11. Differential effects of gram-positive and gram-negative bacterial products on morphine induced inhibition of phagocytosis.

    PubMed

    Ninkovic, Jana; Jana, Ninkovic; Anand, Vidhu; Vidhu, Anand; Dutta, Raini; Raini, Dutta; Zhang, Li; Saluja, Anuj; Meng, Jingjing; Koodie, Lisa; Lisa, Koodie; Banerjee, Santanu; Santanu, Banerjee; Roy, Sabita; Sabita, Roy

    2016-02-19

    Opioid drug abusers have a greater susceptibility to gram positive (Gram (+)) bacterial infections. However, the mechanism underlying opioid modulation of Gram (+) versus Gram (-) bacterial clearance has not been investigated. In this study, we show that opioid treatment resulted in reduced phagocytosis of Gram (+), when compared to Gram (-) bacteria. We further established that LPS priming of chronic morphine treated macrophages leads to potentiated phagocytosis and killing of both Gram (+) and Gram (-) bacteria in a P-38 MAP kinase dependent signaling pathway. In contrast, LTA priming lead to inhibition of both phagocytosis and bacterial killing. This study demonstrates for the first time the differential effects of TLR4 and TLR2 agonists on morphine induced inhibition of phagocytosis. Our results suggest that the incidence and severity of secondary infections with Gram (+) bacteria would be higher in opioid abusers.

  12. TARGETED DELETION OF INDUCIBLE HEAT SHOCK PROTEIN 70 ABROGATES THE LATE INFARCT-SPARING EFFECT OF MYOCARDIAL ISCHEMIC PRECONDITIONING

    EPA Science Inventory

    Abstract submitted for 82nd annual meeting of the American Association for Thoracic Surgery, May 4-8, 2002 in Washington D.C.

    Targeted Deletion of Inducible Heat Shock Protein 70 Abrogates the Late Infarct-Sparing Effect of Myocardial Ischemic Preconditioning

    Craig...

  13. 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.

  14. Comparison of (+)- and (-)-Naloxone on the Acute Psychomotor-Stimulating Effects of Heroin, 6-Acetylmorphine, and Morphine in Mice.

    PubMed

    Eriksen, Guro Søe; Andersen, Jannike Mørch; Boix, Fernando; Bergh, Marianne Skov-Skov; Vindenes, Vigdis; Rice, Kenner C; Huestis, Marilyn A; Mørland, Jørg

    2016-08-01

    Toll-like receptor 4 (TLR4) signaling is implied in opioid reinforcement, reward, and withdrawal. Here, we explored whether TLR4 signaling is involved in the acute psychomotor-stimulating effects of heroin, 6-acetylmorphine (6-AM), and morphine as well as whether there are differences between the three opioids regarding TLR4 signaling. To address this, we examined how pretreatment with (+)-naloxone, a TLR4 active but opioid receptor (OR) inactive antagonist, affected the acute increase in locomotor activity induced by heroin, 6-AM, or morphine in mice. We also assessed the effect of pretreatment with (-)-naloxone, a TLR4 and OR active antagonist, as well as the pharmacokinetic profiles of (+) and (-)-naloxone in the blood and brain. We found that (-)-naloxone reduced acute opioid-induced locomotor activity in a dose-dependent manner. By contrast, (+)-naloxone, administered in doses assumed to antagonize TLR4 but not ORs, did not affect acute locomotor activity induced by heroin, 6-AM, or morphine. Both naloxone isomers exhibited similar concentration versus time profiles in the blood and brain, but the brain concentrations of (-)-naloxone reached higher levels than those of (+)-naloxone. However, the discrepancies in their pharmacokinetic properties did not explain the marked difference between the two isomers' ability to affect opioid-induced locomotor activity. Our results underpin the importance of OR activation and do not indicate an apparent role of TLR4 signaling in acute opioid-induced psychomotor stimulation in mice. Furthermore, there were no marked differences between heroin, 6-AM, and morphine regarding involvement of OR or TLR4 signaling. PMID:27278234

  15. Biochemical and behavioral effects of phospholipase A/sub 2/ and morphine microinjections in the periaqueductal gray of the rat

    SciTech Connect

    Reichman, M.; Abood, L.G.; Costanzo, M.

    1985-02-11

    In order to characterize the in vivo action of phospholipase A/sub 2/ (PLA/sub 2/) on opiate receptors and opiate-induced behaviors, the effects of injections of PLA/sub 2/ into the periaqueductal gray region (PAG) of the rat were assessed on free fatty acid (FFA) release, opiate-binding levels, and morphine-induced behaviors. Rats received bilateral PAG injections of 2 ..mu..g of PLA/sub 2/ while anesthetized. One hour later, regions around the cannulae tracts in PLA/sub 2/-treated rats contained over 2.5 times more FFA than saline-injected controls, and /sup 3/H-dihydromorphine binding was reduced on average more than 70%. In another series of experiments, conscious rats were given 2 ..mu..g of PLA/sub 2/ prior to 10 ..mu..g of morphine through cannulae chronically implanted into the PAG. PLA/sub 2/ did not significantly attenuate morphine-induced analgesia as measured by the tail-flick test to radiant heat, but did prevent the explosive motor behavior observed following morphine injections alone. PLA/sub 2/ by itself did not induce analgesia, but did cause explosive motor behavior 2 hr after the injections. Neither lysophosphatidylcholine nor trypsin resulted in motor seizures following PAG injections. It was concluded that the behavioral effects of PLA/sub 2/ result from the unique properties of the enzyme, rather than generalized membrane damage, and that the opioid sites and mechanisms that mediate analgesia are different from those associated with explosive motor behavior. 36 references, 2 figures, 2 tables.

  16. Opioid-Induced GABA potentiation after chronic morphine attenuates the rewarding effects of opioids in the ventral tegmental area.

    PubMed

    Madhavan, Anuradha; Bonci, Antonello; Whistler, Jennifer L

    2010-10-20

    GABA transmission in the ventral tegmental area (VTA) is critical for fine tuning the activity of dopamine neurons in response to opioids. However, the precise mechanism by which GABA input shapes opioid reward is poorly understood. We observed a reduction of conditioned place preference for low doses of the opioid [d-Ala2, N-MePhe4, Gly5-ol]-enkephalin (DAMGO) and a switch in the functional effects of μ-opioid receptor modulation of GABA postsynaptic currents in the mouse VTA 1 d after chronic morphine treatment. Specifically, whereas in naive mice DAMGO inhibits GABA postsynaptic currents, GABAergic currents are potentiated by DAMGO after chronic morphine treatment. Importantly, pretreatment with the cAMP signaling inhibitor (R)-adenosine, cyclic 3',5'-(hydrogenphosphorothioate) triethylammonium both restored DAMGO reward and reversed the DAMGO-mediated potentiation, thereby reestablishing the inhibitory effects of opioids on GABA currents. Thus, a paradoxical bidirectionality in μ-receptor-mediated control of GABA transmission following chronic morphine treatment is a critical mechanism that determines the expression of opioid reward in the VTA.

  17. Combined effect of fluconazole and thymosin alpha 1 on systemic candidiasis in mice immunosuppressed by morphine treatments.

    PubMed Central

    di Francesco, P; Gaziano, R; Casalinuovo, I A; Belogi, L; Palamara, A T; Favalli, C; Garaci, E

    1994-01-01

    Treatment of systemic infection with Candida albicans with a combination of an antifungal agent (i.e. fluconazole) and a thymus-derived immunostimulant (i.e. thymosin alpha 1 (T alpha 1)) in mice immunosuppressed by morphine treatments was investigated. In normal mice, fluconazole given after infection with 10(6) C. albicans cells was more effective than in mice treated with morphine. Combination treatment with fluconazole and T alpha 1 prolonged survival and reduced the fungal burden in the kidneys of immunosuppressed mice. We also investigated the influence of this combined treatment on killing properties of polymorphonuclear leucocytes (PMN) and natural killer (NK) cell activity, inhibited by morphine administrations. Treatment with T alpha 1 or fluconazole as single agents promoted a recovery of normal NK cell activity and intracellular killing of C. albicans by PMN, while the combination significantly increased both of these responses, probably through the modulation of lymphokine production. Our data suggest that the additive effect of T alpha 1 and fluconazole is due to a direct antifungal action and activation of the immunocompetence. PMID:8082290

  18. Stress-induced sensitization to amphetamine and morphine psychomotor effects depend on stress-induced corticosterone secretion.

    PubMed

    Deroche, V; Piazza, P V; Casolini, P; Maccari, S; Le Moal, M; Simon, H

    1992-12-11

    Repeated exposure to stressful situations has been shown to increase individual reactivity to addictive drugs. However, the biological factors involved in such stress-induced changes are largely unknown. In this study, we investigated the role of corticosterone in the effects of restraint stress on the response to psychostimulants and opioids. The effects of repeated stress on amphetamine- and morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) animals in which stress-induced corticosterone secretion was blocked by adrenalectomy, but who received exogenous corticosterone from a subcutaneous implant. The implanted pellets (50 mg) slowly release corticosterone producing a stable plasma level within the normal physiological range over a period of 20 days. Restraint stress increased the locomotor response to both amphetamine (1.5 mg/kg i.p.) and morphine (2 mg/kg s.c.) in animals with an intact HPA axis, but not in animals in which stress-induced corticosterone secretion was suppressed. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress amplifies behavioral responses to amphetamine and morphine. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings point to a role for glucocorticoids in the susceptibility to drug abuse. PMID:1486498

  19. Effects of spatial memory on morphine CPP and locomotor sensitization in mice.

    PubMed

    Zhu, Xiaolin; Sun, Wei; Li, Xinwang; Tan, Shuping; Zhang, Xiangyang

    2015-10-01

    Drug addiction is associated with memory processes. We simultaneously measured conditioned place preference (CPP) and locomotor sensitization to investigate the influence of spatial memory retrieval on morphine reward and psychomotor excitement. According to their performance in space probe trial involving the Morris water maze mice were assigned to high (including morphine and saline subgroups, H-Mor and H-Sal) and low spatial memory retrieval ability groups (L-Mor and L-Sal). Morphine (10mg/kg) produced significant CPP in L-Mor and H-Mor mice, although, L-Mor mice showed a significantly greater response to morphine. During the development period of behavior sensitization, no significant group-by-day interaction was found. However, locomotor activities of L-Mor mice were also significantly higher than H-Mor mice during the expression period of behavior sensitization. Our findings suggested that the spatial memory retrieval ability of mice influences morphine CPP, as well as behavioral sensitization. Thus, spatial memory might be implicated in drug addiction.

  20. Effects of the fruit essential oil of Cuminum cyminum L. on the acquisition and expression of morphine-induced conditioned place preference in mice.

    PubMed

    Khatibi, Ali; Haghparast, Abbas; Shams, Jamal; Dianati, Elham; Komaki, Alireza; Kamalinejad, Mohammad

    2008-12-19

    Rewarding properties of opioids are now accepted and widely discussed. These properties can lead to long-term usage of these substances. The main purpose of this study was to investigate the effects of Cuminum cyminum fruit essential oil (FEO) on the acquisition and expression of morphine-induced conditioned place preference (CPP) in mice. CPP was induced by subcutaneous (s.c.) injection of morphine (5mg/kg) in 3 days conditioning schedule. Intraperitoneal (i.p.) administration of Cumin FEO (0.001%, 0.01%, 0.1%, 0.5%, 1% and 2%; 5 ml/kg) or Tween-80 (0.5%; 5 ml/kg) did not show any conditioning effects. Administration of Cumin FEO (0.001-2%; 5 ml/kg; i.p.), 60 min before test on day 5 (expression) decreased the conditioning scores at the doses of 1% and 2% while i.p. injection of Cumin FEO (0.001-2%; 5 ml/kg), 60 min before morphine injection (5mg/kg; s.c.) during 3 days of conditioning session (acquisition) significantly resulted in decrement of rewarding properties of morphine at the doses of 0.1%, 0.5%, 1% and 2% in dose-dependent manner. Tween-80 as a vehicle did not suppress the acquisition and expression of morphine-induced CPP. The results showed that the C. cyminum fruit essential oil reduces the acquisition and expression of morphine-induced conditioned place preference in mice.

  1. Effects of swimming exercise on morphine-induced reward and behavioral sensitization in maternally-separated rat pups in the conditioned place preference procedure.

    PubMed

    Abad, Atiyeh Taghavi-Khalil; Miladi-Gorji, Hossein; Bigdeli, Imanollah

    2016-09-19

    This study was designed to examine the effects of swimming exercise during adolescence on morphine-induced conditioned place preference (CPP) and behavioral sensitization in maternally separated male and female rat pups. Male Wistar rats were allowed to mate with female virgin Wistar rats. Pups were separated from the dam daily for 180min during postnatal days 2-14. All pups were weaned on day 21.The exercising pups were allowed to swim (60min/d, five days per a week, for 30days) during adolescence. Then, rat pups were tested for behavioral sensitization and the CPP induced by morphine. Maternal separation produced a significant increase in morphine-induced CPP in both sexes, behavioral sensitization in male pups and tolerance to morphine-induced motor activity in female pups. Swimmer pups separated from the dam exhibited a decrease in morphine-induced CPP in both sexes and behavioral sensitization in male pups than those of their control pups. The present results have shown that swimming exercise during adolescence may exert a protective effect against morphine-induced reward and behavioral sensitization in adult male and female rats following maternal separation. PMID:27519931

  2. Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum.

    PubMed

    Glick, S D; Kuehne, M E; Raucci, J; Wilson, T E; Larson, D; Keller, R W; Carlson, J N

    1994-09-19

    Ibogaine, a naturally occurring alkaloid, has been claimed to be effective in treating addiction to opioid and stimulant drugs and has been reported to decrease morphine and cocaine self-administration in rats. The present study sought to determine if other iboga alkaloids, as well as the chemically related harmala alkaloid harmaline, would also reduce the intravenous self-administration of morphine and cocaine in rats. Because both ibogaine and harmaline induce tremors, an effect that may be causally related to neurotoxicity in the cerebellar vermis, the temorigenic activities of the other iboga alkaloids were assessed. Lastly, in view of the involvement of the dopaminergic mesolimbic system in the actions of drugs of abuse, the effects of some of the iboga alkaloids on extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum were determined. All of the tested alkaloids (i.e., ibogaine, tabernanthine, R- and S-coronaridine, R- and S-ibogamine, desethylcoronaridine, and harmaline) dose-dependently (2.5-80 mg/kg) decreased morphine and cocaine intake in the hour after treatment; decreases in morphine and cocaine intake intake were also apparent the day after administration of some but not all of these alkaloids (i.e., ibogaine, tabernanthine, desethylcoronaridine, and the R-isomers of coronaridine and ibogamine). In some rats, there were persistent decreases in morphine or cocaine intake for several days after a single injection or after two or three weekly injections of one or another of these alkaloids; R-ibogamine produced such effects more consistently than any of the other alkaloids.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7820611

  3. The Induction of Heme Oxygenase 1 Decreases Painful Diabetic Neuropathy and Enhances the Antinociceptive Effects of Morphine in Diabetic Mice

    PubMed Central

    Castany, Sílvia; Carcolé, Mireia; Leánez, Sergi; Pol, Olga

    2016-01-01

    Painful diabetic neuropathy is a common complication of diabetes mellitus which is poorly controlled by conventional analgesics. This study investigates if treatment with an heme oxygenase 1 (HO-1) inducer, cobalt protoporphyrin IX (CoPP), could modulate the allodynia and hyperalgesia induced by diabetes and enhanced the antinociceptive effects of morphine. In a diabetic mice model induced by the injection of streptozotocin (STZ), we evaluated the antiallodynic and antihyperalgesic effects produced by the intraperitoneal administration of 5 and 10 mg/kg of CoPP at several days after its administration. The antinociceptive actions produced by the systemic administration of morphine alone or combined with CoPP were also evaluated. In addition, the effects of CoPP treatment on the expression of HO-1, the microglial activation marker (CD11b/c), the inducible nitric oxide synthase (NOS2) and μ-opioid receptors (MOR), were also assessed. Our results showed that the administration of 10 mg/kg of CoPP during 5 consecutive days completely blocked the mechanical and thermal hypersensitivity induced by diabetes. These effects are accompanied by the increased spinal cord, dorsal root ganglia and sciatic nerve protein levels of HO-1. In addition, the STZ-induced activation of microglia and overexpression of NOS2 in the spinal cord were inhibited by CoPP treatment. Furthermore, the antinociceptive effects of morphine were enhanced by CoPP treatment and reversed by the administration of an HO-1 inhibitor, tin protoporphyrin IX (SnPP). The spinal cord expression of MOR was also increased by CoPP treatment in diabetic mice. In conclusion, our data provide the first evidence that the induction of HO-1 attenuated STZ-induced painful diabetic neuropathy and enhanced the antinociceptive effects of morphine via inhibition of microglia activation and NOS2 overexpression as well as by increasing the spinal cord levels of MOR. This study proposes the administration of CoPP alone or

  4. Differential effects of oxycodone, hydrocodone, and morphine on the responses of D2/D3 dopamine receptors.

    PubMed

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

    2015-05-01

    Oxycodone and hydrocodone are opioids which are widely used for pain management and are also commonly misused and abused. The exposure to opioid analgesics has been associated with altered responses of D2-like dopamine receptors (D2DRs). Our recent results suggest that various opioids will differentially modulate the responses of D2DRs. The D2DRs are known to be involved in the pathology of addiction and other mental illnesses, indicating the need to improve our understanding of the effects of opioid analgesics on the responses of the D2DRs. Thus, in this study, we first established equianalgesic oral doses of oxycodone, hydrocodone, and morphine using the tail withdrawal assay. Then, mice were orally administered (gavage) with the various opioids or saline once daily for 6 days. Twenty-four hours later, the mice were tested for their locomotor response to quinpirole, a D2/D3 dopamine receptor agonist. Mice pretreated with oxycodone showed significantly greater locomotor supersensitivity to quinpirole than did morphine-pretreated mice, while hydrocodone-pretreated mice showed sensitivity in between that of mice treated with morphine and oxycodone. This finding suggests that various opioids differentially modulate the responses of D2DRs. It provides further evidence supporting of the notion that various opioids carry differential risks to the dopamine reward system. PMID:25617530

  5. Effects of the adenosinergic system on the expression and acquisition of sensitization to conditioned place preference in morphine-conditioned rats.

    PubMed

    Listos, Joanna; Talarek, Sylwia; Listos, Piotr; Orzelska, Jolanta; Łupina, Małgorzata; Fidecka, Sylwia

    2016-02-01

    In the presented study, we attempt to investigate if the sensitization to conditioned place preference (CPP) induced by low doses of morphine was developed in rats which have been previously conditioned with morphine. The experiments were performed in the CPP test. Firstly, it has been demonstrated that administration of ineffective dose of morphine on the 9th day induces the increase in time spent of rats at a morphine-paired compartment, confirming that sensitization to CPP has been developed in these animals. Secondly, it has been shown that stimulation of A1 receptor significantly inhibits the expression of morphine-induced of sensitization, and blockade of these receptors produces the opposite effect. Finally, it has been indicated that both stimulation and blockade of A1 and/or A2A receptors inhibit the acquisition of sensitization to CPP. The obtained results have strongly supported the significance of adenosinergic system in both expression and acquisition of studied sensitization. These results seem to be important for the identification of connections in the central nervous system which can help finding new strategies to attenuate rewarding action of morphine.

  6. Distinct changes in the behavioural effects of morphine and naloxone in CCK2 receptor-deficient mice.

    PubMed

    Rünkorg, Kertu; Veraksits, Alar; Kurrikoff, Kaido; Luuk, Hendrik; Raud, Sirli; Abramov, Urho; Matsui, Toshimitsu; Bourin, Michel; Kõks, Sulev; Vasar, Eero

    2003-09-15

    The effects of morphine, mu-opioid receptor agonist, and naloxone, a non-selective opioid receptor antagonist, in the locomotor activity and place conditioning tests were studied in the CCK(2) receptor-deficient male mice. The exposure of mice to the motility boxes for 3 consecutive days induced a significant inhibition of locomotor activity in the wild-type (+/+) mice compared to homozygous (-/-) animals. The administration of naloxone (10 mg/kg i.p.) to animals, adapted to the motility boxes, induced a significant reduction of locomotor activity in the homozygous (-/-), but not in the wild-type (+/+) mice. Treatment of habituated mice with morphine (10 mg/kg i.p.) caused a stronger increase of locomotor activity in the wild-type (+/+) mice compared to the homozygous (-/-) littermates. In the place preference test the pairing of the preferred side with naloxone (1 and 10 mg/kg i.p.) induced a dose-dependent place aversion in the wild-type (+/+) mice. The treatment with naloxone was less effective in the homozygous (-/-) mice, because the high dose of naloxone (10 mg/kg) tended to shift the preference. The pairing of morphine (3 mg/kg i.p.) injections with the non-preferred side induced a significant place preference both in the wild-type (+/+) and homozygous (-/-) mice. The increased density of opioid receptors was established in the striatum of homozygous (-/-) mice, but not in the other forebrain structures. In conclusion, the targeted invalidation of CCK(2) receptors induces a dissociation of behavioural effects of morphine and naloxone. Morphine-induced place preference remained unchanged, whereas hyper-locomotion was less pronounced in the mutant mice compared to the wild-type (+/+) littermates. By contrast, naloxone-induced place aversion was weaker, but naloxone caused a stronger inhibition of locomotor activity in the homozygous (-/-) mice than in the wild-type (+/+) animals. These behavioural alterations can be explained in the light of data that the

  7. Gabapentin enhances the morphine anti-nociceptive effect in neuropathic pain via the interleukin-10-heme oxygenase-1 signalling pathway in rats.

    PubMed

    Bao, Yu-Hua; Zhou, Quan-Hong; Chen, Rui; Xu, Hao; Zeng, Lu-Lu; Zhang, Xin; Jiang, Wei; Du, Dong-Ping

    2014-09-01

    In the present study, we investigated the anti-inflammatory mechanisms by which gabapentin enhances morphine anti-nociceptive effect in neuropathic pain in rats and the interaction between the anti-nociceptive effects of gabapentin on morphine and the interleukin (IL)-10-heme-oxygenase (HO)-1 signal pathway in a rat model of neuropathic pain. The neuropathic pain model was induced via a left L5/6 spinal nerve ligation (SNL) in rats. The anti-nociceptive effect of gabapentin and IL-10 on morphine was examined over a 7-day period, and the effects of the anti-IL-10 and HO-1 inhibitor zinc protoporphyrin (ZnPP) on gabapentin/morphine co-injection were assessed. Drug administration was given over 7 days, and on day 8, both anti-inflammatory cytokine IL-10, a stress-induced protein HO-1 and pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were measured. Gabapentin attenuated morphine tolerance over 7 days of co-administration, and reduced the expression of pro-inflammatory cytokines but increased IL-10 and HO-1 expression. The effect of gabapentin on morphine was partially blocked using the anti-IL-10 antibody or the HO-1 inhibitor zinc protoporphyrin. Our findings indicated that the anti-nociceptive effects of gabapentin on morphine might be caused by activation of the IL-10-HO-1 signalling pathway, which resulted in the inhibition of the expression of pro-inflammatory cytokines in neuropathic pain in the rat spinal cord.

  8. The combination of mitragynine and morphine prevents the development of morphine tolerance in mice.

    PubMed

    Fakurazi, Sharida; Rahman, Shamima Abdul; Hidayat, Mohamad Taufik; Ithnin, Hairuszah; Moklas, Mohamad Aris Mohd; Arulselvan, Palanisamy

    2013-01-01

    Mitragynine (MG) is the major active alkaloid found in Mitragyna speciosa Korth. In the present study, we investigated the enhancement of analgesic action of MG when combined with morphine and the effect of the combination on the development of tolerance towards morphine. Mice were administered intraperitoneally with a dose of MG (15 and 25 mg/kg b.wt) combined with morphine (5 mg/kg b.wt) respectively for 9 days. The antinociceptive effect was evaluated by a hot plate test. The protein expression of cyclic adenosine monophosphate (cAMP) and cAMP response element binding (CREB) was analyzed by immunoblot. Toxicological parameters especially liver and kidney function tests were assessed after the combination treatment with MG and morphine. The concurrent administration of MG and morphine showed significant (p < 0.05) increase in latency time when compared to morphine alone group and the outstanding analgesic effects in the combination regimens were maintained until day 9. For the protein expression, there was a significant increment of cAMP and CREB levels (p < 0.05) in group treated with 5 mg/kg morphine but there was no significant change of these protein expressions when MG was combined with morphine. There was a significant changes in toxicological parameters of various treated groups. The combination treatment of MG and morphine effectively reduce the tolerance due to the chronic administration of morphine. PMID:23292329

  9. The absence of protein--sparing effects utilizing crystalline amino acids in stressed patients.

    PubMed

    Ching, N; Mills, C J; Grossi, C; Angers, J W; Jham, G; Zurawinsky, H; Nealon, T F

    1979-11-01

    The protein-sparing effects of the peripheral infusion of crystalline amino acids (PAA) was studied metabolically in selected surgical patients subjected to various degrees of stress. Twenty-one patients (sixteen cancer patients receiving chemotherapy and/or radiotherapy, three with major abdominal traumatic injuries and four with paralytic ileus) were infused with 2 1/24 hours of a solution of 4.2% Travasol amino acids with only 5% glucose as a source of nonprotein calories. One-half of the cancer patients were also allowed ad libitum oral intake of a regular hospital diet or Vivonex-HN. The nutritional status was evaluated by measuring changes in body weight, serum albumin levels and nitrogen balance. Body weight decreased in only the trauma patients. When these solutions were the sole source of nutrients all patients were in negative nitrogen balance and had significant decreases in their serum albumin levels. Serum albumin levels were preserved only when extra sources of calories were provided. The infusion of the crystalline amino acids without adequate levels of nonprotein energy did not conserve protein in these stressed patients.

  10. Doppler velocimetry of ductus venous in preterm fetuses with brain sparing effect: neonatal outcome

    PubMed Central

    Cosmo, Ynesmara Coelho; Júnior, Edward Araujo; de Sá, Renato Augusto Moreira; de Carvalho, Paulo Roberto Nassar; Mattar, Rosiane; Lopes, Laudelino Marques; Nardozza, Luciano Marcondes Machado; de Souza, Eduardo; Moron, Antonio Fernandes

    2012-01-01

    Summary Objective to evaluate the relationship between ductus venous (DV) and Doppler velocimetry in neonatal outcome in severe compromised preterm fetuses. Methods the study was designed as an observational and cross-sectional study with 52 premature neonates with brain sparing effect. The criteria of neonatal severe morbidity were: severe intraventricular hemorrhage (grades 3 or 4), retinopathy of prematurity (grade 3 or 4), cystic periventricular leukomalatia, bronchopneumo dysplasia and neonatal mortality. The fetuses were divided in two groups: group 0 - all the fetuses with ventricular systole/atrial contraction (S/A) in DV ratio values less them 3.4; group 1 - fetuses with values of S/A ratio greater than 3.4. Results 42% of fetuses showed abnormal S/A ratio in DV and 48% showed birth weight below percentile 3 for gestational age. There was no statistical significance comparing the 02 groups according to bronchopneumo dysplasia, retinopathy of prematurity (grade 3 or 4) and intraventricular hemorrhage (grade 3 or 4). Only one fetus presented cystic periventricular leukomalatia. We found statistically significant association between abnormal DV S/A ratio and neonatal mortality (CI 95%, 1.28 –38.22, p< 0.002). Conclusions our results suggest that abnormal DV blood flow detected by Doppler examination isn’t associated with severe neonatal morbidity but with neonatal mortality. PMID:23181172

  11. PKC and PKA inhibitors reinstate morphine-induced behaviors in morphine tolerant mice.

    PubMed

    Smith, Forrest L; Javed, Ruby R; Smith, Paul A; Dewey, William L; Gabra, Bichoy H

    2006-12-01

    Male Swiss Webster mice exhibited antinociception, hypothermia and Straub tail 3h following a 75mg morphine pellet implantation. These signs disappeared by 72h, and the morphine-pelleted mice were indistinguishable from placebo-pelleted ones, although brain morphine concentrations ranged from 200 to 400ng/gm. We previously demonstrated that chemical inhibitors of protein kinase C (PKC) and A (PKA) are able to reverse morphine tolerance in acutely morphine-challenged mice. However, it was not known whether the reversal of tolerance was due to the interaction of kinase inhibitors with the morphine released from the pellet, the acutely injected morphine to challenge tolerant mice, or both. The present study aimed at determining the interaction between the PKC and PKA inhibitors and the morphine released "solely" from the pellet to reinstate the morphine-induced behavioral and physiological effects, 72h after implantation of morphine pellets. Placebo or 75mg morphine pellets were surgically implanted, and testing was conducted 72h later. Our results showed that the intracerebroventricular (i.c.v.) administration of the PKC inhibitors, bisindolylmaleimide I and Gö-6976 as well as the PKA inhibitors, 4-cyano-3-methylisoquinoline and KT-5720, restored the morphine-induced behaviors of antinociception, Straub tail and hypothermia in morphine-pelleted mice to the same extent observed 3h following the pellet implantation. The tail withdrawal and the hot plate reaction time expressed as percent maximum possible effect (%MPE) was increased to 80-100 and 41-90%, respectively, in PKC and PKA inhibitor-treated morphine tolerant mice compared to 2-10% in non-treated mice. Similarly, a significant hypothermia (1.3-4.0 degrees C decrease in body temperature) was detected in PKC and PKA inhibitor-treated morphine tolerant mice compared to an euthermic state in non-treated morphine tolerant mice. Finally, the Straub tail score was increased to 1.1-1.6 in PKC and PKA inhibitor

  12. Opioid-sparing effects of perioperative paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) in children

    PubMed Central

    Wong, Ivan; St John-Green, Celia; Walker, Suellen M

    2013-01-01

    Background and Objectives Perioperative pain in children can be effectively managed with systemic opioids, but addition of paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce opioid requirements and potentially improve analgesia and/or reduce adverse effects. Methods A systematic literature search was conducted to identify trials evaluating postoperative opioid requirements in children and comparing NSAID and/or paracetamol with placebo. Studies were stratified according to design: continuous availability of intravenous opioid (PCA/NCA) vs intermittent ‘as needed’ bolus; and single vs multiple dose paracetamol/NSAIDs. Primary outcome data were extracted, and the percentage decrease in mean opioid consumption was calculated for statistically significant reductions compared with placebo. Secondary outcomes included differences in pain intensity, adverse effects (sedation, respiratory depression, postoperative nausea and vomiting, pruritus, urinary retention, bleeding), and patient/parent satisfaction. Results Thirty-one randomized controlled studies, with 48 active treatment arms compared with placebo, were included. Significant opioid sparing was reported in 38 of 48 active treatment arms, across 21 of the 31 studies. Benefit was most consistently reported when multiple doses of study drug were administered, and 24 h PCA or NCA opioid requirements were assessed. The proportion of positive studies was less with paracetamol, but was influenced by dose and route of administration. Despite availability of opioid for titration, a reduction in pain intensity by NSAIDs and/or paracetamol was reported in 16 of 29 studies. Evidence for clinically significant reductions in opioid-related adverse effects was less robust. Conclusion This systematic review supports addition of NSAIDs and/or paracetamol to systemic opioid for perioperative pain management in children. PMID:23570544

  13. 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. PMID:26700246

  14. Contrasting effects of acute vs. chronic tricyclic antidepressant treatment on central morphine analgesia.

    PubMed

    Kellstein, D E; Malseed, R T; Goldstein, F J

    1984-12-01

    Antinociception following central opioid microinjection in rats was assessed weekly via a tail-flick procedure during chronic tricyclic antidepressant (TCA) treatment. (1) Daily TCA: Subcutaneous injections of desipramine (DMI), 30 mg/kg, chlorimipramine (CMI), 10 mg/kg, or saline, 1 ml/kg, were given daily for 22 days. Morphine sulfate (M), 5 micrograms, was microinjected into the ventrolateral periaqueductal gray (VLPAG) at 7 day intervals. On day 1, DMI or CMI enhanced M analgesia whereas saline did not. Augmentation of M disappeared by days 8 and 15 for CMI and DMI, respectively, and was replaced by attenuation which was still observed on day 22 for both TCAs. L-Tryptophan (LT), 100 mg/kg, i.p., on days 15 and 22 temporarily restored TCA enhancement of M. Fourteen days after cessation of all daily TCA treatments, enhancement of M by CMI was similar to that observed on day 1, whereas recovery of DMI-induced facilitation was incomplete. (2) Weekly TCA: Weekly treatment with DMI, CMI, or saline in the same doses as above had similar effects. M analgesia was enhanced by the TCAs but not saline on day 1; this facilitation was absent by day 15. Attenuation of M by DMI or CMI was evident on day 22; 2 weeks after cessation of all weekly TCA treatments, complete recovery of TCA-induced augmentation was observed. Loss of M facilitation during chronic daily or weekly TCA administration may be related to reduction of central opioid and/or 5-HT2 receptors. PMID:6097858

  15. Antinociceptive effect of palm date spathe hydroalcoholic extract on acute and chronic pain in mice as compared with analgesic effect of morphine and diclofenac

    PubMed Central

    Peyghambari, Fatemeh; Dashti-Rahmatabadi, Mohammad Hossein; Rozabadi, Mansooreh Dehghanfi; Rozabadi, Razieh Dehghanfi; Rozabadi, Fatemeh Dehghanfi; Pangalizadeh, Mohammadesmaeil; Dehghanimohammadabadi, Narges

    2015-01-01

    Backgrounds: In Persian traditional medicine, palm date spathe (PDS) is introduced as an analgesic. Therefore, this study was designed to investigate the analgesic effect of hydroalcoholic extract of PDS on acute and chronic pain in mice in comparison with diclofenac and morphine. Materials and Methods: In this study, which was conducted in summer 2014, 220 male mice (20–30 g) were randomly divided into two categories, each consists of 11 groups as follows: A normal control group, a solvent (Tween 80) control group, 3 morphine positive control groups (2, 4 and 8 mg/kg), 3 diclofenac positive control groups (10, 20 and 30 mg/kg), and 3 main experimental PDS groups (2, 20, and 200 mg/kg). Hot plate was applied on animals in one category and writing test on the other category to assess acute and chronic pain, respectively. Results: In the writing test, the average writing time and number of animals receiving a maximum dosage of morphine, diclofenac, and PDS were significantly less than the control group. In the hot plate test, only groups receiving different doses of morphine at different time points and those received 30 mg/kg diclofenac at 15 min after the intervention showed significant difference with the control group. Conclusion: 200 mg/kg extract of PDS, revealed a significant analgesic effect on chronic pain, but it did not show any analgesic effect on acute pain. PMID:26693469

  16. The effect of incision choice on outcomes of nipple-sparing mastectomy reconstruction

    PubMed Central

    Rawlani, Vinay; Fiuk, Julia; Johnson, Sarah A; Buck, Donald W; Hirsch, Elliot; Hansen, Nora; Khan, Seema; Fine, Neil A; Kim, John YS

    2011-01-01

    INTRODUCTION The indications for nipple-sparing mastectomy (NSM) are broadening as more breast surgeons appreciate the utility of preserving the nipple-areolar complex. A number of incision locations are available to the mastectomy surgeon, including inframammary, lateral and periareolar approaches. The present study investigated the effect of these three incisions on reconstructive outcomes; specifically, nipple necrosis. METHODS A single-centre, retrospective review of 37 breast NSM reconstructions treated with immediate tissue expander reconstruction with acellular dermis between 2007 and 2008 was performed. The primary outcome was the incidence of nipple necrosis associated with periareolar, lateral and inframammary incisions. Secondary outcomes were the effects of radiation, chemotherapy and breast size on nipple necrosis. RESULTS Thirty-seven breast procedures performed on 20 patients were included in the present study. Periareolar incisions were used in 21 cases, lateral incisions in 14 and inframammary incisions in two. The periareolar incision was associated with a significantly higher incidence of nipple necrosis compared with lateral or inframammary incisions (38.1% versus 6.3%, P=0.028). Patients receiving breast radiation (45.5% versus 15.4%, P=0.066) and those with larger breast size (540.4 g versus 425.7 g, P=0.130) also demonstrated a modest trend toward an increased rate of nipple necrosis. CONCLUSION The periareolar incision results in a higher rate of nipple necrosis following NSM and immediate tissue expander breast reconstruction. Using the lateral or inframammary incision reduces the incidence of nipple necrosis and may help improve overall reconstructive and cosmetic outcomes. PMID:23204883

  17. Dynamic spares provisioning for the DSN

    NASA Technical Reports Server (NTRS)

    Eisenberger, I.; Lorden, G.

    1977-01-01

    A method is proposed to maintain cost-effective spares stockpiles for an entire DSN station or complex as new modules or subsystems are continuously added. Levels of spares are calculated individually for each new module type so as to conform to an established standard for the entire spares pool. Finding the spares levels is computationally simplified and in many cases is reduced to consulting a Down-Time Ratio Chart. A simple modification permits taking into account a criticality factor.

  18. Analgesics and ENT surgery. A clinical comparison of the intraoperative, recovery and postoperative effects of buprenorphine, diclofenac, fentanyl, morphine, nalbuphine, pethidine and placebo given intravenously with induction of anaesthesia.

    PubMed Central

    van den Berg, A A; Honjol, N M; Prabhu, N V; Datta, S; Rozario, C J; Muraleedaran, R; Savva, D

    1994-01-01

    1. Vomiting and restlessness following ENT and eye surgery are undesirable, and may be related to the emetic and analgesic effects of any analgesic given to augment anaesthesia during surgery. 2. To rationalise the choice of analgesic for routine ENT surgery we examined the intraoperative, recovery and postoperative effects following the administration of either buprenorphine (3.0 to 4.5 micrograms kg-1), diclofenac (1 mg kg-1), fentanyl (1.5 to 2.0 micrograms kg-1), morphine (0.1 to 0.15 mg kg-1), nalbuphine (0.1 to 0.15 mg kg-1), pethidine (1.0 to 1.5 mg kg-1) or saline (as control) given with the induction of anaesthesia in 374 patients. A standardised anaesthetic technique with controlled ventilation using 0.6-0.8% isoflurane in nitrous oxide and oxygen was employed. The study population constituted 7 similar groups of patients. 3. Intraoperatively, their effects on heart rate and blood pressure, airway pressure and intraocular pressure, were similar. This implies, most surprisingly, that neither their analgesic nor their histamine releasing effects were clinically evident during surgery. By prolonging the time to extubation at the end of anaesthesia, only buprenorphine, fentanyl, morphine and pethidine provided evidence of intraoperative respiratory depression. 4. Postoperatively, buprenorphine was associated with severe respiratory depression, prolonged somnolence, profound analgesia and the highest emesis rate. Diclofenac exhibited no sedative, analgesic, analgesic sparing, emetic or antipyretic effects. Fentanyl provided no sedative or analgesic effects, but was mildly emetic. Morphine provided poor sedation and analgesia, delayed the requirement for re-medication and was highly emetic. Nalbuphine and pethidine produced sedation with analgesia during recovery, a prolonged time to re-medication and a mild emetic effect. None provided evidence, from analysis of postoperative re-medication times and analgesic consumption, of any pre-emptive analgesic effect. 5

  19. Effect of interaction between acute administration of morphine and cannabinoid compounds on spontaneous excitatory and inhibitory postsynaptic currents of magnocellular neurons of supraoptic nucleus

    PubMed Central

    Yousefpour, Mitra; Naderi, Nima; Motamedi, Fereshteh

    2016-01-01

    Objective(s): Opioids and cannabinoids are two important compounds that have been shown to influence the activity of magnocellular neurons (MCNs) of supraoptic nucleus (SON). The interaction between opioidergic and cannabinoidergic systems in various structures of the brain and spinal cord is now well established, but not in the MCNs of SON. Materials and methods: In this study, whole cell patch clamp recording of neurons in rat brain slice was used to investigate the effect of acute morphine and cannabinoid administration on spontaneous inhibitory and excitatory spostsynaptic currents (sIPSCs and sEPSCs) in MCNs. Results: Bath application of morphine produced an increase in sEPSCs frequency and a decrease in sIPSCs frequency. In contrast, bath application of URB597 (fatty acid amide hydrolase (FAAH) inhibitor) produced a decrease in sEPSCs frequency but an increase in sIPSCs frequency. WIN55212-2 (cannabinoid receptor agonist) decreased both sIPSCs and sEPSCs frequencies of MCNs. Co-application of morphine and URB597 attenuated the effect of morphine on MCNs. Conclusion: Taken together, these data indicated that at the cellular level, pharmacological augmentation of endocannabinoids could attenuate morphine effects on MCNs. PMID:27482350

  20. Morphine: Myths and Reality

    MedlinePlus

    ... and Families Take the Quiz Morphine: Myths and Reality February, 2013 The mere mention of “Morphine” can ... due to misinformation and lack of training. The reality is that Morphine (and other opiates that work ...

  1. Effect of Nerve-Sparing Radical Prostatectomy on Urinary Continence in Patients With Preoperative Erectile Dysfunction

    PubMed Central

    2016-01-01

    Purpose: We aimed to assess whether nerve-sparing radical prostatectomy (nsRP) is associated with improved recovery of urinary continence compared to non–nerve-sparing radical prostatectomy (nnsRP) in patients with localized prostate cancer and preoperative erectile dysfunction. Methods: A total of 360 patients with organ-confined prostate cancer and an International Index of Erectile Function score of less than 17 were treated with nsRP or nnsRP in Seoul St. Mary’s Hospital. Patients who received neoadjuvant or adjuvant androgen deprivation therapy or had a history of prostate-related surgery were excluded. Recovery of urinary continence was assessed at 0, 1, 3, 6, and 12 months. Postoperative recovery of continence was defined as zero pad usage. The association between nerve-sparing status and urinary continence was assessed by using univariate and multivariate Cox regression analyses after controlling for known predictive factors. Results: Urinary continence recovered in 279 patients (77.5%) within the mean follow-up period of 22.5 months (range, 6–123 months). Recovery of urinary continence was reported in 74.6% and 86.4% of patients after nnsRP and nsRP, respectively, at 12 months (P=0.022). All groups had comparable perioperative criteria and had no significant preoperative morbidities. Age, American Society of Anesthesiologists score, and nerve-sparing status were significantly associated with recovery of urinary continence on univariate analysis. On multivariate analysis, age (hazard ratio [HR], 1.254; 95% confidence interval [CI], 1.002–1.478; P=0.026) and nerve-sparing status (HR, 0.713; 95% CI, 0.548–0.929; P=0.012) were independently associated with recovery of urinary continence. Conclusions: nsRP, as compared to nnsRP, improves recovery rates of urinary incontinence and decreases surgical morbidity without compromising pathologic outcomes. PMID:27032560

  2. Effect of chronic neonatal morphine and naloxone on sensorimotor and social development of young rats.

    PubMed

    Najam, N; Panksepp, J

    1989-07-01

    Chronic morphine treatment of newborn Long-Evans rat pups between 3-26 days of age (thrice daily starting with 0.5 mg/kg, increased daily by 0.5 mg/kg to 10 mg/kg) led to lags of 1 to 3 days in physical development (body weights and eye opening times) and motor coordination (catalepsy test, grasping, swimming). Chronic naloxone treatment (5 mg/kg administered thrice daily from day 3-26), in contrast, led to modest gains in development on a number of measures (body weights, vaginal opening). Morphine animals also lagged behind controls and naloxone-tested animals in social behaviors, such as homing and play. Chronic naloxone did not block or retard social development; in fact naloxone-treated animals exhibited more rapid acquisition of homing behavior than controls.

  3. 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

  4. Photoaffinity labeling of opioid receptor with morphine-7,8-oxide (morphine epoxide)

    SciTech Connect

    Takayanagi, I.; Shibata, R.; Miyata, N.; Hirobe, M.

    1982-05-01

    The opioid receptor mediating inhibitory action of morphine in the electrically stimulated guinea pig ileum was irreversibly photoinactivated by morphine epoxide (3 X 10(-6) M). Morphine epoxide (up to 3 X 10(-5) M) did not influence the responses of rat vas deferens (epsilon-receptor) or rabbit vas deferens (kappa-receptor) to electrical stimulation. Effective concentrations of morphine epoxide were much lower in the guinea pig ileum (mu-receptor) than in the mouse vas deference (delta-receptor). The inhibitory action of (Met)-enkephalin on the twitch responses of the rat vas deferens and mouse vas deferens to electrical stimulation were not influenced after irradiation in the presence of morphine epoxide (3 X 10(-6) M). Therefore, morphine epoxide is probably a useful probe for photoaffinity labeling of the mu-receptor in vitro.

  5. Dose-dependent dual effect of morphine on electrophysiologic correlates of positive reinforcement (reward contingent positive variation: RCPV) in the cat.

    PubMed

    Marczynski, T J; Hackett, J T

    1976-08-01

    In cats trained to press a lever for milk reward, the postreinforcement EEG synchronization (PRS) and the associated epicortical steady potential shift, known as "Reward Contingent Positive Variation (RCPV) restricted to the occipital cortex, were studied prior to and after administration of morphine sulfate. Contrary to what has ordinarily been described as a typical feline response to morphine, such as restlessness, aggressiveness, rage, and exaggerated startle reaction to environmental stimuli, associated with an increased tonus of the brainstem-hypothalamic arousal system and desynchronized EEG patterns, doses of 0.1-0.4 mg/kg, IM, caused a strong monophasic enhancement of the PRS-RCPV phenomenon. Doses of 0.6-1.0 mg/kg, IM, had clearly a biphasic action: the initial enhancement of the PRS-RCPV responses was followed by their strong suppression. Chlorpromazine (0.1-1.6 mg/kg, i.e.) promptly restored the EEG responses. During the peak effect of the enhancing doses of morphine, the reward-related EEG phenomena also occurred prior to or after the nonrewarded bar press when the animals licked the empty cup. This dissociation of the PRS-RCPV from consumption was much more conspicuous in animals whose control frequency of the PRS oscillations was higher, and after morphine showed more significant slowing. Despite the strong facilitation of the PRS-RCPV in the presence of light, morphine, in contrast to LSD-25, was not able to restore the reward-induced phenomena in the dark.

  6. [The effects of application of rectal naproxen on postoperative analgesia, sedation and morphine use in heart surgery operations].

    PubMed

    Kayacan, T; Güzelmeriç, F; Oğuş, H; Yaltirik, R; Barutçuoğlu, O; Erentuğ, V; Koçak, T

    2004-04-01

    In this study, effects and side effects of application of rectal naproxen, combined with patient controlled intravenous morphine analgesia, were investigated in the elective coronary bypass operations for postoperative pain control, sedation and opioid use. Following the ethical committee approval and individual patient self consent, 40 patients, who underwent coronary artery bypass surgery were included in the study. A double blind study was performed by administering rectal naproxen to group N (n = 20) and placebo to group P (n = 20), at the end of the operation. Doses were repeated at the 12th hour postoperatively. Patient controlled intravenous morphine analgesia was performed to all patients for postoperative 24 hours. Postoperative pain and sedation levels were assessed, the side effects were noted. There was no difference between two groups with respect to their demographic features duration of surgery, extubation time and side effects (p > 0.05). With respect to group P, decrease in opioid use, better sedation and decrease in pain scores during both resting and coughing was seen in group N (p < 0.05). In conclusion, analgesia applied by addition of rectal naproxen to opioids achieved better pain management in selected patients after cardiac surgery.

  7. Fractionated exposure of high energy iron ions has a sparing effect in vivo

    NASA Astrophysics Data System (ADS)

    Chang, P. Y.; Bakke, J.; Puey, A.

    The radiation environment in deep space is complex and includes a broad spectrum of charged and highly energetic particle radiations. Exposure to these types of radiations may pose potential health risks in manned space missions. The detection of particle radiation-induced genomic alterations in vivo, particularly in slow or non-dividing tissues, is therefore important to provide relevant information in estimating risks. We are using a plasmid-based lacZ transgenic mouse model system to rapidly measure, in a statistically reliable way, the mutagenic potential of charged particle radiations relevant in the space environment. The lacZ transgenic mouse has been constructed so that every cell of the animal contains multiple copies of an integrated target reporter gene, allowing us to measure tissue-specific radiation-induced changes as a function of dosing regime. The nature of these mutations can also be characterized by restriction fragment length polymorphisms (RFLP). To examine the impact of dose protraction, animals were exposed to a single dose or daily fractions of 1 GeV/n iron ions. Cytotoxicity in the peripheral blood was measured by enumerating the frequency of circulating micronucleated reticulocytes (fMN-RET) in a time course from 24 h up to 1 week after completion of the radiation protocol. Brain and spleen tissues were harvested at 8 weeks after exposure and mutant frequencies (MF) in the transgene in these tissues were measured. Results from the fractionated protocol were compared to the responses obtained after the animals were exposed to the single dose treatment. We noted significantly lower levels of micronucleated reticulocytes in peripheral blood at 48 h after fractionated doses of iron ions when compared to the same total dose delivered in a single exposure demonstrating that protracted exposures of particle radiation resulted in an overall sparing effect in cytogenetic toxicity in the hematopoietic system in animals. Transgene mutation analysis

  8. Intrathecal PLC(β3) oligodeoxynucleotides antisense potentiates acute morphine efficacy and attenuates chronic morphine tolerance.

    PubMed

    Quanhong, Zhou; Ying, Xue; Moxi, Chen; Tao, Xu; Jing, Wang; Xin, Zhang; Li, Wang; Derong, Cui; Xiaoli, Zhang; Wei, Jiang

    2012-09-01

    Morphine is a mainstay for chronic pain treatment, but its efficacy has been hampered by physical tolerance. The underlying mechanism for chronic morphine induced tolerance is complicated and not well understood. PLC(β3) is regarded as an important factor in the morphine tolerance signal pathway. In this study, we determined intrathecal (i.t.) administration of an antisense oligodeoxynucleotide (ODN) of PLC(β3) could quicken the on-set antinociceptive efficacy of acute morphine treatment and prolong the maximum effect up to 4h. The antisense could also attenuate the development of morphine-induced tolerance and left shift the ED50 after 7 day of coadministration with morphine. These results probably were contributed by the PLC(β3) antisense ODN as they successfully knocked down protein expression levels and reduced activity of PLC(β3) in spinal cord in rats. The mismatch group had no such effects. The results confirmed the important involvement of PLC(β3) in both acute morphine efficacy and chronic morphine tolerance at spinal level in rats. This study may provide an idea for producing a novel adjuvant for morphine treatment.

  9. Differential effects of intra-accumbal orexin-1 and -2 receptor antagonists on the expression and extinction of morphine-induced conditioned place preference in rats.

    PubMed

    Sadeghzadeh, Fatemeh; Namvar, Parastoo; Naghavi, Farzaneh Sadat; Haghparast, Abbas

    2016-03-01

    Orexinergic neurons originate from the hypothalamic nuclei, sending projections toward mesolimbic regions such as the nucleus accumbens (NAc). In this study, an attempt was made to determine the effects of intra-accumbal administration of SB334867 as an orexin-1 receptor (OX1R) antagonist and TCS OX2 29 as an orexin-2 receptor (OX2R) antagonist in the expression and maintenance of morphine-induced conditioned place preference (CPP) in rats. One hundred and five adult Wistar rats weighing 200-280g were bilaterally implanted with cannulae into the NAc. During the 3-day conditioning phase, animals received daily subcutaneous administration of morphine (5mg/kg). CPP score and locomotor activity of animals were recorded by Ethovision software. Different doses of bilateral injections of the OX1R and OX2R antagonists (3, 30 and 300μg/0.5μl DMSO) were administered just before the conditioning test or daily injection during extinction phase. Our finding revealed that intra-accumbal administration of OX1R not OX2R antagonist just before the CPP test attenuated the expression of the morphine-induced CPP. However, the blockade of these two kinds of receptors shortened the extinction phase in the rats. This effect was more significant in intra-NAc OX1R antagonist-treated animals. The results suggested that OX1R within the NAc may be necessary for the morphine-induced expression. Additionally, it seems that the existence of the orexin receptors in the NAc was important for the maintenance of morphine rewarding properties during the extinction phase. Therefore, orexins may be considered as a promising therapeutic agent in preventing the expression and maintenance of morphine rewarding effects on dependent individuals.

  10. The Effect of Morphine on Regional Cerebral Blood Flow Measured by 99mTc-ECD SPECT in Dogs

    PubMed Central

    Adriaens, Antita; Peremans, Kathelijne; Waelbers, Tim; Vandermeulen, Eva; Croubels, Siska; Duchateau, Luc; Dobbeleir, André; Audenaert, Kurt; Eersels, Jos; Vermeire, Simon; De Spiegeleer, Bart; Polis, Ingeborgh

    2014-01-01

    To gain insights into the working mechanism of morphine, regional cerebral blood flow (rCBF) patterns after morphine administration were assessed in dogs. In a randomized cross-over experimental study, rCBF was estimated with 99mTc-Ethylcysteinate Dimer single photon emission computed tomography in 8 dogs at baseline, at 30 minutes and at 120 minutes after a single bolus of morphine. Perfusion indices (PI) in the frontal, parietal, temporal and occipital cortex and in the subcortical and cerebellar region were calculated. PI was significantly decreased 30 min after morphine compared to baseline in the right frontal cortex. The left parietal cortex and subcortical region showed a significantly increased PI 30 min after morphine compared to baseline. No significant differences were noted for the other regions or at other time points. In conclusion, a single bolus of morphine generated a changing rCBF pattern at different time points. PMID:25295733

  11. Dose and time dependent effects of morphine on the incorporation of (3H)valine into soluble brain and liver proteins

    SciTech Connect

    Roennbaeck, L.; Hansson, E.; Cupello, A.

    1983-03-01

    Morphine (10(-6)-10(-5) M) causes an increase in incorporation of (/sup 3/H)valine into soluble proteins during 4 hr in rat brain cortical slices, liver slices and cultivated astroglial cells. The effects are dose-dependent. They are neither cell specific nor strictly related to classical opiate receptors. Pulse-labeling with (/sup 3/H)valine for 60 min after incubation in 10(-6)-10(-5) M morphine, resolves time-dependent changes in incorporation, with both increases and decreases in protein metabolism.

  12. Tianeptine reduces morphine antinociceptive tolerance and physical dependence.

    PubMed

    Chu, Chin-Chen; Shieh, Ja-Ping; Shui, Hao-Ai; Chen, Jen-Yin; Hsing, Chung-Hsi; Tzeng, Jann-Inn; Wang, Jhi-Joung; Ho, Shung-Tai

    2010-09-01

    Long-term use of morphine can cause neuronal dystrophic changes in specific areas of the brain. These changes may underlie the mechanism for developing morphine antinociceptive tolerance and physical dependence. We evaluated the effect of tianeptine, an antidepressant with prominent neuroprotective and neuroplastic properties, on the development of morphine antinociceptive tolerance and physical dependence. Male C57BL/6 mice were rendered tolerant to or dependent on morphine by subcutaneously injecting them with morphine (10 mg/kg) and intraperitoneally with saline or tianeptine (1, 3, or 5 mg/kg) twice daily for 6 days. The mice were given a daily tail-flick test 1 h after the first morphine injection to evaluate the development of their tolerance to morphine antinociception. To evaluate their physical dependence on morphine, 3 h after the final morphine injection on day 6, naloxone-HCl-precipitated (2 mg/kg, intraperitoneally) withdrawal symptoms were counted for 30 min, and body weight was checked 1 h after the naloxone injection. Tianeptine per se produced no antinociception, neither did it modify the antinociception produced by morphine, nor did it evoke the behavioral responses different from those in the saline controls. The combination of tianeptine with morphine significantly reduced the development of morphine antinociceptive tolerance and suppressed the incidence of naloxone-precipitated withdrawal symptoms. We conclude that tianeptine is an effective inhibitor of morphine-induced antinociceptive tolerance and physical dependence in mice. Our results would imply that comedication with tianeptine and morphine might benefit those who need long-term morphine treatment.

  13. The Comparison of the Effects of Acute and Repeated Morphine Administration on Fast Synaptic Transmission in Magnocellular Neurons of Supraoptic Nucleus, Plasma Vasopressin Levels, and Urine Volume of Male Rats

    PubMed Central

    Yousefpour, Mitra; Naderi, Nima; Mansouri, Zahra; Janahmadi, Mahyar; Alizadeh, Amir-Mohammad; Motamedi, Fereshteh

    2014-01-01

    The activity of the magnocellular neurons (MCNs) of supraoptic nucleus (SON) is regulated by a variety of excitatory and inhibitory inputs. Opioids are one of the important compounds that affect these inputs at SON synapses. In this study, whole-cell patch clamp recording of SON neurons was used to investigate the effect of acute and repeated morphine administration on spontaneous inhibitory and excitatory post synaptic currents (sIPSCs and sEPSCs) in MCNs. While acute bath application of morphine to brain slice of intact rat produced an increase in sEPSCs frequency and a decrease in sIPSCs frequency, repeated in-vivo administration of morphine produced opposite effect. Moreover, repetitive i.c.v. administration of morphine for three consecutive days caused significant increase in urine volume, but had no significant alteration in water consumption compared to control group. The increase in urine volume was consistent with a significant decrease in plasma arginine vasopressin (AVP) levels after repetitive i.p. morphine administration. The results suggest that acute administration of morphine stimulates whereas repeated administration of morphine inhibits the MCNs. Morphine-induced MCN inhibition could result in diminished plasma AVP levels and eventually an increase in urine volume of rats. PMID:25276199

  14. Stress and opioids: role of opioids in modulating stress-related behavior and effect of stress on morphine conditioned place preference.

    PubMed

    Bali, Anjana; Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

    2015-04-01

    Research studies have defined the important role of endogenous opioids in modulating stress-associated behavior. The release of β-endorphins in the amygdala in response to stress helps to cope with a stressor by inhibiting the over-activation of HPA axis. Administration of mu opioid agonists reduces the risk of developing post-traumatic stress disorder (PTSD) following a traumatic event by inhibiting fear-related memory consolidation. Similarly, the release of endogenous enkephalin and nociceptin in the basolateral amygdala and the nucleus accumbens tends to produce the anti-stress effects. An increase in dynorphin levels during prolonged exposure to stress may produce learned helplessness, dysphoria and depression. Stress also influences morphine-induced conditioned place preference (CPP) depending upon the intensity and duration of the stressor. Acute stress inhibits morphine CPP, while chronic stress potentiates CPP. The development of dysphoria due to increased dynorphin levels may contribute to chronic stress-induced potentiation of morphine CPP. The activation of ERK/cyclic AMP responsive element-binding (CREB) signaling in the mesocorticolimbic area, glucocorticoid receptors in the basolateral amygdala, and norepinephrine and galanin system in the nucleus accumbens may decrease the acute stress-induced inhibition of morphine CPP. The increase in dopamine levels in the nucleus accumbens and augmentation of GABAergic transmission in the median prefrontal cortex may contribute in potentiating morphine CPP. Stress exposure reinstates the extinct morphine CPP by activating the orexin receptors in the nucleus accumbens, decreasing the oxytocin levels in the lateral septum and amygdala, and altering the GABAergic transmission (activation of GABAA and inactivation of GABAB receptors). The present review describes these varied interactions between opioids and stress along with the possible mechanism. PMID:25636946

  15. Effects of NMDA receptor antagonists on morphine tolerance: a c-Fos study in the lumbar spinal cord of the rat.

    PubMed

    Le Guen, S; Catheline, G; Besson, J M

    1999-05-28

    This study investigated the contribution of NMDA receptors to the development of tolerance to the antinociceptive properties of morphine at the level of the spinal cord dorsal horn. The expression of c-Fos protein following intraplantar (i.pl.) injection of carrageenin (6 mg/150 microl of saline) was used. In naive rats, acute intravenous (i.v.) administration of morphine (3 mg/kg) decreased the total number per section of Fos-Like-Immunoreactive (Fos-LI) neurons by 51%, observed at 2 h after injection of carrageenin. In tolerant rats, acute morphine did not significantly modify the total number of Fos-like immunoreactive neurons/section. In rats receiving chronic morphine and chronic injections of the non-competitive ((+)-MK 801 maleate: (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,1 0-imine) or the competitive (LY 235959: [3S-(3alpha,4a alpha,6beta,8a alpha)]-Decahydro-6-(phosphonomethyl)-3-isoquinolinecarboxylic+ ++ acid) NMDA receptor antagonists, only partial tolerance to the acute effects of morphine were observed (decrease of 42% and 38%, respectively). Administration of an antagonist at the strychnine-insensitive glycine site of the NMDA receptor ((+)-HA-966: R(+)-3-Amino-1-hydroxypyrrolidin-2-one) did not affect the development of morphine tolerance. These findings suggest that compounds attenuating the actions of the NMDA receptor via blockade of the glycine modulatory site may be substantially different from those acting at the ion channel of the NMDA receptor complex. This in vivo experiment in freely moving animals demonstrates for the first time an attenuation of tolerance at the cellular level.

  16. Opioid-sparing effect of selective cyclooxygenase-2 inhibitors on surgical outcomes after open colorectal surgery within an enhanced recovery after surgery protocol

    PubMed Central

    Lohsiriwat, Varut

    2016-01-01

    AIM: To evaluate the opioid-sparing effect of selective cyclooxygenase-2 (COX-2) inhibitors on short-term surgical outcomes after open colorectal surgery. METHODS: Patients undergoing open colorectal resection within an enhanced recovery after surgery protocol from 2011 to 2015 were reviewed. Patients with combined general anesthesia and epidural anesthesia, and those with acute colonic obstruction or perforation were excluded. Patients receiving selective COX-2 inhibitor were compared with well-matched individuals without such a drug. Outcome measures included numeric pain score and morphine milligram equivalent (MME) consumption on postoperative day (POD) 1-3, gastrointestinal recovery (time to tolerate solid diet and time to defecate), complications and length of postoperative stay. RESULTS: There were 75 patients in each group. Pain score on POD 1-3 was not significantly different between two groups. However, MME consumption and MME consumption per kilogram body weight on POD 1-3 was significantly less in patients receiving a selective COX-2 inhibitor (P < 0.001). Median MME consumption per kilogram body weight on POD 1-3 was 0.09, 0.06 and nil, respectively in patients receiving a selective COX-2 inhibitor and 0.22, 0.25 and 0.07, respectively in the comparative group (P < 0.001), representing at least 59% opioid reduction. Patients prescribing a selective COX-2 inhibitor had a shorter median time to resumption of solid diet [1 (IQR 1-2) d vs 2 (IQR 2-3) d; P < 0.001] and time to first defecation [2 (IQR 2-3) d vs 3 (IQR 3-4) d; P < 0.001]. There was no significant difference in overall postoperative complications between two groups. However, median postoperative stay was significantly 1-d shorter in patients prescribing a selective COX-2 inhibitor [4 (IQR 3-5) d vs 5 (IQR 4-6) d; P < 0.001]. CONCLUSION: Perioperative administration of oral selective COX-2 inhibitors significantly decreased intravenous opioid consumption, shortened time to gastrointestinal

  17. Effect of Moderate Exercise on Serum Interferon-Gamma and Interleukin-17 Levels in the Morphine Withdrawal Period

    PubMed Central

    Heidarianpour, Ali; Vahidian Rezazadeh, Majid; Zamani, Alireza

    2016-01-01

    Background Drug addiction triggers the infliction of a variety of diseases. Various subjects have indicated that during the withdrawal syndrome period, the immune system is weakened. Objectives This study aimed to investigate the changes in serum levels of interferon-gamma (IFN-γ) and interleukin-17 (IL-17) during the morphine withdrawal syndrome induced by 8 weeks of moderate exercise and their effects on the immune system function. Materials and Methods Twenty-four male Wistar rats (220 ± 10 g) were divided into four groups (n = 6): healthy control (HC), addicted control (AC), healthy trained (HT), and addicted trained (AT) groups. AC and AT groups were made addicted to morphine sulfate (0.4 mg/mL) in 21 days. To ensure their dependence on morphine, naloxone (3 mg/kg, i.p.) was injected into the body of a number of the rats. HT and AT groups were made to run on a treadmill 5 days per week for 8 weeks while time and speed gradually increased. Both prior to the exercises and 24 hours after the last training session, blood samples were collected from all the animals, and serum IFN-γ and IL-17 serum levels were measured using the ELISA method. This research was performed at the Bu-Ali Sina University, Hamadan, Iran. Results After 8 weeks of exercise, a significant increase was observed in the serum IFN-γ level in the HT group (251.17 ± 13.045) in comparison with the HC group (234 ± 12.884) (P = 0.045). Furthermore, the serum IFN-γ level in the AT group (218.33 ± 5.164) in comparison to the AC group (190.67 ± 8.477) showed a significant increase (P = 0.000). In addition, the serum level of IFN-γ in the HT group showed a significant increase compared to the AT group (P = 0.000). After 8 weeks of exercise, there was a significant decrease in the serum IL-17 level in the HT group (22.67 ± 4.46) compared with the HC group (38.17 ± 7.68) (P = 0.005). In addition, a significant decrease was observed in serum IL-17 in the AT group (42.17 ± 7.41) in comparison

  18. Effect of Moderate Exercise on Serum Interferon-Gamma and Interleukin-17 Levels in the Morphine Withdrawal Period

    PubMed Central

    Heidarianpour, Ali; Vahidian Rezazadeh, Majid; Zamani, Alireza

    2016-01-01

    Background Drug addiction triggers the infliction of a variety of diseases. Various subjects have indicated that during the withdrawal syndrome period, the immune system is weakened. Objectives This study aimed to investigate the changes in serum levels of interferon-gamma (IFN-γ) and interleukin-17 (IL-17) during the morphine withdrawal syndrome induced by 8 weeks of moderate exercise and their effects on the immune system function. Materials and Methods Twenty-four male Wistar rats (220 ± 10 g) were divided into four groups (n = 6): healthy control (HC), addicted control (AC), healthy trained (HT), and addicted trained (AT) groups. AC and AT groups were made addicted to morphine sulfate (0.4 mg/mL) in 21 days. To ensure their dependence on morphine, naloxone (3 mg/kg, i.p.) was injected into the body of a number of the rats. HT and AT groups were made to run on a treadmill 5 days per week for 8 weeks while time and speed gradually increased. Both prior to the exercises and 24 hours after the last training session, blood samples were collected from all the animals, and serum IFN-γ and IL-17 serum levels were measured using the ELISA method. This research was performed at the Bu-Ali Sina University, Hamadan, Iran. Results After 8 weeks of exercise, a significant increase was observed in the serum IFN-γ level in the HT group (251.17 ± 13.045) in comparison with the HC group (234 ± 12.884) (P = 0.045). Furthermore, the serum IFN-γ level in the AT group (218.33 ± 5.164) in comparison to the AC group (190.67 ± 8.477) showed a significant increase (P = 0.000). In addition, the serum level of IFN-γ in the HT group showed a significant increase compared to the AT group (P = 0.000). After 8 weeks of exercise, there was a significant decrease in the serum IL-17 level in the HT group (22.67 ± 4.46) compared with the HC group (38.17 ± 7.68) (P = 0.005). In addition, a significant decrease was observed in serum IL-17 in the AT group (42.17 ± 7.41) in comparison

  19. The Effects of Paracetamol, Ketorolac, and Paracetamol Plus Morphine on Pain Control after Thyroidectomy

    PubMed Central

    Lee, Sun Yeul; Lee, Eun Ha; Han, Kyu Cheol; Ko, Young Kwon

    2010-01-01

    Background The aim of this study was to compare the efficacy of ketorolac, paracetamol, and paracetamol plus morphine on pain relief after thyroidectomy. Methods Eighty patients were randomly allocated to one of the 4 groups: normal saline (group C), ketorolac 30 mg (group K), paracetamol 1 g (group P), and paracetamol 700 mg plus morphine 3 mg (group PM). Each regimen was administered intravenously (IV) 30 min. before the end of surgery. If pain was not relieved, patients received an IV bolus of pethidine hydrochloride 25 mg. Pain intensity using a visual analogue scale (VAS) was recorded at 0.5, 1, 2, 4, and 6 hr after the end of surgery. Results VAS at 0.5 and 1 hr after the end of surgery were significantly lower in group K, group P, and group PM than in group C (P < 0.05). The number of patients receiving pethidine hydrochloride at 0.5 and 1 hr after the end of surgery was significantly lower in group K, group P, and group PM than in group C (P < 0.05). There was no significant difference among the groups in the incidences of adverse events associated with study medications and patient satisfaction (P > 0.05). Conclusions Paracetamol 1 g IV possesses a similar analgesic efficacy to ketorolac 30 mg IV after thyroidectomy. Paracetamol may represent an alternative to ketorolac for pain prevention after mildly to moderately painful surgery in situations where the use of NSAIDs is unsuitable. PMID:20556214

  20. Dapsone in the treatment of pemphigus vulgaris: adverse effects and its importance as a corticosteroid sparing agent*

    PubMed Central

    Quaresma, Maria Victória; Bernardes Filho, Fred; Hezel, Janaína; Peretti, Murilo Calvo; Kac, Bernard Kawa; Azulay-Abulafia, Luna

    2015-01-01

    Pemphigus vulgaris is an autoimmune disease characterized by suprabasal blisters with acantholysis, which has a fatal course in a large number of untreated patients. Systemic corticosteroid therapy is considered first-line therapy. Adjuvant treatment with the goal of sparing corticosteroids include, among others, dapsone. This drug is not without side effects and its use requires clinical and laboratory control. We present a patient with PV initially managed with suboptimal dose of prednisone, evolving into drug-induced hepatitis after introduction of dapsone. PMID:26312673

  1. Mice with neuropathic pain exhibit morphine tolerance due to a decrease in the morphine concentration in the brain.

    PubMed

    Ochiai, Wataru; Kaneta, Mitsumasa; Nagae, Marina; Yuzuhara, Ami; Li, Xin; Suzuki, Haruka; Hanagata, Mika; Kitaoka, Satoshi; Suto, Wataru; Kusunoki, Yoshiki; Kon, Risako; Miyashita, Kazuhiko; Masukawa, Daiki; Ikarashi, Nobutomo; Narita, Minoru; Suzuki, Tsutomu; Sugiyama, Kiyoshi

    2016-09-20

    The chronic administration of morphine to patients with neuropathic pain results in the development of a gradual tolerance to morphine. Although the detailed mechanism of this effect has not yet been elucidated, one of the known causes is a decrease in μ-opioid receptor function with regard to the active metabolite of morphine, M-6-G(morphine-6-glucuronide), in the ventrotegmental area of the midbrain. In this study, the relationship between the concentration of morphine in the brain and its analgesic effect was examined after the administration of morphine in the presence of neuropathic pain. Morphine was orally administered to mice with neuropathic pain, and the relationship between morphine's analgesic effect and its concentration in the brain was analysed. In addition, the expression levels of the conjugation enzyme, UGT2B (uridine diphosphate glucuronosyltransferase), which has morphine as its substrate, and P-gp, which is a transporter involved in morphine excretion, were examined. In mice with neuropathic pain, the concentration of morphine in the brain was significantly decreased, and a correlation was found between this decrease and the decrease in the analgesic effect. It was considered possible that this decrease in the brain morphine concentration may be due to an increase in the expression level of P-gp in the small intestine and to an increase in the expression level and binding activity of UGT2B in the liver. The results of this study suggest the possibility that a sufficient analgesic effect may not be obtained when morphine is administered in the presence of neuropathic pain due to a decrease in the total amount of morphine and M-6-G that reach the brain. PMID:27102159

  2. Protein-sparing effect of carbohydrate in diets for juvenile turbot Scophthalmus maximus reared at different salinities

    NASA Astrophysics Data System (ADS)

    Zeng, Lin; Lei, Jilin; Ai, Chunxiang; Hong, Wanshu; Liu, Bin

    2015-01-01

    The aim of the present study was to investigate the protein-sparing effect of carbohydrate in diets for juvenile turbot ( Scophthalmus maximus) reared at five salinities (12, 18, 24, 30, and 36). The fish were fed three isocaloric and isolipidic diets for 60 days. The results show that specific growth rate (SGR) and feed conversion efficiency (FCE) were higher in fish reared at salinities of 18 and 36, but lower at 12. Fish fed with diet C25P40 (25% carbohydrate and 40% protein) had lower SGR and FCE values compared with those fed with the C5P52 (5% carbohydrate and 52% protein) and C15P46 (15% carbohydrate and 46% protein) diets; however, there was no statistical difference between diet C5P52 and C15P46. SGR and FCE values were unaffected by diet composition in fish reared at salinity 36. Hepatic lipogenic enzyme activities were higher in fish reared at 18 and 36, but lower at 12, while glucokinase (GK) activity was higher in fish reared at 12, and lower at 18 and 36. Dietary starch enhanced GK activity while depressing lipogenic enzyme activity. However, lipogenic enzyme activity increased with increasing dietary starch in fish reared at 36. It is recommended that salinity should be maintained >12 in the farming of juvenile turbot. In addition, an increase in gelatinized starch from 5% to 15% could spare 6% dietary protein in fish reared at salinities of 18-30, while higher salinity (36) could improve dietary carbohydrate use and enhance the protein-sparing effect, which is linked with the induction of lipogenic capacities.

  3. Evaluation of the anti-nociceptive effects of morphine, tramadol, meloxicam and their combinations using the tail-flick test in rats

    PubMed Central

    Foroud, Mehrzad; Vesal, Nasser

    2015-01-01

    The purpose of the present study was to evaluate anti-nociceptive effects of morphine, tramadol, meloxicam and their combinations in rats. Seventy male Wistar rats were divided into seven equal groups and randomly assigned to receive intraperitoneal saline (S) (control group, 1.0 mL kg-1), morphine (MO) (4.0 mg kg-1), tramadol (TR) (12.5 mg kg-1), meloxicam (ML) (1.0 mg kg-1), tramadol- morphine (TR-MO), meloxicam-morphine (ML-MO) and meloxicam-tramadol (ML-TR) at the same doses. Anti-nociception was evaluated using tail flick latency (TFL) test at 45, 60, 75, 90 and 120 min after drug injection. The TFL was significantly higher in TR and MO groups compared to S group for 90 and 120 min, respectively. No significant change in TFL from baseline values was observed at all time points in ML group. Among rats that received combination of analgesics, those that received TR-MO had significantly greater TFL. There was no significant difference in TFL between ML-TR and ML-MO groups. In conclusion, TR, MO and their combination all provided acceptable anti-nociceptive effects in rats. Meloxicam at the given dosage (1.0 mg kg-1) did not demonstrate any anti-nociceptive effect when evaluated by TFL test. PMID:26973767

  4. Dynorphin A-(1-13)-morphine interactions: quantitative and qualitative EEG properties differ in morphine-naive vs. morphine-tolerant rats.

    PubMed

    Meng, Y; Young, G A

    1994-01-01

    The effects of dynorphin A-(1-13) on cumulative IV morphine-induced EEG and EEG power spectra were studied in naive and morphine-tolerant rats. Adult female Sprague-Dawley rats were implanted with cortical EEG electrodes and permanent indwelling ICV and IV cannulae. In naive rats, dynorphin A-(1-13) quantitatively decreased cumulative IV morphine-induced EEG spectral power as well as qualitatively shifting the relative distribution of spectral power to predominantly faster frequencies. In morphine-tolerant rats, the quantitative and qualitative EEG properties were identical to those in dynorphin A-(1-13) pretreated morphine-naive rats. Thus, dynorphin A-(1-13) pretreatment apparently produced instantaneous acute morphine tolerance. Furthermore, in morphine-tolerant rats, dynorphin A-(1-13) pretreatment quantitatively increased morphine-induced EEG power without qualitatively changing the relative distribution of EEG spectral power. This latter effect may be due to a summation of increased endogenous levels of dynorphin A-(1-13) associated with the development of morphine tolerance and the experimentally administered dynorphin A-(1-13). These results indicate that dynorphin-induced quantitative and qualitative EEG changes of morphine may reflect different underlying processes. That is, quantitative changes may reflect the number of receptors that are activated, while qualitative changes may reflect the nature of the receptor-effector coupling.

  5. A randomized controlled trial on the benefits and respiratory adverse effects of morphine for refractory dyspnea in patients with COPD: Protocol of the MORDYC study.

    PubMed

    Verberkt, C A; van den Beuken-van Everdingen, M H J; Franssen, F M E; Dirksen, C D; Schols, J M G A; Wouters, E F M; Janssen, D J A

    2016-03-01

    Dyspnea is one of the most reported symptoms of patients with advanced Chronic Obstructive Pulmonary Disease (COPD) and is often undertreated. Morphine has proven to be an effective treatment for dyspnea and is recommended in clinical practice guidelines, but questions concerning benefits and respiratory adverse effects remain. This study primarily evaluates the impact of oral sustained release morphine (morphine SR) on health-related quality of life and respiratory adverse effects in patients with COPD. Secondary objectives include the impact on exercise capacity, the relationship between description and severity of dyspnea and the presence of a clinically relevant response to morphine, and cost-effectiveness. A single-center, randomized, double blind, placebo controlled intervention study will be performed in 124 patients with COPD who recently completed a comprehensive pulmonary rehabilitation program. Participants will receive 20-30 mg/24h morphine SR or placebo for four weeks. After the intervention, participants will be followed for twelve weeks. Outcomes include: the COPD Assessment Test, six minute walking test, Multidimensional Dyspnea Scale and a cost diary. Furthermore, lung function and arterial blood gasses will be measured. These measures will be assessed during a baseline and outcome assessment, two home visits, two phone calls, and three follow-up assessments. The intervention and control group will be compared using uni- and multivariate regression analysis and logistic regression analysis. Finally, an economic evaluation will be performed from a societal and healthcare perspective. The current manuscript describes the rationale and methods of this study and provides an outline of the possible strengths, weaknesses and clinical consequences. PMID:26825021

  6. Clavulanic acid reduces rewarding, hyperthermic and locomotor-sensitizing effects of morphine in rats: a new indication for an old drug?

    PubMed Central

    Schroeder, Joseph A.; Tolman, Nicholas G.; McKenna, Faye F.; Watkins, Kelly L.; Passeri, Sara M.; Hsu, Alexander H.; Shinn, Brittany R.; Rawls, Scott M.

    2014-01-01

    Background Despite the efficacy of ceftriaxone (CTX) in animal models of CNS diseases, including drug addiction, its utility as a CNS-active therapeutic may be limited by poor brain penetrability and cumbersome parenteral administration. An alternative is the β-lactamase inhibitor clavulanic acid (CA), a constituent of Augmentin that prevents antibiotic degradation. CA possesses the β-lactam core necessary for CNS activity but, relative to CTX, possesses: 1) oral activity; 2) 2.5-fold greater brain penetrability; and 3) negligible antibiotic activity. Methods To compare the effectiveness of CA (10 mg/kg) and CTX (200 mg/kg) against centrally-mediated endpoints, we investigated their effects against morphine’s rewarding, hyperthermic, and locomotor-sensitizing actions. Endpoints were based on prior evidence that CTX attenuates morphine-induced physical dependence, tolerance, and hyperthermia. Results As expected, rats treated with morphine (4 mg/kg) displayed hyperthermia and conditioned place preference (CPP). Co-treatment with CTX or CA inhibited development of morphine-induced CPP by approximately 70%. Morphine’s hyperthermic effect was also suppressed, with CTX and CA producing 57% and 47% inhibition, respectively. Locomotor sensitization induced by repeated morphine exposures was inhibited by CA but not CTX. Conclusions The present findings are the first to suggest that CA disrupts the in vivo actions of morphine and point toward further studying CA as a potential therapy for drug addiction. Further, its ability to disrupt morphine’s rewarding effects at 20-fold lower doses than CTX identifies CA as an existing, orally-active alternative to direct CTX therapy for CNS diseases. PMID:24998018

  7. Effective management of intractable neuropathic pain using an intrathecal morphine pump in a patient with acute transverse myelitis

    PubMed Central

    Wu, Wei-Ting; Huang, Yu-Hui; Chen, Der-Cherng; Huang, Yu-Hsuan; Chou, Li-Wei

    2013-01-01

    Transverse myelitis is a rare inflammatory myelopathy characterized by loss of motor and sensory function below the affected level of the spinal cord, and causes neurogenic bowel and bladder. Occasionally, it also causes neuropathic pain with spasticity. Traditional therapies for neuropathic pain are multiple, including multimodal analgesic regimens, antiepileptic or antidepressant medications, opioids, sympathetic blocks, and spinal cord stimulation. Persistent neuropathic pain can cause emotional distress by affecting sleep, work, recreation, and emotional well-being. Here we report the case of a patient suffering from intractable neuropathic pain following acute transverse myelitis that was not relieved by combinations of nonsteroidal anti-inflammatory, anti-epileptic, antidepressant, and opioid medications, or by acupuncture. Implantation of an intrathecal morphine pump controlled the pain successfully without side effects, and enabled the patient to embark on intensive rehabilitation. The patient’s muscle strength has improved significantly and the patient may soon be able to use a walker with minimal assistance. PMID:23935366

  8. Comparing the analgesic effect of intravenous acetaminophen and morphine on patients with renal colic pain referring to the emergency department: A randomized controlled trial

    PubMed Central

    Azizkhani, Reza; Pourafzali, Seyed Mehdi; Baloochestani, Elahe; Masoumi, Babak

    2013-01-01

    Background: Kidney stone is normally treated by opioids with a variety of side-effects including hypotension, respiratory depression and apnea, nausea and vomiting. Regarding less complications of intravenous acetaminophen, we aimed to compare it with intravenous morphine in management of renal colic pain. Materials and Methods: A randomized controlled clinical trial was applied with a convenience sampling method, as 124 patients suffering from renal colic pain were randomly assigned into two groups of 62 patients. Pain was assessed using visual analog scale ruler. Results were analyzed by SPSS.18 using the descriptive statistic, Chi-square, ANOVA, independent t-test and logistic regression. Results: According to the findings, 84 subjects (67.7%) were male. The mean age of participants were 39.06 (11.58). The mean of pain scores were not significantly different between two groups before administration of drugs (P = 0.415), while the more pain relief was achieved in morphine group after the intervention. Sex and age as influencing factors did not develop a significant difference in both groups. About the adverse effects, morphine had more complications and both groups showed a significant difference in occurrence of dizziness (P = 0.000) and hypotension (P = 0.014). Conclusion: Comparing intravenous morphine and acetaminophen in renal colic pain reviled that morphine can develop greater pain relief, but more complications such as dizziness and hypotension. Acetaminophen can be also be effective in renal colic pain, so it is concluded that acetaminophen can be administered as a less harmful drug for patients with renal colic pain. PMID:24381620

  9. Skin-sparing reduction effects of thermoplastics used for patient immobilization in head and neck radiotherapy.

    PubMed

    Fiorino, C; Cattaneo, G M; Del Vecchio, A; Fusca, M; Longobardi, B; Signorotto, P; Calandrino, R

    1994-03-01

    Skin-sparing benefits derived from the use of megavoltage photon beams can be strongly reduced when filters are inserted between the source and the patient. The use of plastic masks for immobilizing the patient is the most important cause of this reduction in head and neck treatments. The influence of thermoplastics, commercially available for patient immobilization systems (Orfit Raycast (Luxilon Ind. Co.), Posicast (Sinmed bv) and Optimold (WFR Aquaplast Corp.)), on the patient skin dose value has been investigated by using an NE2534 'Markus' chamber. Indicative measurements with moulded masks (carried out with 2-mm Orfit and 3.2-mm Optimold layers) show significant differences between masks moulded with the two thermoplastics.

  10. Measuring the effectiveness of the episodic control program Spare the Air in the San Francisco Bay Area

    SciTech Connect

    Lee, T.G.; Hinman, T.T.

    1997-12-31

    Episodic control programs that ask the public to voluntarily reduce activities that pollute on days when ozone excesses are predicted are now operating in many parts of the country. The activities include driving, using consumer products that contain reactive organic compounds and lawn and garden equipment with small gasoline engines like lawn mowers and leaf blowers. The effectiveness of these programs as public education tools, their impact in changing behavior and their potential as control tools needs to be assessed. In the nine-county San Francisco Bay Area the Spare the Air program has been operating for five years. The program has a strong employer component as well as a program directed at the general public. During the 1996 ozone season, the Bay Area AQMD, in cooperation with the business community, used several methods to assess awareness and behavior change on Spare the Air days. This included telephone public opinion surveys, a pilot program that offered free transit for employees at 8 companies with measurement feedback from the companies, a telecommuting web page that measured participation, a special carpool matching program and a broad based Capture the Credit initiative by business. This paper describes these initiatives, their results and the next steps anticipated for the 1997 program.

  11. Itch and analgesia resulting from intrathecal application of morphine: contrasting effects on different populations of trigeminothalamic tract neurons.

    PubMed

    Moser, Hannah R; Giesler, Glenn J

    2013-04-01

    Intrathecal application of morphine is among the most powerful methods used to treat severe chronic pain. However, this approach commonly produces itch sufficiently severe that patients are forced to choose between relief of pain or itch. The neuronal populations responsible for processing and transmitting information underlying itch caused by intrathecal application of morphine have not been identified and characterized. We describe two populations of antidromically identified trigeminothalamic tract (VTT) neurons in anesthetized rats that are differentially affected by morphine and explain several aspects of opioid-induced itch and analgesia. We found that intrathecal application of morphine increased ongoing activity of itch-responsive VTT neurons. In addition, intrathecal application of morphine increased responses to pruritogens injected into the skin and greatly heightened responses to innocuous mechanical stimuli. In contrast, the ongoing activity and responses to noxious pinches in nociceptive VTT neurons were frequently inhibited by the same dose of morphine. These results reveal that i.t. application of morphine affects specific subpopulations of VTT neurons in ways that may produce itch, hyperknesis, alloknesis, and analgesia.

  12. Effect of morphine on /sup 3/H-thymidine incorporation in the subependyma of the rat: an autoradiographic study

    SciTech Connect

    Miller, C.R.; O'Steen, W.K.; Deadwyler, S.A.

    1982-06-20

    Following morphine treatment, an autoradiographic study investigated the uptake of /sup 3/H-thymidine by the subependymal cells in the rat brain. /sup 3/H-thymidine was administered subcutaneously to adult, male Sprague-Dawley rats 30 minutes after saline or morphine (19 mg/kg) injection. The animals were sacrified 1 hour after /sup 3/H-thymidine administration. In some experiments the opioid antagonist, naloxone, was given alone 45 minutes before /sup 3/H-thymidine or 125 minutes before morphine treatment. Three areas of the subependyma were evaluated in terms of the percentage labeled cells and number of grains per nucleus, and a dorsal-to-ventral gradiant was described. Morphine treatment significantly increased the number of /sup 3/H-thymidine labeled subependymal cells and number of grains/nucleus within labeled cells. Examination of the distribution of grains/nucleus showed that morphine-treated animals had significantly more cells labeled with 30 or more grains than did saline-injected controls. Prior administration of naloxone blocked the increased /sup 3/H-thymidine uptake in morphine-treated animals but had no significant influence on cell proliferation when administered alone. The data are discussed in terms of morphine's possible dual influence on mechanisms which enhance cell transition from G to S phase and/or which accelerate DNA synthesis once these cells have entered the S phase of cell replication.

  13. Immunomodulation by morphine and marijuana.

    PubMed

    Yahya, M D; Watson, R R

    1987-12-01

    The immunomodulatory effects of morphine and the active components of marijuana, particularly tetrahydrocannabinol, on various aspects of the host immune parameters include alterations in humoral, cell-mediated and innate immunity. Most studies have shown immunosuppressive effects due to use of these abused substances, although there are reports that they may not produce any deleterious effect and may even enhance some aspects of host immunity. They reduce resistance to cancer growth and microbial pathogens in animals.

  14. Expression of spinal cord GABA transporter 1 in morphine-tolerant male Wistar rats.

    PubMed

    Shokoofeh, Siroosi; Homa, Manaheji; Leila, Dargahi; Samira, Daniali

    2015-11-15

    Chronic morphine exposure produces morphine tolerance. One of the mechanisms of morphine tolerance involves γ-aminobutric acid (GABA), whose level is regulated by GABA transporter 1 (GAT-1). The aim of this study was to investigate the expression of GAT-1 in the spinal cord during morphine treatment. Morphine was administrated to rats via drinking water for 21 days. On day 21, a single dose of morphine (10mg/kg) was injected, followed by the administration of 5% formalin after 30 min. Expression of GAT-1 in the lumbar spinal cord during morphine treatment was analyzed by Western blotting and immunohistochemistry assay. In another set of experiments, a morphine-tolerant group was treated with a GAT-1 inhibitor, ethyl nipecotate (60 mg/kg), 5 min prior to the formalin test. To assess a possible analgesic effect of the GAT-1 inhibitor, a non-tolerant group was injected only with ethyl nipecotate 5 min prior to the formalin test. Our results indicated that a chronic consumption of morphine led to morphine tolerance. Morphine tolerance was also concomitant with GAT-1 up-regulation in the lumbar spinal cord. The GAT-1 inhibitor ethyl nipecotate improved the antinociceptive effect of morphine in the morphine-tolerant group. Ethyl nipecotate also had an antinociceptive effect on the non-tolerant group. Thus, our data suggest that GAT-1 overexpression in the spinal cord plays an important role in morphine tolerance.

  15. Morphine-induced conditioned place preference and the alterations of p-ERK, p-CREB and c-fos levels in hypothalamus and hippocampus: the effects of physical stress.

    PubMed

    Pahlevani, P; Fatahi, Z; Moradi, M; Haghparast, A

    2014-12-08

    The hypothalamus and hippocampus are important areas involved in stress responses and reward processing. In addition, ERK/CREB pathway plays a critical role in the control of cellular responses to stress and reward. In the current study, effects of acute and subchronic stress on the alteration of p-ERK, p-CREB and c-fos levels in the hypothalamus and hippocampus of saline- or morphine-treated animals during morphine-induced conditioned place preference (CPP) procedure were investigated. Male Wistar rats were divided into two saline- and morphine-treated supergroups. Each supergroup includes of control, acute stress and subchronic stress groups. In all of groups, the CPP procedure was done, afterward the alternation of p-ERK/ERK ratio, p-CREB/CREB ratio and c-fos level in the hypothalamus and hippocampus were estimated by Western blot analysis. The results indicated that in saline- or morphine-treated animals, p-ERK/ERK ratio, p-CREB/CREB ratio and c-fos level increased after application of acute and subchronic stress (except for p-ERK/ERK ratio in morphine-control group). Our findings revealed that in saline- or morphine-treated animals, acute and subcronic stress increased the p-ERK/ERK ratio, p-CREB/CREB ratio and c-fos level in the hypothalamus and hippocampus and this enhancement in morphine-treated animals, was more considerable than that in saline-treated animals.

  16. Cannabidiol inhibits the reward-facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus.

    PubMed

    Katsidoni, Vicky; Anagnostou, Ilektra; Panagis, George

    2013-03-01

    Cannabidiol is a non-psychotomimetic constituent of Cannabis sativa, which induces central effects in rodents. It has been shown that cannabidiol attenuates cue-induced reinstatement of heroin seeking. However, to the best of our knowledge, its effects on brain stimulation reward and the reward-facilitating effects of drugs of abuse have not yet been examined. Therefore, we investigated the effects of cannabidiol on brain reward function and on the reward-facilitating effect of morphine and cocaine using the intracranial self-stimulation (ICSS) paradigm. Rats were prepared with a stimulating electrode into the medial forebrain bundle (MFB), and a guide cannula into the dorsal raphe (microinjection experiments), and were trained to respond for electrical brain stimulation. A low dose of cannabidiol did not affect the reinforcing efficacy of brain stimulation, whereas higher doses significantly elevated the threshold frequency required for MFB ICSS. Both cocaine and morphine lowered ICSS thresholds. Cannabidiol inhibited the reward-facilitating effect of morphine, but not cocaine. This effect was reversed by pre-treatment with an intra-dorsal raphe injection of the selective 5-HT1A receptor antagonist WAY-100635. The present findings indicate that cannabidiol does not exhibit reinforcing properties in the ICSS paradigm at any of the doses tested, while it decreases the reward-facilitating effects of morphine. These effects were mediated by activation of 5-HT1A receptors in the dorsal raphe. Our results suggest that cannabidiol interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids, thus indicating that cannabidiol may be clinically useful in attenuating the rewarding effects of opioids.

  17. Increased brain uptake of morphine in the presence of the antihistamine tripelennamine.

    PubMed

    Vadlamani, N L; Pontani, R B; Misra, A L

    1984-01-01

    Disposition of [6 3H (N)]morphine in plasma, brain and liver of rats was studied 15 min after intravenous injection of either a 2 mg kg-1 dose of morphine or a combination of the same dose of morphine with a 6 mg kg-1 dose of tripelennamine. The concentrations of morphine in brain and the brain to plasma morphine ratios in animals receiving the combination of drugs concurrently were significantly higher than those in the control morphine group. No significant differences were seen in the morphine or morphine metabolite concentrations in plasma and liver or liver to plasma morphine concentration ratios in the 2 groups. Data suggest that pharmacokinetic factors play a role in the potentiation of opiate effects by antihistamine on concurrent i.v. administration of the two drugs. PMID:6141270

  18. Central amygdala nicotinic and 5-HT1A receptors mediate the reversal effect of nicotine and MDMA on morphine-induced amnesia.

    PubMed

    Tirgar, F; Rezayof, A; Zarrindast, M-R

    2014-09-26

    The present study was designed to investigate possible involvement of the central amygdala (CeA) nicotinic acetylcholine (nACh) and 5-hydroxytryptamine 1A (5-HT1A) receptors in the reversal effect of nicotine and 3,4-methylenedioxy-N-methylamphetamine (MDMA or ecstasy) on morphine-induced amnesia. Two guide cannulas were stereotaxically implanted in the CeA regions and a step-through passive avoidance task was used for the assessment of memory retrieval in adult male Wistar rats. Our results indicated that post-training s.c. administration of morphine (3-7-mg/kg) impaired memory retrieval. Pre-test administration of nicotine (0.3- and 0.5-mg/kg, s.c.) reversed morphine-induced amnesia. In addition, pre-test intra-CeA injection of MDMA (1-2-μg/rat) with an ineffective dose of nicotine (0.1-mg/kg, s.c.) improved memory retrieval, suggesting the interactive effect of the drugs on memory formation. It should be noted that that pre-test intra-CeA injection of 2-μg/rat of MDMA by itself produced amnesia. Interestingly, pre-test intra-CeA injection of mecamylamine, a nACh receptor antagonist (1-2-μg/rat) or (S)-WAY 100135 (0.25-1-μg/rat), a selective 5-HT1A receptor antagonist inhibited the improvement of morphine-induced amnesia which was produced by pre-test co-injection of nicotine and MDMA. Pre-test intra-CeA injection of the same doses of MDMA, mecamylamine or (S)-WAY 100135 by itself had no effect on morphine-induced amnesia. Moreover, pre-test injection of the same doses of mecamylamine or (S)-WAY 100135 into the CeA alone could not change memory retrieval. Taken together, it can be concluded that there is a functional interaction between morphine, nicotine and MDMA via the CeA nicotinic and serotonergic receptor mechanisms in passive avoidance memory retrieval. Moreover, cross state-dependent memory retrieval may have been induced between the drugs and this probably depends on the rewarding effects of the drugs.

  19. 18-Methoxycoronaridine, a non-toxic iboga alkaloid congener: effects on morphine and cocaine self-administration and on mesolimbic dopamine release in rats.

    PubMed

    Glick, S D; Kuehne, M E; Maisonneuve, I M; Bandarage, U K; Molinari, H H

    1996-05-01

    Ibogaine, a naturally occurring iboga alkaloid, has been claimed to be effective in treating addiction to opioids and stimulants, and has been reported to inhibit morphine and cocaine self-administration in rats. However, ibogaine also has acute nonspecific side effects (e.g. tremors, decreased motivated behavior in general) as well as neurotoxic effects (Purkinje cell loss) manifested in the vermis of the cerebellum. 18-Methoxycoronaridine (MC) is a novel, synthetic iboga alkaloid congener that mimics ibogaine's effects on drug self-administration without appearing to have ibogaine's other adverse effects. Acutely, in rats, MC decreased morphine and cocaine self-administration but did not affect bar-press responding for water. In some rats, treatment with MC (40 mg/kg) induced prolonged decreases in morphine or cocaine intake lasting several days or weeks. MC had no apparent tremorigenic effect, and there was no evidence of cerebellar toxicity after a high dose (100 mg/kg) of MC. Similar to the effects of ibogaine and other iboga alkaloids that inhibit drug self-administration, MC (40 mg/kg) decreased extracellular levels of dopamine in the nucleus accumbens. MC therefore appears to be a safer, ibogaine-like agent that might be useful in the treatment of addictive disorders. PMID:8782860

  20. Valproate attenuates the development of morphine antinociceptive tolerance.

    PubMed

    Dobashi, Tamae; Tanabe, Serabi; Jin, Hisayo; Nishino, Takashi; Aoe, Tomohiko

    2010-11-19

    Morphine is a potent opioid analgesic. Repeated administration of morphine induces tolerance, thus reducing the effectiveness of analgesic treatment. Although some adjuvant analgesics can increase morphine analgesia, the precise molecular mechanism behind their effects remains unclear. Opioids bind to the mu opioid receptor (MOR). Morphine tolerance may be derived from alterations in the intracellular signal transduction after MOR activation. Chronic morphine treatment activates glycogen synthase kinase 3β (GSK3β), whose inhibition diminishes morphine tolerance. Valproate is widely prescribed as an anticonvulsant and a mood stabilizer for bipolar disorders because it increases the amount of γ-aminobutyric acid (GABA) in the central nervous system. Although the activation of GABAergic neurons may be responsible for the chief pharmacologic effect of valproate, recent studies have shown that valproate also suppresses GSK3β activity. We examined the effect of valproate on the development of morphine antinociceptive tolerance in a mouse model of thermal injury. Mice were treated with morphine alone or with morphine and valproate twice daily for 5 days. The resulting antinociceptive effects were assessed using a hot plate test. While mice treated with morphine developed tolerance, co-administration of valproate attenuated the development of tolerance and impaired the activation of GSK3β in mice brains. Valproate alone did not show analgesic effects; nevertheless, it functioned as an adjuvant analgesic to prevent the development of morphine tolerance. These results suggest that the modulation of GSK3β activity by valproate may be useful and may play a role in the prevention of morphine tolerance. PMID:20816918

  1. 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.

  2. Functional and psychosocial effects of multimodality limb-sparing therapy in patients with soft tissue sarcomas

    SciTech Connect

    Chang, A.E.; Steinberg, S.M.; Culnane, M.; Lampert, M.H.; Reggia, A.J.; Simpson, C.G.; Hicks, J.E.; White, D.E.; Yang, J.J.; Glatstein, E. )

    1989-09-01

    We have documented functional and psychosocial changes in patients with extremity soft tissue sarcomas who have undergone multimodality limb-sparing treatments. In 88 patients, parameters related to economic status, sexual activity, pain, limb function, and global quality of life (QOL) were recorded prior to surgery and every 6 months postoperatively. Changes from the preoperative assessment for every parameter were analyzed in each patient. Six months after surgery, there was a decrease in employment status, sexual activity, and in limb function in a significant number of patients. At 12 months, these decreases were still evident. Despite these changes, global QOL measured by a standardized test showed at least some improvement in a significant proportion of patients at 12 months. These findings highlight the difficulty in defining QOL. It could not be ascertained if radiation therapy and/or chemotherapy were causative factors in specific changes because of the small numbers of patients in each subgroup. However, among 60 patients with high-grade sarcomas, significant wound problems developed in 10 of 33 who received postoperative radiation therapy in combination with adjuvant doxorubicin and cyclophosphamide chemotherapy compared with one of 27 patients who received adjuvant chemotherapy alone (P = .016). Also, among high-grade sarcoma patients with 12-month follow-up, six of 19 patients who received radiation therapy and chemotherapy developed joint contractures compared with zero of 15 patients who received chemotherapy alone (P less than .04). The combination of postoperative radiation therapy and chemotherapy appeared to be associated with significantly more tissue-related injury in patients with high-grade sarcomas compared with chemotherapy alone.

  3. Morphine modulates the effects of histamine H1 and H3 receptors on seizure susceptibility in pentylenetetrazole-induced seizure model of mice.

    PubMed

    Amini-Khoei, Hossein; Rahimi-Balaei, Maryam; Amiri, Shayan; Haj-Mirzaian, Arya; Hassanipour, Mahsa; Shirzadian, Armin; Gooshe, Maziar; Alijanpour, Sakineh; Mehr, Shahram Ejtemaie; Dehpour, Ahmad Reza

    2015-12-15

    Histamine regulates release of neurotransmitters such as dopamine, serotonin, gamma-aminobutyric acid (GABA), glutamate and also is involved in several functions in central nervous system (CNS). It has been shown that histamine participates in disorders like seizure. It has been well documented that morphine dose-dependently induces anti or proconvulsant effects. In the current study, we firstly showed that morphine (1mg/kg) exerts anticonvulsant effects which significantly reversed by naltrexone administration. Secondly, we determined seizure threshold for H1 and H3 receptors agonists and antagonists in mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. Our results showed that activation of H1 receptors by 2-(2-Pyridyl)-ethylamine exerts anticonvulsant properties while inhibition of H1 receptors by pyrilamine maleate induced proconvulsant effects. Furthermore, we showed that immepip dihydrobromide, a H3 receptor agonist, increased seizure susceptibility to PTZ whereas thioperamide, a H3 receptor antagonist increased seizure threshold. We also revealed that pretreatment with morphine potently reversed the effects of histaminergic system on seizure threshold suggesting the involvement of opioid system in alteration of seizure threshold by histaminergic drugs.

  4. Effects of morphine dependence on the performance of rats in reference and working versions of the water maze.

    PubMed

    Miladi Gorji, Hossein; Rashidy-Pour, Ali; Fathollahi, Yaghoub

    2008-02-27

    Numerous studies have dealt with the role of opiate system in tasks aimed at measurement of cognitive behavior, but the role of morphine dependence on learning and memory is still controversial. In this study chronic exposure to morphine was employed to evaluate learning ability and spatial short-term memory (working memory) and long-term memory (reference memory) in the water maze task. Male albino rats were made dependent by chronic administration of morphine in drinking water that lasted at least 21 days. In Experiment 1, the performance of animals was evaluated in reference memory version of the water maze. Rats were submitted to a session of 6 trials for 6 consecutive days to find the submerged platform that was located in the center of a quadrant. Latency and traveled distance to find the platform were measured as indexes of learning. Memory retention was tested 24 h after the last training session in a probe trial (60 s) in which there was no platform and the time spent in each quadrant of the water maze was recorded. Results indicated that latency and traveled distance to find the platform were same in control and dependent rats during training days, but during the probe test morphine-dependent group spent significantly less time in the target quadrant. In Experiment 2, training on working memory version of the water maze task was started. Only two trials per day were given until the performance of animals was stabilized (at least 5 days). Final test was done at day 6. Acquisition-retention interval was 75 min. No significant differences were found on acquisition and retention trials between morphine and control groups. Our findings indicate that chronic exposure to morphine did not impair learning ability, but partially impaired retention of spatial long-term (reference) memory. Moreover, dependence on morphine did not affect either acquisition or retention of spatial short (working) memory.

  5. Effects of morphine, physostigmine and raphe nuclei stimulation on 5-hydroxytryptamine release from the cerebral cortex of the cat.

    PubMed Central

    Aiello-Malmberg, P; Bartolini, A; Bartolini, R; Galli, A

    1979-01-01

    1. The release of 5-hydroxytryptamine (5-HT) from the cerebral cortex and caudate nucleus of brainstem-transected cats and from the cerebral cortex of rats anaesthetized with urethane was determined by radioenzymatic and biological assay. 2. The stimulation of nucleus linearis intermedius of raphe doubles the basal 5-HT release in the caudate nucleus and increases it 3 fold in the cerebral cortex. The effects of the electrical stimulation of the raphe are potentiated by chlorimipramine. 3. Brain 5-HT release is greatly increased by morphine hydrochloride (6 mg/kg i.v.) and by physostigmine (100 microgram/kg i.v.), but not by DL-DOPA (50 mg/kg i.v.). 4. It is suggested that the 5-HT releasing action of physostigmine can contribute to some of its pharmacological effects such as the analgesic effect so far attributed exclusively to its indirect cholinomimetic activity. 5. The 5-HT releasing action of physostigmine seems unrelated to its anticholinesterase activity. PMID:435680

  6. Differential analgesic effects of morphine and gabapentin on behavioural measures of pain and disability in a model of osteoarthritis pain in rats.

    PubMed

    Vonsy, Jean Laurent; Ghandehari, Javid; Dickenson, Anthony Henry

    2009-09-01

    Osteoarthritis (OA) is associated with chronic debilitating joint pain. Pain is the result of an emotional and sensory experience and preclinical models of OA can thus be useful to better understand the underlying mechanisms of the disease and test new therapeutic options. We induced unilateral knee OA in Sprague-Dawley rats using monosodium iodoacetate (MIA), a glycolysis inhibitor and assessed the effects of acute and chronic morphine and gabapentin using a battery of quantitative behavioural outcome measures of pain and disability. Animals received a single intra-articular injection of 2mg MIA in 25 microl saline, causing inflammation and progressive cartilage degradation. Mechanical and thermal sensitivity as well as ambulatory-evoked pain were then monitored using von Frey hairs, acetone and a rotarod. Once maximum nociceptive responses were reached, chronic bi-daily morphine (3mg/kg s.c.) or gabapentin (30 mg/kg s.c.) were administered for 5 days. We observed a marked biphasic mechanical hypersensitivity that increased and reached a plateau from day 14 (317.6% of control response, p<0.01, with von Frey 6g). Moreover we found a marked cooling hypersensitivity, and validated a novel ambulatory-evoked pain score. These measures were significantly reduced after both acute (13.3% of sham response, p<0.01, von Frey 6g) and chronic (38.3%, p<0.05) morphine whilst only chronic gabapentin (37.0%, p<0.05) had an effect. We show the reliability of the model in terms of mechanical hypersensitivity and demonstrate cooling hypersensitivity and ambulatory-evoked pain. In terms of translational research, the effects of morphine and gabapentin validate the model and suggest trials of these therapeutic approaches in OA patients. PMID:18955000

  7. Blockade of tolerance to morphine analgesia by cocaine.

    PubMed

    Misra, A L; Pontani, R B; Vadlamani, N L

    1989-07-01

    Tolerance to morphine analgesia was induced in male Sprague-Dawley rats by s.c. implantation of a morphine base pellet (75 mg) on the first and second day and determining the magnitude of tolerance 72 h after the first implant by s.c. injection of a test dose of morphine (5 mg/kg). Implantation of a cocaine hydrochloride pellet (25 mg), concurrently with morphine pellets or of a cocaine hydrochloride (50 mg) pellet after the development of tolerance, blocked both the development and expression of morphine analgesic tolerance. In morphine-pelleted animals pretreatment for 3 days with desipramine or zimelidine or phenoxybenzamine but not haloperidol produced no significant morphine tolerance. Pretreatment with a combination of desipramine and zimelidine, however, was as effective as cocaine in blocking morphine tolerance. Alpha-Methyl-p-tyrosine methyl ester counteracted the effect of cocaine in blocking morphine tolerance and potentiated the tolerance development. Blockade of morphine tolerance by cocaine was reinforced and facilitated by pretreatment with fenfluramine or p-chlorophenylalanine ethyl ester and to a lesser extent by clonidine and haloperidol. Acute administration of fenfluramine or zimelidine or a combination of desipramine and zimelidine or alpha-methyl-p-tyrosine methyl ester or p-chlorophenylalanine ethyl ester did not significantly affect morphine analgesia. The study suggests an important role of the concomitant depletion of both central noradrenaline and serotonin in the blockade of morphine tolerance by cocaine and stresses the importance of the counter-balancing functional relationship between these two neurotransmitters in the central nervous system. PMID:2780065

  8. [Effect of N-stearoylethanolamine on the lipid peroxidation process and lipid composition of the rat liver in acute morphine intoxication].

    PubMed

    Horid'ko, T M; Hula, N M; Stohniĭ, N A; Mehed', O F; Klimashevs'kyĭ, V M; Shovkun, S A; Kindruk, N L; Berdyshev, A H

    2007-01-01

    The effect of N-stearoylethanolamine (NSE) on the lipid peroxidation process, antioxidant enzymes activity, phospholipid and fatty acid content in the rat liver tissues under acute morphine administration was studied. It was shown that morphine administration (30 mg/kg of body weight) caused an increase of the amount of thiobarbituric acid reactive substances (TBARS), alteration of antioxidant enzymes activity, decrease the protein level, quantity of total lipids and phospholipids, phosphatidylcholine, cholesterol esters; altered the content of some individual fatty acids. NSE administration (50 mg/kg of body weight) promoted normalization of the antioxidant enzymes activity and prevented the TBARS accumulation and decreased the total lipid and phospholipid quantity, increased the content of free and total cholesterol, corrected the level of free and individual fatty acids. It was assumed that NSE possessed antioxidative, membranoprotective and adaptive properties.

  9. Morphine in the treatment of acute pulmonary oedema--Why?

    PubMed

    Ellingsrud, C; Agewall, S

    2016-01-01

    Morphine has for a long time, been used in patients with acute pulmonary oedema due to its anticipated anxiolytic and vasodilatory properties, however a discussion about the benefits and risks has been raised recently. A literature search in Medline and Embase using the keywords "pulmonary oedema" OR "lung oedema" OR "acute heart failure" AND "morphine" was performed. A certain vasodilation has been described after morphine administration, but the evidence for this mechanism is relatively poor and morphine-induced anxiolysis may possibly be the most important factor of morphine in pulmonary oedema and therefore some authors have suggested benzodiazepines as an alternative treatment. Respiratory depression seems to be a less relevant clinical problem according to the literature, whereas vomiting is common, which may cause aspiration. In the largest outcome study, based on the ADHERE registry, morphine given in acute decompensated heart failure was an independent predictor of increased hospital mortality, with an odds ratio of 4.8 (95% CI: 4.52-5.18, p<0.001). Other, smaller studies have shown a significant association between morphine administration and mortality, which was lost after adjusting for confounding factors. Morphine is still used for pulmonary oedema in spite of poor scientific background data. A randomised, controlled study is necessary in order to determine the effect--and especially the risk--when using morphine for pulmonary oedema. Since the positive effects are not sufficiently documented, and since the risk for increased mortality cannot be ruled out, one can advocate that the use should be avoided.

  10. Comparison of (+)- and (−)-Naloxone on the Acute Psychomotor-Stimulating Effects of Heroin, 6-Acetylmorphine, and Morphine in Mice

    PubMed Central

    Andersen, Jannike Mørch; Boix, Fernando; Bergh, Marianne Skov-Skov; Vindenes, Vigdis; Rice, Kenner C.; Huestis, Marilyn A.; Mørland, Jørg

    2016-01-01

    Toll-like receptor 4 (TLR4) signaling is implied in opioid reinforcement, reward, and withdrawal. Here, we explored whether TLR4 signaling is involved in the acute psychomotor-stimulating effects of heroin, 6-acetylmorphine (6-AM), and morphine as well as whether there are differences between the three opioids regarding TLR4 signaling. To address this, we examined how pretreatment with (+)-naloxone, a TLR4 active but opioid receptor (OR) inactive antagonist, affected the acute increase in locomotor activity induced by heroin, 6-AM, or morphine in mice. We also assessed the effect of pretreatment with (−)-naloxone, a TLR4 and OR active antagonist, as well as the pharmacokinetic profiles of (+) and (−)-naloxone in the blood and brain. We found that (−)-naloxone reduced acute opioid-induced locomotor activity in a dose-dependent manner. By contrast, (+)-naloxone, administered in doses assumed to antagonize TLR4 but not ORs, did not affect acute locomotor activity induced by heroin, 6-AM, or morphine. Both naloxone isomers exhibited similar concentration versus time profiles in the blood and brain, but the brain concentrations of (−)-naloxone reached higher levels than those of (+)-naloxone. However, the discrepancies in their pharmacokinetic properties did not explain the marked difference between the two isomers’ ability to affect opioid-induced locomotor activity. Our results underpin the importance of OR activation and do not indicate an apparent role of TLR4 signaling in acute opioid-induced psychomotor stimulation in mice. Furthermore, there were no marked differences between heroin, 6-AM, and morphine regarding involvement of OR or TLR4 signaling. PMID:27278234

  11. Development of anxiety-like behavior via hippocampal IGF-2 signaling in the offspring of parental morphine exposure: effect of enriched environment.

    PubMed

    Li, Chang-Qi; Luo, Yan-Wei; Bi, Fang-Fang; Cui, Tao-Tao; Song, Ling; Cao, Wen-Yu; Zhang, Jian-Yi; Li, Fang; Xu, Jun-Mei; Hao, Wei; Xing, Xiao-Wei; Zhou, Fiona H; Zhou, Xin-Fu; Dai, Ru-Ping

    2014-11-01

    Opioid addiction is a major social, economic, and medical problem worldwide. Long-term adverse consequences of chronic opiate exposure not only involve the individuals themselves but also their offspring. Adolescent maternal morphine exposure results in behavior and morphologic changes in the brain of their adult offspring. However, few studies investigate the effect of adult opiate exposure on their offspring. Furthermore, the underlying molecular signals regulating the intergenerational effects of morphine exposure are still elusive. We report here that morphine exposure of adult male and female rats resulted in anxiety-like behavior and dendritic retraction in the dentate gyrus (DG) region of the hippocampus in their adult offspring. The behavior and morphologic changes were concomitant with the downregulation of insulin-like growth factor (IGF)-2 signaling in the granular zone of DG. Overexpression of hippocampal IGF-2 by bilateral intra-DG injection of lentivirus encoding the IGF-2 gene prevented anxiety-like behaviors in the offspring. Furthermore, exposure to an enriched environment during adolescence corrected the reduction of hippocampal IGF-2 expression, normalized anxiety-like behavior and reversed dendritic retraction in the adult offspring. Thus, parental morphine exposure can lead to the downregulation of hippocampal IGF-2, which contributed to the anxiety and hippocampal dendritic retraction in their offspring. An adolescent-enriched environment experience prevented the behavior and morphologic changes in their offspring through hippocampal IGF-2 signaling. IGF-2 and an enriched environment may be a potential intervention to prevention of anxiety and brain atrophy in the offspring of parental opioid exposure.

  12. Development of Anxiety-Like Behavior via Hippocampal IGF-2 Signaling in the Offspring of Parental Morphine Exposure: Effect of Enriched Environment

    PubMed Central

    Li, Chang-Qi; Luo, Yan-Wei; Bi, Fang-Fang; Cui, Tao-Tao; Song, Ling; Cao, Wen-Yu; Zhang, Jian-Yi; Li, Fang; Xu, Jun-Mei; Hao, Wei; Xing, Xiao-Wei; Zhou, Fiona H; Zhou, Xin-Fu; Dai, Ru-Ping

    2014-01-01

    Opioid addiction is a major social, economic, and medical problem worldwide. Long-term adverse consequences of chronic opiate exposure not only involve the individuals themselves but also their offspring. Adolescent maternal morphine exposure results in behavior and morphologic changes in the brain of their adult offspring. However, few studies investigate the effect of adult opiate exposure on their offspring. Furthermore, the underlying molecular signals regulating the intergenerational effects of morphine exposure are still elusive. We report here that morphine exposure of adult male and female rats resulted in anxiety-like behavior and dendritic retraction in the dentate gyrus (DG) region of the hippocampus in their adult offspring. The behavior and morphologic changes were concomitant with the downregulation of insulin-like growth factor (IGF)-2 signaling in the granular zone of DG. Overexpression of hippocampal IGF-2 by bilateral intra-DG injection of lentivirus encoding the IGF-2 gene prevented anxiety-like behaviors in the offspring. Furthermore, exposure to an enriched environment during adolescence corrected the reduction of hippocampal IGF-2 expression, normalized anxiety-like behavior and reversed dendritic retraction in the adult offspring. Thus, parental morphine exposure can lead to the downregulation of hippocampal IGF-2, which contributed to the anxiety and hippocampal dendritic retraction in their offspring. An adolescent-enriched environment experience prevented the behavior and morphologic changes in their offspring through hippocampal IGF-2 signaling. IGF-2 and an enriched environment may be a potential intervention to prevention of anxiety and brain atrophy in the offspring of parental opioid exposure. PMID:24889368

  13. Effect of circadian rhythm disturbance on morphine preference and addiction in male rats: Involvement of period genes and dopamine D1 receptor.

    PubMed

    Garmabi, B; Vousooghi, N; Vosough, M; Yoonessi, A; Bakhtazad, A; Zarrindast, M R

    2016-05-13

    It is claimed that a correlation exists between disturbance of circadian rhythms by factors such as alteration of normal light-dark cycle and the development of addiction. However, the exact mechanisms involved in this relationship are not much understood. Here we have studied the effect of constant light on morphine voluntary consumption and withdrawal symptoms and also investigated the involvement of Per1, Per2 and dopamine D1 receptor in these processes. Male wistar rats were kept under standard (LD) or constant light (LL) conditions for one month. The plasma concentration of melatonin was evaluated by enzyme-linked immunosorbent assay (ELISA). Real-time PCR was used to determine the mRNA expression of Per1, Per2 and dopamine D1 receptor in the striatum and prefrontal cortex. Morphine preference (50mg/L) was evaluated in a two-bottle-choice paradigm for 10 weeks and withdrawal symptoms were recorded after administration of naloxone (3mg/kg). One month exposure to constant light resulted in a significant decrease of melatonin concentration in the LL group. In addition, mRNA levels of Per2 and dopamine D1 receptor were up-regulated in both the striatum and prefrontal cortex of the LL group. However, expression of Per1 gene was only up-regulated in the striatum of LL rats in comparison to LD animals. Furthermore, after one month exposure to constant light, morphine consumption and preference ratio and also severity of naloxone-induced withdrawal syndrome were significantly greater in LL animals. It is concluded that exposure to constant light by up-regulation of Per2 and dopamine D1 receptor in the striatum and prefrontal cortex and up-regulation of Per1 in the striatum and the possible involvement of melatonin makes animals vulnerable to morphine preference and addiction.

  14. Subjective Effects of Ethanol, Morphine, Δ(9)-Tetrahydrocannabinol, and Ketamine Following a Pharmacological Challenge Are Related to Functional Brain Connectivity.

    PubMed

    Kleinloog, Daniël; Rombouts, Serge; Zoethout, Remco; Klumpers, Linda; Niesters, Marieke; Khalili-Mahani, Najmeh; Dahan, Albert; van Gerven, Joop

    2015-12-01

    This analysis examines the neuronal foundation of drug-induced psychomimetic symptoms by relating the severity of these symptoms to changes in functional connectivity for a range of different psychoactive compounds with varying degrees of psychomimetic effects. The repeated measures design included 323 resting-state functional magnetic resonance imaging time series and measures of subjective effects in 36 healthy male volunteers. Four different pharmacological challenges with ethanol, morphine, Δ(9)-tetrahydrocannabinol, and ketamine (12 subjects per drug) were applied. A set of 10 "template" resting-state networks was used to determine individual connectivity maps. Linear regression was used for each individual subject to relate these connectivity maps to three clusters of drug-induced subjective psychomimetic effects ("perception," "relaxation," and "dysphoria") as measured with visual analogue scales. Group analysis showed that the subjective effects of perception correlated significantly across drugs with the connectivity of the posterior cingulate cortex and precentral gyrus with the sensorimotor network (p < 0.005, corrected). No significant correlations were found for relaxation or dysphoria. The posterior cingulate cortex has a role in visuospatial evaluation and the precentral gyrus has been associated with auditory hallucinations. Both the posterior cingulate cortex and the precentral gyrus show changes in activation in patients with schizophrenia, which can be related to the severity of positive symptoms (i.e., hallucinations and delusions), and have previously been related to changes induced by psychoactive drugs. The similarity of functional connectivity changes for drug-induced psychomimetic effects and symptoms of psychosis provides further support for the use of pharmacological challenges with psychomimetic drugs as models for psychosis.

  15. Effects of perinatal exposure to lead (Pb) on purine receptor expression in the brain and gliosis in rats tolerant to morphine analgesia.

    PubMed

    Baranowska-Bosiacka, Irena; Listos, Joanna; Gutowska, Izabela; Machoy-Mokrzyńska, Anna; Kolasa-Wołosiuk, Agnieszka; Tarnowski, Maciej; Puchałowicz, Kamila; Prokopowicz, Adam; Talarek, Sylwia; Listos, Piotr; Wąsik, Agnieszka; Chlubek, Dariusz

    2016-01-01

    The aim of the present study was to investigate the molecular effects of perinatal exposure to lead (Pb) on protein and mRNA expression of purine receptors: P2X4, P2X7, adenosine receptor A1; and astrocytes (GFAP mRNA expression) and on microglia activation (Iba1 mRNA expression) in several structures of the mesolimbic system (striatum, hippocampus, prefrontal cortex) in rats expressing tolerance to the antinociceptive effect of morphine. Rat mothers were orally treated with 0.1% lead acetate from conception, through gestation, and postnatally, as well as to offspring up to day (PND) 28; subsequently molecular studies were conducted on adult (PND 60) male rats. Morphine tolerance developed more strongly in rats perinatally exposed to Pb. The analysis revealed a significant up-regulation of protein and mRNA P2X4 receptor expression in the striatum and prefrontal cortex but not in the hippocampus; P2X7 protein and mRNA receptor expression in the striatum and hippocampus, but not in the prefrontal cortex; A1 protein receptor expression in all investigated structures and A1 mRNA expression in the striatum and hippocampus; Iba1 mRNA expression in the striatum and hippocampus; and GFAP mRNA expression in the striatum and prefrontal cortex. Immunohistochemical analysis has also revealed significant alterations. Strong expressions of P2X4, P2X7, A1 receptors, astrocytes and microglia activation were observed in the hippocampus in Pb and/or morphine treated rats. The higher expression of purine receptors and glial cell activation are important markers of neuroinflammatory processes. Therefore, we conclude that Pb-induced neuroinflammation may be responsible for the intensification of morphine tolerance in the Pb-treated rats. Additionally, the dysregulation of A1 adenosine receptors, mainly in the hippocampus, may also be involved in the intensification of morphine tolerance in Pb-treated rats. Our study demonstrates the significant participation of environmental factors in

  16. 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

  17. Food-induced behavioral sensitization, its cross-sensitization to cocaine and morphine, pharmacological blockade, and effect on food intake.

    PubMed

    Le Merrer, Julie; Stephens, David N

    2006-07-01

    Repeated administration of abused drugs sensitizes their stimulant effects and results in a drug-paired environment eliciting conditioned activity. We tested whether food induces similar effects. Food-deprived male mice were given novel food during 30 min tests in a runway (FR group) that measured locomotor activity. Whereas the activity of this group increased with repeated testing, that of a group exposed to the runways but that received the food in the home cage (FH group), or of a group satiated by prefeeding before testing (SAT group), decreased. When exposed to the runways in the absence of food, the paired group was more active than the other groups (conditioned activity); no activity differences were seen in an alternative, non-food-paired, apparatus. Conditioned activity survived a 3-week period without runway exposure. Conditioned activity was selectively reduced by the opiate antagonist naltrexone (10-20 mg/kg) and by the noncompetitive AMPA receptor antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] (5-10 mg/kg). The D1 antagonist SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] (15-30 microg/kg) and D2 antagonist sulpiride (25-125 mg/kg) reduced activity nonspecifically. A single intraperitoneal dose of cocaine (10 mg/kg) or morphine (20 mg/kg) increased activity compared with saline, the stimulant effect being larger in the FR group, suggesting "cross-sensitization" to these drugs. However, pretreatment with GYKI 52466 or naltrexone at doses that suppressed conditioned activity in FR animals suppressed cross-sensitization to cocaine. When allowed ad libitum access to food in the runway, FR mice consumed more pellets in a time-limited test. Thus, many of the features of behavioral sensitization to drugs can be demonstrated using food reward and may contribute to excessive eating.

  18. Dopamine-dependent responses to morphine depend on glucocorticoid receptors

    PubMed Central

    Marinelli, Michela; Aouizerate, Bruno; Barrot, Michel; Le Moal, Michel; Piazza, Pier Vincenzo

    1998-01-01

    Previous work has shown that glucocorticoid hormones facilitate the behavioral and dopaminergic effects of morphine. In this study we examined the possible role in these effects of the two central corticosteroid receptor types: mineralocorticoid receptor (MR), and glucocorticoid receptor (GR). To accomplish this, specific antagonists of these receptors were infused intracerebroventricularly and 2 hr later we measured: (i) locomotor activity induced by a systemic injection of morphine (2 mg/kg); (ii) locomotor activity induced by an infusion of morphine (1 μg per side) into the ventral tegmental area, which is a dopamine-dependent behavioral response to morphine; (iii) morphine-induced dopamine release in the nucleus accumbens, a dopaminergic projection site mediating the locomotor and reinforcing effects of drugs of abuse. Blockade of MRs by spironolactone had no significant effects on locomotion induced by systemic morphine. In contrast, blockade of GRs by either RU38486 or RU39305, which is devoid of antiprogesterone effects, reduced the locomotor response to morphine, and this effect was dose dependent. GR antagonists also reduced the locomotor response to intraventral tegmental area morphine as well as the basal and morphine-induced increase in accumbens dopamine, as measured by microdialysis in freely moving rats. In contrast, spironolactone did not modify dopamine release. In conclusion, glucocorticoids, via GRs, facilitate the dopamine-dependent behavioral effects of morphine, probably by facilitating dopamine release. The possibility of decreasing the behavioral and dopaminergic effects of opioids by an acute administration of GR antagonists may open new therapeutic strategies for treatment of drug addiction. PMID:9636221

  19. Morphine reduces social cohesion in rats.

    PubMed

    Panksepp, J; Najam, N; Soares, F

    1979-08-01

    The effect of low (1 mg/kg) doses of morphine on maintenance of physical proximity were evaluated in paired rats observed in a 4 square foot test arena. Morphine reliably reduced proximity maintenance time, and this was apparently not due to sedation, since the effect was unmodified by doses of amphetamine which substantially increased motor activity. The effects of naloxone were inconsistent on this measure of social motivation. In general, the results are consistent with the theoretical proposition that a brain neurochemical change which might lead to social attraction is the activation of endogenous opioid systems. When opiate activity is exogenously sustained, animals exhibit a subnormal tendency to be gregarious.

  20. Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers.

    PubMed

    Soergel, David G; Subach, Ruth Ann; Burnham, Nancy; Lark, Michael W; James, Ian E; Sadler, Brian M; Skobieranda, Franck; Violin, Jonathan D; Webster, Lynn R

    2014-09-01

    Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating μ-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5mg), placebo, or morphine (10mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratory values), and analgesia (cold pain test) versus placebo. Other measures included respiratory drive (minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5mg) elicited higher peak analgesia (105, 116 seconds latency vs 75 seconds for morphine, P<.02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180 seconds) with TRV130 (3, 4.5mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (-15.9 for morphine versus -7.3, -7.6, and -9.4 h*L/min, P<.05). More subjects experienced severe nausea after morphine (n=7) than TRV130 1.5 or 3mg (n=0, 1), but not 4.5mg (n=9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.

  1. Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers.

    PubMed

    Soergel, David G; Subach, Ruth Ann; Burnham, Nancy; Lark, Michael W; James, Ian E; Sadler, Brian M; Skobieranda, Franck; Violin, Jonathan D; Webster, Lynn R

    2014-09-01

    Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating μ-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5mg), placebo, or morphine (10mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratory values), and analgesia (cold pain test) versus placebo. Other measures included respiratory drive (minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5mg) elicited higher peak analgesia (105, 116 seconds latency vs 75 seconds for morphine, P<.02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180 seconds) with TRV130 (3, 4.5mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (-15.9 for morphine versus -7.3, -7.6, and -9.4 h*L/min, P<.05). More subjects experienced severe nausea after morphine (n=7) than TRV130 1.5 or 3mg (n=0, 1), but not 4.5mg (n=9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy. PMID:24954166

  2. Hypoxia, an adjunct in helium-cold hypothermia - Sparing effect on hepatic and cardiac metabolites.

    NASA Technical Reports Server (NTRS)

    Anderson, G. L.; Resch, G. E.; Musacchia, X. J.

    1973-01-01

    Investigation of the effect of hypoxia on the depletion of metabolites that occurs in helium-aided induction of hypothermia. Hypoxic slowing of the heart of a hamster while exposed to cold helox is demonstrated. An attempt is made to evaluate the relative importance of cardiac slowing and limitation of thermogenesis in determining the effect of hypoxia. In explanation of the results presented, it is suggested that hypoxia limits the energy expenditure by the heart during induction.

  3. Involvement of protein kinase C in the modulation of morphine-induced analgesia and the inhibitory effects of exposure to 60-hz magnetic fields in the land snail, Cepaea nemoralis

    SciTech Connect

    Kavaliers, M.; Ossenkopp, K.P. )

    1990-02-26

    One of the more consistent and dramatic effects of exposure to magnetic fields is the attenuation of morphine-induced analgesia. Results of previous studies have implicated alterations in calcium channel functioning and Ca{sup ++} flux in the mediation of these effects. It is generally accepted that Ca{sup ++}-activated-phospholipid-dependent protein kinase (Protein kinase C; PKC) plays an important role in relaying trans-membrane signaling in diverse Ca{sup ++} dependent cellular processes. In experiment 1 we observed that morphine-induced analgesia in the land snail, Cepaea nemoralis, as measured by the latency of an avoidance behavior to a warmed surface, was reduced by the PKC activator, SC-9, and was enhanced by the PKC inhibitors, H-7 and H-9. In contrast, HA-10004, a potent inhibitor of other protein kinases, but only a very weak inhibitor of PKC, had no effect on morphine-induced analgesia. In experiment 2 exposure of snails for 30 minutes to a 1.0 gauss (rms) 60-Hz magnetic field reduced morphine-induced analgesia. This inhibitory effect of the magnetic field was reduced by the PKC inhibitors, H-7 and H-9, and was augmented by the PKC activator SC-9. These results suggest that: (i) PKC is involved in the modulation of morphine-induced analgesia and, (ii) the inhibitory effects of magnetic fields involve PKC.

  4. Morphine as a Potential Oxidative Stress-Causing Agent

    PubMed Central

    Skrabalova, Jitka; Drastichova, Zdenka; Novotny, Jiri

    2013-01-01

    Morphine exhibits important pharmacological effects for which it has been used in medical practice for quite a long time. However, it has a high addictive potential and can be abused. Long-term use of this drug can be connected with some pathological consequences including neurotoxicity and neuronal dysfunction, hepatotoxicity, kidney dysfunction, oxidative stress and apoptosis. Therefore, most studies examining the impact of morphine have been aimed at determining the effects induced by chronic morphine exposure in the brain, liver, cardiovascular system and macrophages. It appears that different tissues may respond to morphine diversely and are distinctly susceptible to oxidative stress and subsequent oxidative damage of biomolecules. Importantly, production of reactive oxygen/nitrogen species induced by morphine, which have been observed under different experimental conditions, can contribute to some pathological processes, degenerative diseases and organ dysfunctions occurring in morphine abusers or morphine-treated patients. This review attempts to provide insights into the possible relationship between morphine actions and oxidative stress. PMID:24376392

  5. Steroid-sparing effect of omalizumab for allergic bronchopulmonary aspergillosis and cystic fibrosis.

    PubMed

    Zirbes, Jacquelyn M; Milla, Carlos E

    2008-06-01

    Allergic bronchopulmonary aspergillosis (ABPA) is a complication commonly encountered in patients with CF that produces significant respiratory morbidity. Chronic airway colonization with Aspergillus induces strong inflammatory responses with high IgE levels. Current guidelines for therapy include prolonged courses of systemic corticosteroids as the main therapeutic strategy. However this has the potential to induce significant detrimental side effects in children. Omalizumab is a humanized monoclonal antibody directed against IgE that prevents its binding to high- and low-affinity receptors on effector cells. It has been shown to be effective in improving asthma control in patients with a strong allergic component. We present our long term experience with the use of Anti-IgE therapy in three children with CF and ABPA (mean age at start of therapy 14.2 years) who were steroid dependent. All three were already experiencing significant side effects from chronic steroid therapy. After the start of Omalizumab these children have experienced significant and sustained clinical improvements at the same time that they were discontinued from chronic systemic steroids. Our experience suggests that IgE blockade has tremendous potential as a strategy to control this disease in steroid dependent patients.

  6. An opiate cocktail that reduces morphine tolerance and dependence.

    PubMed

    He, Li; Whistler, Jennifer L

    2005-06-01

    Morphine is an exceptionally effective analgesic whose utility is compromised by the development of tolerance and dependence to the drug. Morphine analgesia and dependence are mediated by its activity at the mu opioid peptide (MOP) receptor [1]. The MOP receptor is activated not only by morphine, but also by other opiate drugs such as methadone and endogenous opioids such as endorphins. Morphine, however, is a unique opioid agonist ligand because it fails to induce endocytic trafficking of the MOP receptor [2], whereas the endogenous ligands and methadone do facilitate endocytosis [3]. Using the unique pharmacology of the MOP receptor and its proposed existence as an oligomeric structure [4], we designed a pharmacological cocktail that facilitates endocytosis of the MOP receptor in response to morphine. This cocktail consists of morphine and a small dose of methadone. Importantly, this cocktail, while retaining full analgesic potency, does not promote morphine dependence. We further demonstrate that dependence is reduced, at least in part, because endocytosis of the MOP receptor in response to morphine prevents the upregulation of N-methyl-D-aspartate (NMDA) receptors.

  7. Spared and Impaired Spoken Discourse Processing in Schizophrenia: Effects of Local and Global Language Context

    PubMed Central

    Boudewyn, Megan A.; Long, Debra L.; Luck, Steve J.; Kring, Ann M.; Ragland, J. Daniel; Ranganath, Charan; Lesh, Tyler; Niendam, Tara; Solomon, Marjorie; Mangun, George R.; Carter, Cameron S.

    2013-01-01

    Individuals with schizophrenia are impaired in a broad range of cognitive functions, including impairments in the controlled maintenance of context-relevant information. In this study, we used ERPs in human subjects to examine whether impairments in the controlled maintenance of spoken discourse context in schizophrenia lead to overreliance on local associations among the meanings of individual words. Healthy controls (n = 22) and patients (n = 22) listened to short stories in which we manipulated global discourse congruence and local priming. The target word in the last sentence of each story was globally congruent or incongruent and locally associated or unassociated. ERP local association effects did not significantly differ between control participants and schizophrenia patients. However, in contrast to controls, patients only showed effects of discourse congruence when targets were primed by a word in the local context. When patients had to use discourse context in the absence of local priming, they showed impaired brain responses to the target. Our findings indicate that schizophrenia patients are impaired during discourse comprehension when demands on controlled maintenance of context are high. We further found that ERP measures of increased reliance on local priming predicted reduced social functioning, suggesting that alterations in the neural mechanisms underlying discourse comprehension have functional consequences in the illness. PMID:24068824

  8. Spared and impaired spoken discourse processing in schizophrenia: effects of local and global language context.

    PubMed

    Swaab, Tamara Y; Boudewyn, Megan A; Long, Debra L; Luck, Steve J; Kring, Ann M; Ragland, J Daniel; Ranganath, Charan; Lesh, Tyler; Niendam, Tara; Solomon, Marjorie; Mangun, George R; Carter, Cameron S

    2013-09-25

    Individuals with schizophrenia are impaired in a broad range of cognitive functions, including impairments in the controlled maintenance of context-relevant information. In this study, we used ERPs in human subjects to examine whether impairments in the controlled maintenance of spoken discourse context in schizophrenia lead to overreliance on local associations among the meanings of individual words. Healthy controls (n = 22) and patients (n = 22) listened to short stories in which we manipulated global discourse congruence and local priming. The target word in the last sentence of each story was globally congruent or incongruent and locally associated or unassociated. ERP local association effects did not significantly differ between control participants and schizophrenia patients. However, in contrast to controls, patients only showed effects of discourse congruence when targets were primed by a word in the local context. When patients had to use discourse context in the absence of local priming, they showed impaired brain responses to the target. Our findings indicate that schizophrenia patients are impaired during discourse comprehension when demands on controlled maintenance of context are high. We further found that ERP measures of increased reliance on local priming predicted reduced social functioning, suggesting that alterations in the neural mechanisms underlying discourse comprehension have functional consequences in the illness.

  9. Modified muscle sparing posterolateral thoracotomy.

    PubMed Central

    Ashour, M

    1990-01-01

    A modified posterolateral thoracotomy is described that combines the advantages of complete muscle sparing through a thoracolumbar fascial slide with excellent exposure. The technique is easy to perform. The procedure was associated with relatively little postoperative pain, coughing was effective, and early ambulation was achieved. Experience with this approach in the first 49 patients suggests that it offers an attractive alternative to the standard muscle cutting posterolateral thoracotomy approach for elective procedures. PMID:2281426

  10. Gastrointestinal-Sparing Effects of Novel NSAIDs in Rats with Compromised Mucosal Defence

    PubMed Central

    Blackler, Rory; Syer, Stephanie; Bolla, Manlio; Ongini, Ennio; Wallace, John L.

    2012-01-01

    Nonsteroidal anti-inflammatory drugs are among the most commonly used prescription and over-the-counter medications, but they often produce significant gastrointestinal ulceration and bleeding, particularly in elderly patients and patients with certain co-morbidities. Novel anti-inflammatory drugs are seldom tested in animal models that mimic the high risk human users, leading to an underestimate of the true toxicity of the drugs. In the present study we examined the effects of two novel NSAIDs and two commonly used NSAIDs in models in which mucosal defence was expected to be impaired. Naproxen, celecoxib, ATB-346 (a hydrogen sulfide- and naproxen-releasing compound) and NCX 429 (a nitric oxide- and naproxen-releasing compound) were evaluated in healthy, arthritic, obese, and hypertensive rats and in rats of advanced age (19 months) and rats co-administered low-dose aspirin and/or omeprazole. In all models except hypertension, greater gastric and/or intestinal damage was observed when naproxen was administered in these models than in healthy rats. Celecoxib-induced damage was significantly increased when co-administered with low-dose aspirin and/or omeprazole. In contrast, ATB-346 and NCX 429, when tested at doses that were as effective as naproxen and celecoxib in reducing inflammation and inhibiting cyclooxygenase activity, did not produce significant gastric or intestinal damage in any of the models. These results demonstrate that animal models of human co-morbidities display the same increased susceptibility to NSAID-induced gastrointestinal damage as observed in humans. Moreover, two novel NSAIDs that release mediators of mucosal defence (hydrogen sulfide and nitric oxide) do not induce significant gastrointestinal damage in these models of impaired mucosal defence. PMID:22496907

  11. Analgesic effect of iridoid glycosides from Paederia scandens (LOUR.) MERRILL (Rubiaceae) on spared nerve injury rat model of neuropathic pain.

    PubMed

    Liu, Mei; Zhou, Lanlan; Chen, Zhiwu; Hu, Caibiao

    2012-09-01

    Iridoid glycosides of Paederia scandens (IGPS) is a major active component isolated from traditional Chinese herb P. scandens (LOUR.) MERRILL (Rubiaceae). The aim of the present study was to investigate the analgesic effect of IGPS on spared nerve injury (SNI) model of neuropathic pain. The SNI model in rats was established by complete transection of the common peroneal and tibial distal branches of the sciatic nerve, leaving the sural branch intact. The mechanical withdrawal threshold (MWT) in response to mechanical stimulation was measured by electronic von Frey filaments on day 1 before operation and on days 1, 3, 5, 7, 10, and 14 after operation, respectively. Nitric oxide synthase (NOS) activity and nitric oxide (NO) production of spinal cord were measured by spectrophotometry and its cyclic guanosine monophosphate (cGMP) content by radioimmunoassay, mRNA expression of inducible NOS (iNOS) and protein kinase G type I (PKG-I, including PKG Ια and PKG Iβ) of spinal cord were analyzed by RT-PCR. There was a marked mechanical hypersensitivity response observed on day 1 after operation in SNI model, which accompanied with decreased MWT. Treatment with IGPS (70, 140, 280 mg/kg) significantly alleviated SNI-induced mechanical hypersensitivity response evidenced by increased MWT; as well as markedly decreased NOS activity, NO and cGMP levels. At the same time, IGPS (70, 140, 280 mg/kg) could also inhibit mRNA expression of iNOS, PKG Ια and PKG Iβ in the spinal cord. The results suggested that IGPS possesses antinociceptive effect, which may be partly related to the inhibition of NO/cGMP/PKG signaling pathway in the rat SNI model of neuropathic pain. PMID:22698486

  12. 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.

  13. Differing alpha-tocopherol oxidative lability and ascorbic acid sparing effects in buoyant and dense LDL.

    PubMed

    Tribble, D L; Thiel, P M; van den Berg, J J; Krauss, R M

    1995-11-01

    The enhanced oxidizability of smaller, more dense LDL is explained in part by a lower content of antioxidants, including ubiquinol-10 and alpha-tocopherol. In the present studies, we also observed greater rates of depletion of alpha-tocopherol (mole per mole LDL per minute) in dense (d = 1,040 to 1,054 g/mL) compared with buoyant (d = 1,026 to 1,032 g/mL) LDL in the presence of either Cu2+ or the radical-generating agent 2-2'-azobis (2-amidinopropane)dihydrochloride. Differences were particularly pronounced at the lowest Cu2+ concentration tested (0.25 mumol/L), with a fivefold greater rate in dense LDL. At higher concentrations (1.0 and 2.5 mumol/L Cu2+), there was a greater dependence of depletion rate on initial amount of alpha-tocopherol, which was reduced in dense LDL, thus resulting in smaller subfraction-dependent differences in depletion rates. Inclusion of ascorbic acid (15 mumol/L), an aqueous antioxidant capable of recycling alpha-tocopherol by hydrogen donation, was found to extend the course of Cu(2+)-induced alpha-tocopherol depletion in both buoyant and dense LDL, but this effect was more pronounced in dense LDL (time to half-maximal alpha-tocopherol depletion was extended 15.6-fold and 21.2-fold in buoyant and dense LDL, respectively, at 2.5 mumol/L Cu2+; P< .05). Thus, dense LDL exhibits more rapid alpha-tocopherol depletion and conjugated diene formation than buoyant LDL when oxidation is performed in the absence of ascorbic acid, but these differences are reversed in the presence of ascorbic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Lymphocyte-Sparing Effect of Stereotactic Body Radiation Therapy in Patients With Unresectable Pancreatic Cancer

    PubMed Central

    Wild, Aaron T.; Herman, Joseph M.; Dholakia, Avani S.; Moningi, Shalini; Lu, Yao; Rosati, Lauren M.; Hacker-Prietz, Amy; Assadi, Ryan K.; Saeed, Ali M.; Pawlik, Timothy M.; Jaffee, Elizabeth M.; Laheru, Daniel A.; Tran, Phuoc T.; Weiss, Matthew J.; Wolfgang, Christopher L.; Ford, Eric; Grossman, Stuart A.; Ye, Xiaobu; Ellsworth, Susannah G.

    2016-01-01

    severe RIL with survival in LAPC, further study of the effect of radiation technique on immune status is warranted. PMID:26867885

  15. The Analgesic Effects of Morphine and Tramadol Added to Intra-articular Levobupivacaine-Tenoxicam Combination for Arthroscopic Knee Surgery on Postoperative Pain; a Randomized Clinical Trial

    PubMed Central

    Oral, Ebru Gelici; Hanci, Ayse; Ulufer Sivrikaya, Gulcihan; Dobrucali, Hale; Turkoglu Kilinc, Leyla

    2015-01-01

    Background: Arthroscopic knee surgery is commonly performed as an outpatient procedure and is often associated with postoperative pain. Objectives: We aimed to compare the effects of intra-articular levobupivacaine-tenoxicam-tramadol and levobupivacaine-tenoxicam-morphine combinations on postoperative pain in patients undergoing elective arthroscopic knee surgery. Materials and Methods: A total of 90 ASA I-II patients undergoing elective arthroscopic meniscectomy under general anesthesia were enrolled. The participants were randomly allocated to three groups to receive the following intra-articular medications after completion of the surgery and before deflation of the tourniquet: Group S, 20 mL of saline; Group T, 35 mg of levobupivacaine, 20 mg of tenoxicam, and 100 mg of tramadol in 20 mL saline; and Group M, 35 mg of levobupivacaine, 20 mg of tenoxicam, and 4 mg of morphine in 20 mL saline. Visual analogue scale values at rest (VASr) and at active flexion of knee (VASa) at postoperation hours 1, 2, 4, 8, 12, and 24, duration of analgesia, total analgesic consumption, and number of rescue analgesia at 24 hours were evaluated. Results: VASr and VASa were significantly higher in group S in comparison to other groups (P < 0.05). Duration of analgesia was significantly longer in Group T and Group M than in Group S (P < 0.05). The difference between group T and group M was also significant (P < 0.05). Number of rescue analgesia and total analgesic consumption at postoperative hour 24 was significantly fewer in group M compared with other groups (P < 0.05). Conclusions: Intra-articular levobupivacaine-tenoxicam-morphine combination provides effective pain relief, longer analgesic duration, and less analgesic requirement when compared with intra-articular levobupivacaine-tenoxicam-tramadol combination and saline after knee arthroscopic surgery. PMID:26161321

  16. Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat

    PubMed Central

    Lilius, T O; Jokinen, V; Neuvonen, M S; Niemi, M; Kalso, E A; Rauhala, P V

    2015-01-01

    Background and Purpose The effects of ketamine in attenuating morphine tolerance have been suggested to result from a pharmacodynamic interaction. We studied whether ketamine might increase brain morphine concentrations in acute coadministration, in morphine tolerance and morphine withdrawal. Experimental Approach Morphine minipumps (6 mg·day–1) induced tolerance during 5 days in Sprague–Dawley rats, after which s.c. ketamine (10 mg·kg–1) was administered. Tail flick, hot plate and rotarod tests were used for behavioural testing. Serum levels and whole tissue brain and liver concentrations of morphine, morphine-3-glucuronide, ketamine and norketamine were measured using HPLC-tandem mass spectrometry. Key Results In morphine-naïve rats, ketamine caused no antinociception whereas in morphine-tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90 min after administration) lasting up to 150 min. In the brain of morphine-tolerant ketamine-treated rats, the morphine, ketamine and norketamine concentrations were 2.1-, 1.4- and 3.4-fold, respectively, compared with the rats treated with morphine or ketamine only. In the liver of morphine-tolerant ketamine-treated rats, ketamine concentration was sixfold compared with morphine-naïve rats. After a 2 day morphine withdrawal period, smaller but parallel concentration changes were observed. In acute coadministration, ketamine increased the brain morphine concentration by 20%, but no increase in ketamine concentrations or increased antinociception was observed. Conclusions and Implications The ability of ketamine to induce antinociception in rats made tolerant to morphine may also be due to increased brain concentrations of morphine, ketamine and norketamine. The relevance of these findings needs to be assessed in humans. PMID:25297798

  17. [Nerve-sparing radical prostatectomy].

    PubMed

    Okada, K; Tada, M; Nakano, A; Konno, T

    1988-04-01

    The neuroanatomy of the pelvic space was studied in order to clarify the course of cavernous nerves responsible for erectile function. The cavernous nerves travel along the dorsolateral portion at the base toward the apex of the prostate, then penetrate urogenital diaphragm at the lateral aspect of the membranous urethra. According to the anatomical findings, nerve-sparing radical prostatectomy was performed through the antegrade approach in 28 patients with prostate cancer. No significant surgical complications were encountered in the present series. Of the 28, evaluable cases were limited to 22 in terms of erection. Fifteen patients (68%) recovered their erectile function after nerve-sparing surgery. Therefore, the present surgical technique seems to be effective for the preservation of male sexual function following radical pelvic surgery.

  18. Monochromatic Minibeams Radiotherapy: From Healthy Tissue-Sparing Effect Studies Toward First Experimental Glioma Bearing Rats Therapy

    SciTech Connect

    Deman, Pierre; Vautrin, Mathias; Edouard, Magali; Stupar, Vasile; Bobyk, Laure; Farion, Regine; Elleaume, Helene; Remy, Chantal; Barbier, Emmanuel L.; Esteve, Francois; Adam, Jean-Francois

    2012-03-15

    Purpose: The purpose of this study was to evaluate high-dose single fraction delivered with monochromatic X-rays minibeams for the radiotherapy of primary brain tumors in rats. Methods and Materials: Two groups of healthy rats were irradiated with one anteroposterior minibeam incidence (four minibeams, 123 Gy prescribed dose at 1 cm depth in the brain) or two interleaved incidences (54 Gy prescribed dose in a 5 Multiplication-Sign 5 Multiplication-Sign 4.8 mm{sup 3} volume centered in the right hemisphere), respectively. Magnetic resonance imaging (MRI) follow-up was performed over 1 year. T2-weighted (T2w) images, apparent diffusion coefficient (ADC), and blood vessel permeability maps were acquired. F98 tumor bearing rats were also irradiated with interleaved minibeams to achieve a homogeneous dose of 54 Gy delivered to an 8 Multiplication-Sign 8 Multiplication-Sign 7.8 mm{sup 3} volume centered on the tumor. Anatomic and functional MRI follow-up was performed every 10 days after irradiation. T2w images, ADC, and perfusion maps were acquired. Results: All healthy rats were euthanized 1 year after irradiation without any clinical alteration visible by simple examination. T2w and ADC measurements remain stable for the single incidence irradiation group. Localized Gd-DOTA permeability, however, was observed 9 months after irradiation for the interleaved incidences group. The survival time of irradiated glioma bearing rats was significantly longer than that of untreated animals (49 {+-} 12.5 days versus 23.3 {+-} 2 days, p < 0.001). The tumoral cerebral blood flow and blood volume tend to decrease after irradiation. Conclusions: This study demonstrates the sparing effect of minibeams on healthy tissue. The increased life span achieved for irradiated glioma bearing rats was similar to the one obtained with other radiotherapy techniques. This experimental tumor therapy study shows the feasibility of using X-ray minibeams with high doses in brain tumor radiotherapy.

  19. Postoperative morphine requirements, nausea and vomiting following anaesthesia for tonsillectomy. Comparison of intravenous morphine and non-opioid analgesic techniques.

    PubMed

    Mather, S J; Peutrell, J M

    1995-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be as effective as opioid analgesia following tonsillectomy in children. Opioids are still frequently used but tonsillectomy is associated with a high incidence of vomiting. This study has attempted to assess postoperative analgesic consumption and nausea and vomiting after general anaesthesia for tonsillectomy using either paracetamol premedication, paracetamol plus a NSAID or intravenous morphine to provide postoperative analgesia. Some children required a rescue dose of morphine in the recovery room, including some who had received intravenous morphine at induction. Least supplementary morphine was required by those who had received paracetamol plus ketorolac. Postoperative nausea and vomiting was significantly less in the two groups which were not given intraoperative morphine. The number of vomiting incidents was also much less. We conclude that the preoperative administration of paracetamol alone provides satisfactory analgesia in many children but that supplementary analgesia is still required for some.

  20. Postoperative morphine requirements, nausea and vomiting following anaesthesia for tonsillectomy. Comparison of intravenous morphine and non-opioid analgesic techniques.

    PubMed

    Mather, S J; Peutrell, J M

    1995-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be as effective as opioid analgesia following tonsillectomy in children. Opioids are still frequently used but tonsillectomy is associated with a high incidence of vomiting. This study has attempted to assess postoperative analgesic consumption and nausea and vomiting after general anaesthesia for tonsillectomy using either paracetamol premedication, paracetamol plus a NSAID or intravenous morphine to provide postoperative analgesia. Some children required a rescue dose of morphine in the recovery room, including some who had received intravenous morphine at induction. Least supplementary morphine was required by those who had received paracetamol plus ketorolac. Postoperative nausea and vomiting was significantly less in the two groups which were not given intraoperative morphine. The number of vomiting incidents was also much less. We conclude that the preoperative administration of paracetamol alone provides satisfactory analgesia in many children but that supplementary analgesia is still required for some. PMID:7489439

  1. Continuous morphine produces more tolerance than intermittent or acute treatment.

    PubMed

    Dighe, Shveta V; Madia, Priyanka A; Sirohi, Sunil; Yoburn, Byron C

    2009-05-01

    Dosing protocol and analgesic efficacy have been proposed to be important determinants of the magnitude of opioid tolerance. The present study examined the effect of acute, intermittent and continuous treatment with the low analgesic efficacy agonist morphine on analgesic tolerance. Mice were implanted s.c. with a 25 mg morphine pellet for 1-7 days. Other mice were implanted s.c. with two 25 mg, or one 75 mg morphine pellet for 7 days. The release of morphine from subcutaneous implanted pellets was quantitated using a spectrophotometric assay. In other studies, mice were injected with morphine once (18.5-185 mg/kg/day; approximately 10-100 times ED(50) for morphine analgesia) or once/day for 7 days. Controls were implanted with a placebo pellet or injected with saline. Analysis of drug release from a 25 mg pellet indicated that release was greatest during the first 24 h, declined and then remained relatively constant. The amount of morphine released over 7 days by a 75 mg pellet (23.9 mg) was more than that of a single 25 mg pellet (15.4 mg) but less than two 25 mg pellets (30.8 mg). Following treatment, morphine cumulative dose-response studies were conducted (tail flick). Continuous treatment with morphine using pellet implantation produced a dose-dependent shift in the morphine ED(50) by 3.3, 5.8 and 8.5 fold for one 25 mg pellet, one 75 mg pellet and two 25 mg pellets, respectively. Acute and intermittent morphine administration produced substantially less analgesic tolerance than continuous release of morphine by implant pellets. The maximum shift in the ED(50) was 1.6 for acute treatment and 2.7 for 7 day intermittent treatment; despite a larger total daily dose. The present results indicate that continuous treatment with morphine results in greater analgesic tolerance than acute or intermittent morphine treatment even at comparable daily doses. These results are consistent with the suggestion that intermittent dosing has reduced risk of producing opioid

  2. Post-thoracotomy pain relief: combined use of cryoprobe and morphine infusion techniques.

    PubMed Central

    Orr, I. A.; Keenan, D. J.; Dundee, J. W.; Patterson, C. C.; Greenfield, A. A.

    1983-01-01

    In a reported study we found that freezing of the intercostal nerves under direct vision at thoracotomy provided better postoperative analgesia than im morphine on demand. Infusions of morphine were also more effective than when used by the intramuscular route. The benefit on the eighth postoperative day was greatest following the use of the cryoprobe. Further studies were carried out to evaluate the benefit of combining 'cryoprobe' analgesia with infusions of morphine. The combined use of morphine infusion and a cryoprobe did not produce greater postoperative pain relief than the use of the cryoprobe alone with im morphine on demand. PMID:6638849

  3. Abuse-related effects of mu opioid analgesics in an assay of intracranial self-stimulation in rats: modulation by chronic morphine exposure

    PubMed Central

    Altarifi, Ahmad A.; Rice, Kenner C.; Negus, S. Stevens

    2013-01-01

    Intracranial self-stimulation (ICSS) is an operant procedure in which responding is maintained by electrical brain stimulation. Stimulation frequency can be rapidly varied to maintain a wide range of baseline response rates, and drugs effects can be simultaneously evaluated on both low ICSS rates maintained by low stimulation frequencies and high ICSS rates maintained by high stimulation frequencies. ICSS “facilitation” denotes drug-induced increases in low ICSS rates and is often interpreted as an abuse-related effect, whereas ICSS “depression” denotes decreases in high ICSS rates and may indicate abuse-limiting effects. This study examined the roles of drug efficacy and of prior mu agonist exposure as determinants of mu agonist effects on ICSS in rats with electrodes implanted in the medial forebrain bundle. The high-, intermediate- and low-efficacy mu agonists methadone, fentanyl and nalbuphine were tested during escalating regimens of morphine exposure (Vehicle, 3.2, 18 mg/kg/day). During vehicle treatment, methadone and fentanyl primarily depressed ICSS, whereas nalbuphine produced weak facilitation that was not dose-dependent. Chronic morphine produced tolerance to ICSS depression and increased expression of ICSS facilitation. These results suggest that mu agonist exposure increases expression of abuse-related ICSS facilitation by mu agonists with a broad range of efficacies at mu receptors. PMID:23881045

  4. Abuse-related effects of µ-opioid analgesics in an assay of intracranial self-stimulation in rats: modulation by chronic morphine exposure.

    PubMed

    Altarifi, Ahmad A; Rice, Kenner C; Negus, S Stevens

    2013-09-01

    Intracranial self-stimulation (ICSS) is an operant procedure in which responding is maintained by electrical brain stimulation. Stimulation frequency can be varied rapidly to maintain a wide range of baseline response rates, and drugs' effects can be evaluated simultaneously on both low ICSS rates maintained by low stimulation frequencies and high ICSS rates maintained by high stimulation frequencies. ICSS 'facilitation' indicates drug-induced increases in low ICSS rates and is often considered an abuse-related effect, whereas ICSS 'depression' indicates decreases in high ICSS rates and may indicate abuse-limiting effects. This study examined the roles of µ-agonist efficacy and of previous µ-agonist exposure as determinants of µ-agonist effects on ICSS in rats with electrodes implanted into the medial forebrain bundle. The high-efficacy, intermediate-efficacy, and low-efficacy µ agonists methadone, fentanyl, and nalbuphine were tested during escalating regimens of morphine exposure (vehicle, 3.2, and 18 mg/kg/day). During vehicle treatment, methadone and fentanyl primarily depressed ICSS, whereas nalbuphine produced weak facilitation that was not dose dependent. Chronic morphine produced tolerance to ICSS depression and increased expression of ICSS facilitation. These results suggest that µ-agonist exposure increases the expression of abuse-related ICSS facilitation by µ agonists with a broad range of efficacies at µ receptors.

  5. The role of nitric oxide in the effects of cumin (Cuminum Cyminum L.) fruit essential oil on the acquisition of morphine-induced conditioned place preference in adult male mice.

    PubMed

    Kermani, Mojtaba; Azizi, Pegah; Haghparast, Abbas

    2012-01-12

    OBJECTIVE: Nitric oxide is a neural messenger molecule in the central nervous system that is generated from L-arginine via the nitric oxide synthase (NOS) and is involved in many important oplold-induced effects. In Iranian ancient medicine, Cuminum cyminum L (green seed) has been used for the treatment of some diseases. In the present study, the effect of intraperitoneal (ip) administration of different doses of cumin fruit essential oil (FEO) on the acquisition of morphine-induced conditioned place preference (GPP) in L-arginine-treated mice was investigated. METHODS: A total of 213 adult male albino Wistar mice were used in these experiments. The CPP paradigm was carried out in 5 continuous days, pre-conditioning, conditioning and post-conditioning. Animals were randomly assigned to one of the two groups for place conditioning. CPP was induced by subcutaneous (sc) injection of morphine (5 mg/kg) in 3 days conditioning schedule. On the test day, conditioning scores and locomotor activity were recorded by Ethovision software. RESULTS: Sole administration of different doses of cumin FEO (0.01%, 0.1%, 0.5%, 1% and 2%; lp) or L-arginine (50, 100 and 200 mg/kg; lp) during the CPP protocol could not induce CPP. Nonetheless, morphine-induced CPP was decreased by different doses of cumin FEO (0.01%-2%), whereas it was increased by L-arginine (50-200 mg/kg) when they were injected before morphine (5 rug/kg) during a 3-day conditioning phase (acquisition period). Additionally, cumin FEO could interestingly attenuate the raising effect of L-arginine on morphine-induced CPP in a dose-dependent manner. CONCLUSIONS: It is suggested that some components of the Cuminum cyminum L. seed attenuate the excessive effect of L-arginine on morphine-induced CPP through the NOS inhibitory mechanism. It seems that cumin FEO possibly acts as a NOS inhibitor.

  6. Optical properties of aqueous morphine solutions

    NASA Astrophysics Data System (ADS)

    Kuznetsov, Pavel E.; Gracheva, Anna A.; Zlobin, Vladimir A.; Nazarov, Georgy V.; Kuznetsova, Nina B.; Rogacheva, Svetlana M.

    2003-10-01

    We have studied morphine action on mobility and structure of water by means of fluorescent investigations and light scattering analysis. Wave-like concentration dependences have been plotted in the both cases. Theoretical description of the discovered effect has been made based on the formalism of N.N.Bogolubov.

  7. The effect of chronic morphine or methadone exposure and withdrawal on clock gene expression in the rat suprachiasmatic nucleus and AA-NAT activity in the pineal gland.

    PubMed

    Pačesová, D; Novotný, J; Bendová, Z

    2016-07-18

    The circadian rhythms of many behavioral and physiological functions are regulated by the major circadian pacemaker in the suprachiasmatic nucleus. Long-term opiate addiction and drug withdrawal may affect circadian rhythmicity of various hormones or the sleep/activity pattern of many experimental subjects; however, limited research has been done on the long-term effects of sustained opiate administration on the intrinsic rhythmicity in the suprachiasmatic nucleus and pineal gland. Here we compared the effects of repeated daily treatment of rats with morphine or methadone and subsequent naloxone-precipitated withdrawal on the expression of the Per1, Per2, and Avp mRNAs in the suprachiasmatic nucleus and on arylalkylamine N-acetyltransferase activity in the pineal gland. We revealed that 10-day administration and withdrawal of both these drugs failed to affect clock genes and Avp expression in the SCN. Our results indicate that opioid-induced changes in behavioral and physiological rhythms originate in brain structures downstream of the suprachiasmatic nucleus regulatory output pathway. Furthermore, we observed that acute withdrawal from methadone markedly extended the period of high night AA-NAT activity in the pineal gland. This suggests that withdrawal from methadone, a widely used drug for the treatment of opioid dependence, may have stronger impact on melatonin synthesis than withdrawal from morphine. PMID:27070740

  8. Steroid-sparing effect of wormwood (Artemisia absinthium) in Crohn's disease: a double-blind placebo-controlled study.

    PubMed

    Omer, B; Krebs, S; Omer, H; Noor, T O

    2007-02-01

    received the placebo deteriorated after the tapering of steroids, and re-starting steroids became necessary in 16 (80%) patients in this group after week 10. These results strongly suggest that wormwood has a steroid sparing effect. The improvements in HAMD scores indicate that wormwood also has an effect on the mood and quality of life of CD patients, which is not achieved by other standard medications.

  9. 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.

  10. Morphine dependence and withdrawal induced changes in cholinergic signaling

    PubMed Central

    Neugebauer, Nichole M.; Einstein, Emily B.; Lopez, Maria B.; McClure-Begley, Tristan D.; Mineur, Yann S.; Picciotto, Marina R.

    2013-01-01

    Cholinergic signaling is thought to be involved in morphine dependence and withdrawal, but the specific mechanisms involved remain unclear. The current study aimed to identify alterations in the cholinergic system that may contribute to the development of morphine dependence and withdrawal. Acetylcholinesterase (AChE) activity and [3H]-epibatidine binding were evaluated in order to determine if morphine dependence and withdrawal induces alterations in cholinergic signaling or expression of high affinity nicotinic acetylcholine receptors (nAChRs) in the midbrain (MB), medial habenula (MHb) and interpeduncular nucleus (IPN). The effect of cholinergic signaling through nAChRs on morphine-withdrawal induced jumping behavior was then determined. Lastly, the contribution of β4-containing nAChRs receptors in the MHb to morphine-withdrawal induced jumping behavior and neuronal activity as indicated by c-fos expression was assessed. Chronic morphine administration decreased AChE activity in MB and MHb, an effect that was no longer present following precipitated withdrawal. Morphine dependent mice showed increased nicotinic acetylcholine receptor (nAChR) levels in MB. Further, nicotine (0.4 mg/kg) and lobeline (3 mg/kg) decreased jumping behavior while mecamylamine (1 mg/kg) had no effect. Knock-down of β4 subunit-containing nAChRs in the MHb attenuated c-fos activation, but did not decrease morphine withdrawal-induced jumping. Thus, morphine withdrawal induces cholinergic signaling in the MHb, but this does not appear to be responsible for the effects of cholinergic drugs on somatic signs of opiate withdrawal, as measured by jumping behavior. PMID:23651795

  11. Evidence of active transport involvement in morphine transport via MDCKII and MDCK-PGP cell lines.

    PubMed

    Mashayekhi, S O; Sattari, M R; Routledge, P A

    2010-07-01

    Several transporters appear to be important in transporting various drugs. Many patients, who receive morphine as analgesic medication, also receive other medications with potency of changing morphine transport by affecting P-glycoprotein (P-GP) and oatp2 transport system. This could influence morphine pharmacokinetics and pharmacodynamics. The aim of present study was to elucidate the transport mechanisms involved in transporting morphine via MDCKII and MDCK-PGP cells. Morphine permeability was examined in the presence of various compounds with ability in inhibiting different transport systems including: digoxin, probenecid and d- glucose. The effect of morphine concentration changes on its transport was also examined. Morphine concentration was measured using HPLC with electrochemical detector. Morphine permeability via a MDCK II cells was greater than sucrose permeability, and reduced when a P-GP expressed cell line was used. Its permeability was increased significantly in the presence of a strong P-GP inhibitor. Morphine permeability decreased significantly in the presence of digoxin but not in the presence of d-glucose or probenecid. These results showed that morphine was a P-GP substrate, and digoxin related transporters such as oatp2 were involved in its transport. Morphine was not substrate for glucose or probenecid-sensitive transporters. PMID:21589798

  12. Evidence of active transport involvement in morphine transport via MDCKII and MDCK-PGP cell lines

    PubMed Central

    Mashayekhi, S.O.; Sattari, M.R.; Routledge, P.A.

    2010-01-01

    Several transporters appear to be important in transporting various drugs. Many patients, who receive morphine as analgesic medication, also receive other medications with potency of changing morphine transport by affecting P-glycoprotein (P-GP) and oatp2 transport system. This could influence morphine pharmacokinetics and pharmacodynamics. The aim of present study was to elucidate the transport mechanisms involved in transporting morphine via MDCKII and MDCK-PGP cells. Morphine permeability was examined in the presence of various compounds with ability in inhibiting different transport systems including: digoxin, probenecid and d- glucose. The effect of morphine concentration changes on its transport was also examined. Morphine concentration was measured using HPLC with electrochemical detector. Morphine permeability via a MDCK II cells was greater than sucrose permeability, and reduced when a P-GP expressed cell line was used. Its permeability was increased significantly in the presence of a strong P-GP inhibitor. Morphine permeability decreased significantly in the presence of digoxin but not in the presence of d-glucose or probenecid. These results showed that morphine was a P-GP substrate, and digoxin related transporters such as oatp2 were involved in its transport. Morphine was not substrate for glucose or probenecid-sensitive transporters. PMID:21589798

  13. Cardiac adverse effects of naloxone-precipitated morphine withdrawal on right ventricle: Role of corticotropin-releasing factor (CRF) 1 receptor

    SciTech Connect

    Navarro-Zaragoza, J.; Martínez-Laorden, E.; Mora, L.; Hidalgo, J.; Milanés, M.V.; Laorden, M.L.

    2014-02-15

    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-induced 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.

  14. Comparative evaluation of morphine, pentazocine and ciramadol in postaddicts.

    PubMed

    Preston, K L; Bigelow, G E; Liebson, I A

    1987-03-01

    The subjective, physiological and behavioral effects of morphine, pentazocine and ciramadol, an opioid agonist/antagonist, were studied in adult male nondependent opioid abusers living on a clinical research ward. Fifteen subjects were assigned randomly to one of three groups. Each group received, by i.m. injection, placebo and three doses of one active drug, twice in randomized block order under double-blind conditions in 4.5-hr experimental sessions. Physiological measures did not differentiate between the three drugs. All three drugs decreased respiratory rate and pupil diameter and increased blood pressure. However, morphine, ciramadol and pentazocine produced different profiles on the subjective effect measures. All three drugs increased "liking," "good effects," "any effects" and "high" subjective effect scales. Pentazocine increased subjective "bad effects" scale scores and scales measuring dysphoria and sedation. Observers reported significant behavioral changes after administration of morphine and pentazocine, but not after ciramadol. Overall, the effects of morphine (7.5, 15 and 30 mg) and pentazocine (22.5, 45 and 90 mg) were dose-related. Although pentazocine produced increases in scales that indicated negative subjective effects, it also produced significant changes in most self-report measures that were increased by morphine, including liking and good effects scales. The effects of ciramadol were not dose-related, with all three doses (30, 60 and 120 mg) producing effects approximately equivalent to morphine 15 mg. Thus, ciramadol exhibited a ceiling effect typical of the opioid agonist/antagonist.

  15. Enhancement of Cisplatin Nephrotoxicity by Morphine and Its Attenuation by the Opioid Antagonist Naltrexone.

    PubMed

    Aminian, Atefeh; Javadi, Shiva; Rahimian, Reza; Dehpour, Ahmad Reza; Asadi Amoli, Fahimeh; Moghaddas, Payman; Ejtemaei Mehr, Shahram

    2016-07-01

    Nephrotoxicity is a major side effect of cisplatin, a widely used chemotherapy agent. Morphine and other opioids are also used extensively in different types of cancer for the clinical management of pain associated with local or metastatic neoplastic lesions. In addition to its analgesic effects, morphine has also been reported to possess potential immunomodulatory and antioxidant properties. Herein, we investigated the effects of morphine in a rat model of cisplatin-induced nephrotoxicity. Following administration of a single dose of cisplatin (5 mg/kg), animals received intraperitoneal injections of morphine (5 mg/kg/day) and/or naltrexone (20 mg/kg/day), an opioid antagonist, for 5 days. Cisplatin-induced nephrotoxicity was detected by a significant increase in plasma urea and creatinine levels in addition to alterations in kidney tissue morphology. Levels of TNF-α and IL-1β were significantly increased in the renal tissue in cisplatin group. Moreover, glutathione (GSH) concentration and superoxide dismutase activity were significantly reduced in renal tissue in cisplatin group compared with control animals. Treatment with morphine aggravated the deleterious effects of cisplatin at clinical, biochemical and histopathological levels; whereas naltrexone diminished the detrimental effects of morphine in animals receiving morphine and cisplatin. Morphine or naltrexone alone had no effect on the mentioned parameters. Our findings indicate that concomitant treatment with morphine might intensify cisplatin-induced renal damage in rats. These findings suggest that morphine and other opioids should be administered cautiously in patients receiving cisplatin chemotherapy. PMID:27424012

  16. Role of fosaprepitant, a neurokinin Type 1 receptor antagonist, in morphine-induced antinociception in rats

    PubMed Central

    Prasoon, Pranav; Gupta, Shivani; Kumar, Rahul; Gautam, Mayank; Kaler, Saroj; Ray, Subrata Basu

    2016-01-01

    Objectives: Opioids such as morphine form the cornerstone in the treatment of moderate to severe pain. However, opioids also produce serious side effects such as tolerance. Fosaprepitant is a substance P (SP) receptor antagonist, which is used for treating chemotherapy-induced nausea and vomiting. SP is an important neuropeptide mediating transmission of pain at the spinal level. Thus, it was hypothesized that combining morphine with fosaprepitant would increase the antinociceptive effect of morphine. The objectives were to evaluate the effect of fosaprepitant on morphine-induced antinociception in rats and to investigate its mechanism of action. Methods: Sprague-Dawley rats were injected with morphine (10 mg/kg twice daily) and/or fosaprepitant (30 mg/kg once daily) for 7 days. Pain threshold was assessed by the hot plate test. Expression of SP and calcitonin gene-related peptide (CGRP) in the spinal cords of these rats was evaluated by immunohistochemistry. Results: Morphine administration resulted in an antinociceptive effect compared to the control group (day 1 and to a lesser extent on day 4). The decreased antinociception despite continued morphine treatment indicated development of tolerance. Co-administration of fosaprepitant attenuated tolerance to morphine (days 1 and 3) and increased the antinociceptive effect compared to control group (days 1–4). Expression of SP was increased in the morphine + fosaprepitant group. Conclusions: The results show that fosaprepitant attenuates the development of tolerance to morphine and thereby, increases the antinociceptive effect. This is likely linked to decreased release of SP from presynaptic terminals.

  17. Is the pain-reducing effect of opioid medication reliable? A psychophysical study of morphine and pentazocine analgesia.

    PubMed

    King, Christopher D; Goodin, Burel; Glover, Toni L; Riley, Joseph L; Hou, Wei; Staud, Roland; Fillingim, Roger B

    2013-03-01

    A number of laboratory studies have confirmed the efficacy of opioid medication in reducing pain generated by a number of psychophysical modalities. However, one implicit assumption of clinical and experimental pain testing of analgesics is that the analgesic response is stable and will be comparable across repeated administrations. In the current study, the repeatability of opioid analgesia was assessed in a randomized, double-blinded study using 3 psychophysical pain modalities (e.g., thermal, pressure, and ischemic) over 4 medication sessions (2 with active drug, 2 with placebo). Psychophysical responses were evaluated before and after intravenous administration of either morphine (0.08mg/kg; n=52) or pentazocine (0.5mg/kg; n=49). To determine the ability of a drug to reduce pain, 4 analytic methods (i.e., absolute change, percent change, ratio, and residualized change scores) were calculated to generate separate analgesic index scores for each measure and drug condition. All analgesic index scores demonstrated a greater analgesic response compared to saline for both medications, but stability (i.e., test-retest correlations) of the opioid analgesic indices depended on the pain measurement. Ischemic pain outcomes were moderately stable across sessions for both opioid medications; however, heat and pressure analgesic index scores were moderately stable for only morphine and pentazocine, respectively. Finally, within stimulus modalities, analgesic index scores were highly correlated with each other, suggesting that the different methods for computing analgesic responses provided comparable results. These results suggest that analgesic measures are able to distinguish between active drugs. In addition, analgesic responses to morphine and pentazocine demonstrate at least moderate reliability.

  18. Changes in morphine reward in a model of neuropathic pain.

    PubMed

    Cahill, Catherine M; Xue, Lihua; Grenier, Patrick; Magnussen, Claire; Lecour, Samantha; Olmstead, Mary C

    2013-06-01

    In addition to sensory disturbances, neuropathic pain is associated with an ongoing and persistent negative affective state. This condition may be reflected as altered sensitivity to rewarding stimuli. We examined this hypothesis by testing whether the rewarding properties of morphine are altered in a rat model of neuropathic pain. Neuropathic pain was induced by chronic constriction of the common sciatic nerve. Drug reward was assessed using an unbiased, three-compartment conditioned place preference (CPP) paradigm. The rats underwent two habituation sessions beginning 6 days after surgery. Over the next 8 days, they were injected with drug or vehicle and were confined to one CPP compartment for 30 min. On the following test day, the rats had access to all three compartments for 30 min. Consistent with the literature, systemic administration of morphine dose-dependently increased the CPP in pain-naive animals. In rats with neuropathic pain, however, the dose-dependent effects of morphine were in a bell-shaped curve, with a low dose of morphine (2 mg/kg) producing a greater CPP than a higher dose of morphine (8 mg/kg). In a separate group of animals, acute administration of morphine reversed mechanical allodynia in animals with neuropathic pain at the same doses that produced a CPP. The increased potency of systemic morphine to produce a CPP in animals with neuropathic pain suggests that the motivation for opioid-induced reward is different in the two states.

  19. Specific serum binding of morphine, levorphanol and heroin

    PubMed Central

    Herndon, B. L.; Baeder, D. H.; Ringle, D. A.

    1976-01-01

    Effects of repeated subcutaneous pellet implantation of a series of narcotic drugs on the serum binding of [14C]morphine was studied in rabbits. Three of the compounds, morphine, heroin and levorphanol, elicited production of a morphine-binding globulin in the implanted rabbits. This serum response did not occur with several other compounds tested, including the potent analgesic methadone, and the narcotic antagonist naloxone. The time course of production of this globulin response, as well as the specificity of the binding for the drug that induced the response are both characteristic of an immunological reaction.

  20. 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.

  1. Involvement of free radicals followed by the activation of phospholipase A2 in the mechanism that underlies the combined effects of methamphetamine and morphine on subacute toxicity or lethality in mice: comparison of the therapeutic potential of fullerene, mepacrine, and cooling.

    PubMed

    Mori, Tomohisa; Ito, Shinobu; Namiki, Mizuho; Suzuki, Tadashi; Kobayashi, Shizuko; Matsubayashi, Kenji; Sawaguchi, Toshiko

    2007-07-17

    An increase in polydrug abuse is a major problem worldwide. The coadministration of methamphetamine and morphine increased subacute toxicity or lethality in rodents. However, the underlying mechanisms by which lethality is increased by the coadministration of methamphetamine and morphine are not yet fully understood. Coadministered methamphetamine and morphine induced lethality by more than 80% in BALB/c mice, accompanied by the rupture of cells in the kidney and liver, and an increase in poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP-immunoreactive cells induced by the coadministration of methamphetamine and morphine was significantly attenuated by pretreatment with mepacrine (phospholipase A(2) inhibitor) or fullerene (a radical scavenger), or by cooling from 30 to 90 min after drug administration. Furthermore, based on the results of the electron spin resonance spin-trapping technique, hydroxyl radicals were increased by the administration of methamphetamine and morphine, and these increased hydroxyl radicals were potently attenuated by fullerene and cooling. These results suggest that hydroxyl radicals plays an important role in the increased lethality induced by the coadministration of methamphetamine plus morphine. The potency of cooling or drugs for decreasing the subacute toxicity or lethality induced by the coadministration of methamphetamine and morphine was in the order fullerene=cooling>mepacrine. These results indicate that fullerene and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine.

  2. Rectal wall sparing by dosimetric effect of rectal balloon used during intensity-modulated radiation therapy (IMRT) for prostate cancer.

    PubMed

    Teh, Bin S; Dong, Lei; McGary, John E; Mai, Wei-Yuan; Grant, Walter; Butler, E Brian

    2005-01-01

    interface recovered quickly and the dose reductions due to air cavity were 50%, 28%, 11%, and 1% at 2, 5, 10, and 15 mm, respectively, from the distal air-tissue interface. Evaluating the dose profiles of the more clinically relevant situation revealed the dose at air-tissue interface was approximately 15% lower in comparison to that without an air cavity. The dose built up rapidly so that at 1 and 2 mm, there was only an 8% and 5% differential, respectively. The dosimetric coverage at the depth of the posterior prostate wall was essentially equal with or without the air cavity. The median follow-up was 31.3 months. Rectal toxicity profile was very favorable: 81% (94/116) patients had no rectal complaint while 10.3% (12/116), 6.9% (8/116), and 1.7% (2/116) had grade 1, 2, and 3 toxicity, respectively. There was no grade 4 rectal toxicity. DVH analysis revealed that none of the patients had more than 25% of the rectum receiving 70 Gy or greater. Rectal balloon has rendered anterior rectal wall sparing by its dosimetric effects. In addition, it has reduced rectal volume, especially posterior and lateral rectal wall receiving high-dose radiation by rectal wall distension. Both factors may have contributed to decreased rectal toxicity achieved by IMRT despite dose escalation and higher than conventional fraction size. The findings have clinical significance for future very high-dose escalation trials whereby radiation proctitis is a major limiting factor.

  3. Effects of Lateral Funiculus Sparing, Spinal Lesion Level, and Gender on Recovery of Bladder Voiding Reflexes and Hematuria in Rats

    PubMed Central

    Ferrero, Sunny L.; Brady, Tiffany D.; Dugan, Victoria P.; Armstrong, James E.; Hubscher, Charles H.

    2015-01-01

    Abstract Deficits in bladder function are complications following spinal cord injury (SCI), severely affecting quality of life. Normal voiding function requires coordinated contraction of bladder and urethral sphincter muscles dependent upon intact lumbosacral reflex arcs and integration of descending and ascending spinal pathways. We previously reported, in electrophysiological recordings, that segmental reflex circuit neurons in anesthetized male rats were modulated by a bilateral spino-bulbo-spinal pathway in the mid-thoracic lateral funiculus. In the present study, behavioral measures of bladder voiding reflexes and hematuria (hemorrhagic cystitis) were obtained to assess the correlation of plasticity-dependent recovery to the degree of lateral funiculus sparing and mid-thoracic lesion level. Adult rats received mid-thoracic-level lesions at one of the following severities: complete spinal transection; bilateral dorsal column lesion; unilateral hemisection; bilateral dorsal hemisection; a bilateral lesion of the lateral funiculi and dorsal columns; or a severe contusion. Voiding function and hematuria were evaluated by determining whether the bladder was areflexic (requiring manual expression, i.e., “crede maneuver”), reflexive (voiding initiated by perineal stroking), or “automatic” (spontaneous voiding without caretaker assistance). Rats with one or both lateral funiculi spared (i.e., bilateral dorsal column lesion or unilateral hemisection) recovered significantly faster than animals with bilateral lateral funiculus lesions, severe contusion, or complete transection. Bladder reflex recovery time was significantly slower the closer a transection lesion was to T10, suggesting that proximity to the segmental sensory and sympathetic innervation of the upper urinary tract (kidney, ureter) should be avoided in the choice of lesion level for SCI studies of micturition pathways. In addition, hematuria duration was significantly longer in males, compared to

  4. Stability and compatibility of morphine.

    PubMed

    Vermeire, A; Remon, J P

    1999-09-30

    Morphine is a widely used analgesic for the treatment of severe cancer pain. For a large number of terminally ill patients oral administration is no longer possible and morphine is administered parenterally using portable pumps allowing comfortable treatment of the patient at home. In this situation the storage of pre-filled reservoirs and/or the administration over a longer period of time are daily practices and require data on the stability of morphine solutions. As most of these patients suffer from several other symptoms, the administration of admixtures with other drugs is common and requires information on the compatibility of morphine. Morphine degrades in aqueous solutions with the formation of mainly pseudomorphine, to a lesser extent morphine-N-oxide and probably apomorphine. From the study of the kinetics of morphine degradation it was concluded that the degradation of morphine is accelerated in the presence of oxygen and at higher pH of the solution, whereas temperature and light have only a minor influence on the degradation rate. The data reported on the stability of morphine infusion solutions kept under ambient conditions indicated that oxygen, light, the type of reservoir, the type of diluent, the salt form and the concentration of morphine do not affect the stability of morphine solutions stored for up to 3 months. Morphine solutions should preferably be stored at room temperature in order to avoid precipitation at low temperatures and water evaporation at higher temperatures causing increase in morphine concentration when stored in polymer reservoirs. Analyzing the data available on the compatibility of morphine infusion solutions revealed that differences in the formulation of the drug solutions (drug concentration, salt form, type and concentration of additives) and diluent, as well as temperature and order and ratio of mixing might affect the compatibility. Only few reports provide all necessary information, limiting the information useful for

  5. A review of morphine and morphine-6-glucuronide's pharmacokinetic-pharmacodynamic relationships in experimental and clinical pain.

    PubMed

    Sverrisdóttir, Eva; Lund, Trine Meldgaard; Olesen, Anne Estrup; Drewes, Asbjørn Mohr; Christrup, Lona Louring; Kreilgaard, Mads

    2015-07-10

    Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can be used to quantify dose-response relationships for the population as well as interindividual and interoccasion variability. Additionally, relevant covariates for population subgroups that deviate from the typical population can be identified and help clinicians in dose optimisation. This review provides a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates. Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course of response. Lastly, the impact of study design on the likelihood of determining accurate pharmacodynamic parameters for morphine response was evaluated.

  6. Effects of age, but not sex, on elevated startle during withdrawal from acute morphine in adolescent and adult rats.

    PubMed

    Radke, Anna K; Gewirtz, Jonathan C; Carroll, Marilyn E

    2015-08-01

    Investigations into animal models of drug withdrawal have largely found that emotional signs of withdrawal (e.g. anxiety, anhedonia, and aversion) in adolescents are experienced earlier and less severely than in their adult counterparts. The majority of these reports have examined withdrawal from ethanol or nicotine. To expand our knowledge about the emotional withdrawal state in adolescent rats, we used potentiation of the acoustic startle reflex after an acute dose of morphine (10 mg/kg, subcutaneously) as a measure of opiate withdrawal. Startle was measured at four time points after morphine injection (2, 3, 4, and 5 h) in 28-day-old and 90-day-old male and female rats. The results of this experiment revealed that peak potentiation of the startle reflex occurred at 3 h in the adolescent rats and at 5 h in the adult rats, and that the magnitude of withdrawal was larger in the adults. No sex differences were observed. Overall, these results affirm that, similar to withdrawal from ethanol and nicotine, opiate withdrawal signs are less severe in adolescent than in adult rats.

  7. Effects of age, but not sex, on elevated startle during withdrawal from acute morphine in adolescent and adult rats

    PubMed Central

    Radke, Anna K.; Gewirtz, Jonathan C.; Carroll, Marilyn E.

    2015-01-01

    Investigations into animal models of drug withdrawal have largely found that emotional signs of withdrawal (e.g., anxiety, anhedonia, and aversion) in adolescents are experienced earlier and less severely than in their adult counterparts. The majority of these reports have examined withdrawal from ethanol or nicotine. In order to expand our knowledge about the emotional withdrawal state in adolescent rats, we used potentiation of the acoustic startle reflex after an acute dose of morphine (10 mg/kg, s.c.) as a measure of opioid withdrawal. Startle was measured at four time points after morphine injection (2, 3, 4, and 5 h) in 28 and 90 day old male and female rats. The results of this experiment revealed that peak potentiation of the startle reflex occurred at 3 h in the adolescent rats and at 5 h in the adult rats, and that the magnitude of withdrawal was larger in the adults. No sex differences were observed. Overall, these results affirm that, similar to withdrawal from ethanol and nicotine, opiate withdrawal signs are less severe in adolescent than in adult rats. PMID:26154436

  8. Continuous measurement of cerebral blood volume in rats with the photoelectric technique: effect of morphine and naloxone.

    PubMed

    Sandor, P; Cox-van Put, J; de Jong, W; de Wied, D

    1986-11-01

    The validity of a photoelectric method for continuous cerebral blood volume (CBV) measurement was tested and modified for the rat's brain. A new way of introducing a miniature light source between the two hemispheres and fixing a light sensitive silicone blue cell to the outer surface of the parietal bone was developed. Light extinction factor of the rat's blood was determined experimentally (Eb rat = 1.38 +/- 0.15) in order to calculate absolute CBV value in this species, resulting in a 4.77 +/- 0.13 vol % absolute CBV value. Data obtained in anesthetized, artificially ventilated rats by simultaneous recording of CBV and local cerebral blood flow (H2-gas clearance technique) show that local hypothalamic blood flow decreased significantly after morphine (1.0 mg/kg s.c.), while total CBV remained unchanged. Opiate receptor blockade with naloxone (1.0 mg/kg s.c.) on the contrary, as well as naloxone and morphine administration, caused no change in local hypothalamic blood flow, but resulted in a significant increase of total cerebral blood volume.

  9. PKC-mediated potentiation of morphine analgesia by St. John's Wort in rodents and humans.

    PubMed

    Galeotti, Nicoletta; Farzad, Mersedeh; Bianchi, Enrica; Ghelardini, Carla

    2014-01-01

    Our purpose was to combine the use of morphine with clinically available inhibitors of protein kinase C (PKC), finally potentiating morphine analgesia in humans. Thermal tests were performed in rodents and humans previously administered with acute or chronic morphine combined or not with increasing doses of the PKC-blocker St. John's Wort (SJW) or its main component hypericin. Phosphorylation of the γ subunit of PKC enzyme was assayed by western blotting in the periaqueductal grey matter (PAG) from rodents co-administered with morphine and hypericin and was prevented in rodent PAG by SJW or hypericin co-administration with morphine, inducing a potentiation of morphine analgesia in thermal pain. The score of pain assessment in healthy volunteers were decreased by 40% when morphine was co-administered with SJW at a dose largely below those used to obtain an antidepressant or analgesic effect in both rodents and humans. The SJW/hypericin potentiating effect lasted in time and preserved morphine analgesia in tolerant mice. Our findings indicate that, in clinical practice, SJW could reduce the dose of morphine obtaining the same analgesic effect. Therefore, SJW and one of its main components, hypericin, appear ideal to potentiate morphine-induced analgesia.

  10. Myoelectric activity of the small intestine during morphine dependence and withdrawal in rats

    SciTech Connect

    Kuperman, D.A.; Sninsky, C.A.; Lynch, D.F.

    1987-04-01

    The authors investigated (1) the effect of morphine dependence on the migrating myoelectric complex (MMC) of the small intestine, (2) whether bacterial overgrowth developed in morphine-dependent rats, and (3) the effect of naloxone and methylbromide naltrexone, a peripheral opioid antagonist, on the MMC in morphine-naive and morphine-dependent rats. They also evaluated intestinal motility during naloxone-induced withdrawal in animals pretreated with clonidine. Intestinal myoelectric activity was monitored by four indwelling electrodes in unanesthetized, fasted rats. D-(/sup 14/C)xylose breath tests were performed before and after morphine-pellet implantation to evaluate the presence of bacterial overgrowth of the small intestine. Naloxone had no effect on myoelectric activity of the small intestine in morphine-naive rats. Cycling activity fronts were present in morphine-dependent animals, but there was a significant prolongation of activity front periodicity and slowing of the propagation velocity. No significant increase in /sup 14/CO/sub 2/ excretion was noted in the morphine-dependent rats. They conclude from their studies that (1) myoelectric activity of the small intestine develops incomplete tolerance to morphine; (2) bacterial overgrowth is not a feature of morphine dependence in the rat; (3) alterations of intestinal myoelectric activity are a component of the opiate withdrawal syndrome, and they appear at least partially mediated by a peripheral mechanism that can be suppressed by an ..cap alpha../sub 2/-adrenergic agonist.

  11. Memory impairment and reduced exploratory behavior in mice after administration of systemic morphine.

    PubMed

    Kitanaka, Junichi; Kitanaka, Nobue; Hall, F Scott; Fujii, Mei; Goto, Akiko; Kanda, Yusuke; Koizumi, Akira; Kuroiwa, Hirotoshi; Mibayashi, Satoko; Muranishi, Yumi; Otaki, Soichiro; Sumikawa, Minako; Tanaka, Koh-Ichi; Nishiyama, Nobuyoshi; Uhl, George R; Takemura, Motohiko

    2015-01-01

    In the present study, the effects of morphine were examined on tests of spatial memory, object exploration, locomotion, and anxiety in male ICR mice. Administration of morphine (15 or 30 mg/kg, intraperitoneally (i.p.)) induced a significant decrease in Y-maze alternations compared to saline vehicle-treated mice. The reduced Y-maze alternations induced by morphine were completely blocked by naloxone (15 mg/kg) or β-funaltrexamine (5 mg/kg) but not by norbinaltorphimine (5 mg/kg) or naltrindole (5 mg/kg), suggesting that the morphine-induced spatial memory impairment was mediated predominantly by μ-opioid receptors (MOPs). Significant spatial memory retrieval impairments were observed in the Morris water maze (MWM) in mice treated with morphine (15 mg/kg) or scopolamine (1 mg/kg), but not with naloxone or morphine plus naloxone. Reduced exploratory time was observed in mice after administration of morphine (15 mg/kg), in a novel-object exploration test, without any changes in locomotor activity. No anxiolytic-like behavior was observed in morphine-treated mice in the elevated plus maze. A significant reduction in buried marbles was observed in morphine-treated mice measured in the marble-burying test, which was blocked by naloxone. These observations suggest that morphine induces impairments in spatial short-term memory and retrieval, and reduces exploratory behavior, but that these effects are not because of overall changes in locomotion or anxiety.

  12. Memory Impairment and Reduced Exploratory Behavior in Mice after Administration of Systemic Morphine

    PubMed Central

    Kitanaka, Junichi; Kitanaka, Nobue; Hall, F Scott; Fujii, Mei; Goto, Akiko; Kanda, Yusuke; Koizumi, Akira; Kuroiwa, Hirotoshi; Mibayashi, Satoko; Muranishi, Yumi; Otaki, Soichiro; Sumikawa, Minako; Tanaka, Koh-ichi; Nishiyama, Nobuyoshi; Uhl, George R; Takemura, Motohiko

    2015-01-01

    In the present study, the effects of morphine were examined on tests of spatial memory, object exploration, locomotion, and anxiety in male ICR mice. Administration of morphine (15 or 30 mg/kg, intraperitoneally (i.p.)) induced a significant decrease in Y-maze alternations compared to saline vehicle-treated mice. The reduced Y-maze alternations induced by morphine were completely blocked by naloxone (15 mg/kg) or β-funaltrexamine (5 mg/kg) but not by norbinaltorphimine (5 mg/kg) or naltrindole (5 mg/kg), suggesting that the morphine-induced spatial memory impairment was mediated predominantly by μ-opioid receptors (MOPs). Significant spatial memory retrieval impairments were observed in the Morris water maze (MWM) in mice treated with morphine (15 mg/kg) or scopolamine (1 mg/kg), but not with naloxone or morphine plus naloxone. Reduced exploratory time was observed in mice after administration of morphine (15 mg/kg), in a novel-object exploration test, without any changes in locomotor activity. No anxiolytic-like behavior was observed in morphine-treated mice in the elevated plus maze. A significant reduction in buried marbles was observed in morphine-treated mice measured in the marble-burying test, which was blocked by naloxone. These observations suggest that morphine induces impairments in spatial short-term memory and retrieval, and reduces exploratory behavior, but that these effects are not because of overall changes in locomotion or anxiety. PMID:25987850

  13. The mGluR5 Antagonist Fenobam Induces Analgesic Conditioned Place Preference in Mice with Spared Nerve Injury

    PubMed Central

    Lax, Neil C.; George, David C.; Ignatz, Christopher; Kolber, Benedict J.

    2014-01-01

    Antagonists of metabotropic glutamate receptors (mGluRs) have the potential to act as analgesic drugs that may help alleviate chronic pain. This study was done to look at the possible rewarding properties of the mGluR5 antagonist, fenobam, in a cognitive assay. Analgesic conditioned place preference (aCPP) was used to examine the effects of fenobam (30 mg/kg) and the prototypical mGluR5 antagonist, MPEP, and these effects were compared to those of a drug with known analgesic properties, morphine (10 mg/kg). In each experiment, one group of mice received spared nerve injury (SNI) surgery to model chronic pain; the other group received a control sham surgery. Both fenobam and MPEP induced preference in the SNI mice, such that SNI mice spent significantly more time in the mGluR5 antagonist-paired chamber compared to a vehicle-paired chamber. No such preference developed for sham mice. Morphine induced preference in male and female mice in both the SNI and sham groups. The results showed that fenobam and MPEP likely reduced on-going distress in the SNI mice, causing them to prefer the chamber paired with the drug compared to the vehicle-paired chamber. Since sham animals did not prefer the drug-paired chamber, these data demonstrate that mGluR5 antagonism is non-rewarding in the absence of pain-like injury. PMID:25061818

  14. Effects of amphetamine, morphine, and CP 55, 940 on Go/No-Go task performance in rhesus monkeys.

    PubMed

    Koek, Wouter; Gerak, Lisa R; France, Charles P

    2015-08-01

    In humans, impulsivity measured as false alarms in a Go/No-Go task is reportedly decreased by amphetamine and is not affected by oxycodone and delta(9)-tetrahydrocannabinol. To model these findings in animals, three rhesus monkeys were trained to perform a food-reinforced Go/No-Go task. In this task, amphetamine was found to decrease false alarms (i.e. responding during No-Go trials), but only at doses that also decreased hits (i.e. responding during Go trials). Morphine generally decreased hits but not false alarms. The cannabinoid receptor agonist CP 55, 940 decreased both false alarms and hits, but only at doses that also decreased the number of trials completed. Additional studies in animals and humans are necessary to delineate the conditions under which amphetamine and other psychoactive drugs affect impulsivity in Go/No-Go tasks. PMID:26061355

  15. Reduced nocturnal morphine analgesia in mice following a geomagnetic disturbance.

    PubMed

    Ossenkopp, K P; Kavaliers, M; Hirst, M

    1983-10-10

    Latency to respond to an aversive thermal stimulus and the degree of analgesia induced by morphine were examined in mice injected with either isotonic saline or morphine sulfate (10 mg/kg) during midscotophase of a 12:12 h LD cycle. When mean response latencies were compared to the degree of geomagnetic disturbance (Ap index) present on test days, it was found that during the geomagnetic storm on December 17th, 1982, a significant reduction (P less than 0.01) in response latency was evident in both saline- and morphine-treated mice. The reduction in response latencies was greater, and lasted longer in the morphine-treated animals. It is suggested that the pineal gland may mediate this biomagnetic effect. PMID:6646507

  16. Dose-Effect Relationships for the Submandibular Salivary Glands and Implications for Their Sparing by Intensity Modulated Radiotherapy

    SciTech Connect

    Murdoch-Kinch, Carol-Anne; Vineberg, Karen A.; Ship, Jonathan

    2008-10-01

    Purpose: Submandibular salivary glands (SMGs) dysfunction contributes to xerostomia after radiotherapy (RT) of head-and-neck (HN) cancer. We assessed SMG dose-response relationships and their implications for sparing these glands by intensity-modulated radiotherapy (IMRT). Methods and Materials: A total of 148 HN cancer patients underwent unstimulated and stimulated SMG salivary flow rate measurements selectively from Wharton's duct orifices, before RT and periodically through 24 months after RT. Correlations of flow rates and mean SMG doses were modeled throughout all time points. IMRT replanning in 8 patients whose contralateral level I was not a target incorporated the results in a new cost function aiming to spare contralateral SMGs. Results: Stimulated SMG flow rates decreased exponentially by (1.2%){sup Gy} as mean doses increased up to 39 Gy threshold, and then plateaued near zero. At mean doses {<=}39 Gy, but not higher, flow rates recovered over time at 2.2%/month. Similarly, the unstimulated salivary flow rates decreased exponentially by (3%){sup Gy} as mean dose increased and recovered over time if mean dose was <39 Gy. IMRT replanning reduced mean contralateral SMG dose by average 12 Gy, achieving {<=}39 Gy in 5 of 8 patients, without target underdosing, increasing the mean doses to the parotid glands and swallowing structures by average 2-3 Gy. Conclusions: SMG salivary flow rates depended on mean dose with recovery over time up to a threshold of 39 Gy. Substantial SMG dose reduction to below this threshold and without target underdosing is feasible in some patients, at the expense of modestly higher doses to some other organs.

  17. Dose-Effect Relationships for the Submandibular Salivary Glands and Implications for Their Sparing by Intensity Modulated Radiotherapy

    PubMed Central

    Murdoch-Kinch, Carol-Anne; Kim, Hyugnjin M.; Vineberg, Karen A; Ship, Jonathan A.; Eisbruch, Avraham

    2012-01-01

    Purpose Submandibular salivary glands (SMGs) dysfunction contributes to xerostomia after radiotherapy (RT) of head and neck (HN) cancer. We assessed SMG dose-response relationships and their implications for sparing these glands by intensity modulated radiotherapy (IMRT). Patients and Methods 148 HN cancer patients underwent unstimulated and stimulated SMG salivary flow rate measurements selectively from Wharton’s duct orifices, before RT and periodically through 24 months after RT. Correlations of flow rates and mean SMG doses were modeled throughout all time points. IMRT re-planning in eight patients whose contralateral level I was not a target incorporated the results in a new cost function aiming to spare contralateral SMGs. Results Stimulated SMG flow rates decreased exponentially by (1.2%)Gy as mean doses increased up to 39 Gy threshold, and then plateaued near zero. At mean doses ≤39 Gy, but not higher, flow rates recovered over time at 2.2%/month. Similarly, the unstimulated salivary flow rates decreased exponentially by (3%)Gy as mean dose increased and recovered over time if mean dose was <39 Gy. IMRT re-planning reduced mean contralateral SMG dose by average 12 Gy, achieving ≤39 Gy in 5/8 patients, without target under-dosing, increasing the mean doses to the parotid glands and swallowing structures by average 2–3 Gy. Conclusions SMG salivary flow rates depended on mean dose with recovery over time up to a threshold of 39 Gy. Substantial SMG dose reduction to below this threshold and without target under-dosing is feasible in some patients, at the expense of modestly higher doses to some other organs. PMID:18337023

  18. Different neural systems mediate morphine reward and its spontaneous withdrawal aversion.

    PubMed

    Vargas-Perez, Hector; Ting-A-Kee, Ryan; van der Kooy, Derek

    2009-05-01

    The opponent-process theory posits that the aversive state of acute opiate withdrawal is a consequence of, and depends on, the previous rewarding state evoked by acute morphine reward. Although the brainstem tegmental pedunculopontine nucleus (TPP) is crucial for the rewarding component of morphine, the source of the later aversive component is not known. It is possible that (i) the second aversive process takes place within the TPP itself or (ii) morphine reward in the TPP activates an unconditioned opponent motivational process in another region of the brain. The effects of reversible inactivation of the TPP on the motivational properties of acute morphine and its spontaneous withdrawal effects in non-drug-dependent rats were examined using a place-conditioning paradigm. Reversible inactivation of the TPP with lidocaine or bupivacaine immediately before the morphine injection blocked the rewarding properties of morphine in non-dependent rats. Blocking the rewarding effects of morphine also blocked the opponent aversive effects of acute morphine withdrawal. In contrast, reversible inactivation of the TPP during the acute morphine withdrawal did not block this opponent aversive process. Our results confirm that the TPP is a critical neural substrate underlying the acute rewarding effects of morphine in non-dependent rats. Furthermore, the opponent aversive process of acute morphine withdrawal is induced by the acute rewarding effects of morphine. However, the TPP does not directly mediate the spontaneous withdrawal aversion (the opponent process), suggesting that a different system, triggered by the changes in the TPP after the primary drug response, produces the aversion itself.

  19. Different neural systems mediate morphine reward and its spontaneous withdrawal aversion.

    PubMed

    Vargas-Perez, Hector; Ting-A-Kee, Ryan; van der Kooy, Derek

    2009-05-01

    The opponent-process theory posits that the aversive state of acute opiate withdrawal is a consequence of, and depends on, the previous rewarding state evoked by acute morphine reward. Although the brainstem tegmental pedunculopontine nucleus (TPP) is crucial for the rewarding component of morphine, the source of the later aversive component is not known. It is possible that (i) the second aversive process takes place within the TPP itself or (ii) morphine reward in the TPP activates an unconditioned opponent motivational process in another region of the brain. The effects of reversible inactivation of the TPP on the motivational properties of acute morphine and its spontaneous withdrawal effects in non-drug-dependent rats were examined using a place-conditioning paradigm. Reversible inactivation of the TPP with lidocaine or bupivacaine immediately before the morphine injection blocked the rewarding properties of morphine in non-dependent rats. Blocking the rewarding effects of morphine also blocked the opponent aversive effects of acute morphine withdrawal. In contrast, reversible inactivation of the TPP during the acute morphine withdrawal did not block this opponent aversive process. Our results confirm that the TPP is a critical neural substrate underlying the acute rewarding effects of morphine in non-dependent rats. Furthermore, the opponent aversive process of acute morphine withdrawal is induced by the acute rewarding effects of morphine. However, the TPP does not directly mediate the spontaneous withdrawal aversion (the opponent process), suggesting that a different system, triggered by the changes in the TPP after the primary drug response, produces the aversion itself. PMID:19453632

  20. Trans-stilbene oxide administration increased hepatic glucuronidation of morphine but decreased biliary excretion of morphine glucuronide in rats

    SciTech Connect

    Fuhrman-Lane, C.; Fujimoto, J.M.

    1982-09-01

    The effect of the inducing agent trans-stilbene oxide (TSO) on the metabolism and biliary excretion of (/sup 14/C)morphine was studied in the isolated in situ perfused rat liver. After administration of morphine by intraportal injection or by the segmented retrograde intrabiliary injection technique, the TSO-treated group showed a marked decrease in the biliary recovery of morphine as its glucuronide conjugate (morphine-3-glucuronide (MG)). However, recovery of MG in the venous outflow of the single pass perfusate was greatly increased. These findings suggested that TSO treatment enhanced the formation of MG from morphine and changed the primary route of hepatic elimination of MG. TSO treatment also decreased the excretion of morphine (as MG) in the bile of anesthetized renal-ligated rats. This decreased biliary function required several days to develop and appeared closely associated with the inductive effect of TSO. After i.v. administration of (/sup 14/C)MG itself, biliary recovery was also markedly decreased in TSO-treated rats. It is postulated that the effect of the TSO treatment led to either a decrease in canalicular transport of MG into bile or an increase in the efficiency of transfer of MG to the blood at the sinusoidal side of the hepatocyte. Regardless of the mechanism, the results indicate the need to study compartmentalization of drug transport and metabolism functions.

  1. Morphine-induced antinociception and reward in "humanized" mice expressing the mu opioid receptor A118G polymorphism.

    PubMed

    Henderson-Redmond, Angela N; Yuill, Matthew B; Lowe, Tammy E; Kline, Aaron M; Zee, Michael L; Guindon, Josée; Morgan, Daniel J

    2016-05-01

    The rewarding and antinociceptive effects of opioids are mediated through the mu-opioid receptor. The A118G single nucleotide polymorphism in this receptor has been implicated in drug addiction and differences in pain response. Clinical and preclinical studies have found that the G allele is associated with increased heroin reward and self-administration, elevated post-operative pain, and reduced analgesic responsiveness to opioids. Male and female mice homozygous for the "humanized" 118AA or 118GG alleles were evaluated to test the hypothesis that 118GG mice are less sensitive to the rewarding and antinociceptive effects of morphine. We found that 118AA and 118GG mice of both genders developed conditioned place preference for morphine. All mice developed tolerance to the antinociceptive and hypothermic effects of morphine. However, morphine tolerance was not different between AA and GG mice. We also examined sensitivity to the antinociceptive and hypothermic effects of cumulative morphine doses. We found that 118GG mice show reduced hypothermic and antinociceptive responses on the hotplate for 10mg/kg morphine. Finally, we examined basal pain response and morphine-induced antinociception in the formalin test for inflammatory pain. We found no gender or genotype differences in either basal pain response or morphine-induced antinociception in the formalin test. Our data suggests that homozygous expression of the GG allele in mice blunts morphine-induced hypothermia and hotplate antinociception but does not alter morphine CPP, morphine tolerance, or basal inflammatory pain response. PMID:26521067

  2. 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.

  3. Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish.

    PubMed

    Khor, Beng-Siang; Jamil, Mohd Fadzly Amar; Adenan, Mohamad Ilham; Shu-Chien, Alexander Chong

    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

  4. 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

  5. Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish.

    PubMed

    Khor, Beng-Siang; Jamil, Mohd Fadzly Amar; Adenan, Mohamad Ilham; Shu-Chien, Alexander Chong

    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.

  6. Treadmill running reverses retention deficit induced by morphine.

    PubMed

    Alaei, Hojjatallah; Borjeian, Lila; Azizi, Mohammad; Orian, Shahrbanoo; Pourshanazari, Aliasghar; Hanninen, Osmo

    2006-04-24

    Human and animal studies have suggested that exercise has benefits overall health and cognitive function. The aim of this study was to investigate the effect of treadmill running on passive avoidance learning and memory deficit in morphine-treated rats. The passive avoidance learning was measured in different time intervals (1, 2 and 24 h as well as 1 week and 1 month). Four groups of rats were included as follows: control, morphine-treated, exercised-saline and exercised-morphine-treated group. The electrical foot shock and treadmill training (2 h at a speed of 5 m/min for 10 days) were applied for all the groups. The data obtained was analyzed using unpaired Students t-test and ANOVA test with group as the independent variable, and performance in each session (avoidances and crossings) as the dependent variables. The results show that the total time staying in dark box was decreased in exercised-saline and exercised-morphine-treated rats by treadmill running (P<0.05). The avoidance learning was significantly reduced in morphine-treated group as indicated by the increased total time of staying in the dark box compared with the control group (P<0.05). We could conclude that exercise increased the delay time of entry to the dark electrical foot shock box, suggesting that morphine impaired the short-term memory and learning and this was reversed by the treadmill running.

  7. Pharmacological modulation of neuropathic pain-related depression of behavior: effects of morphine, ketoprofen, bupropion and [INCREMENT]9-tetrahydrocannabinol on formalin-induced depression of intracranial self-stimulation in rats.

    PubMed

    Leitl, Michael D; Negus, S Stevens

    2016-06-01

    Neuropathic pain is often associated with behavioral depression. Intraplantar formalin produces sustained, neuropathy-associated depression of intracranial self-stimulation (ICSS) in rats. This study evaluated pharmacological modulation of formalin-induced ICSS depression. Rats with intracranial electrodes targeting the medial forebrain bundle responded for electrical brain stimulation in an ICSS procedure. Bilateral intraplantar formalin administration depressed ICSS for 14 days. Morphine (0.32-3.2 mg/kg), ketoprofen (0.1-10 mg/kg), bupropion (3.2-32 mg/kg), and [INCREMENT]9-tetrahydrocannabinol (THC; 0.32-3.2 mg/kg) were evaluated for their effectiveness to reverse formalin-induced depression of ICSS. Drug effects on formalin-induced mechanical allodynia were evaluated for comparison. Morphine and bupropion reversed both formalin-induced ICSS depression and mechanical allodynia, and effects on ICSS were sustained during repeated treatment. Ketoprofen failed to reverse either formalin effect. THC blocked mechanical allodynia, but decreased ICSS in control rats and exacerbated formalin-induced depression of ICSS. The failure of ketoprofen to alter formalin effects suggests that formalin effects result from neuropathy rather than inflammation. The effectiveness of morphine and bupropion to reverse formalin effects agrees with other evidence that these drugs block pain-depressed behavior in rats and relieve neuropathic pain in humans. The effects of THC suggest general behavioral suppression and do not support the use of THC to treat neuropathic pain.

  8. Forced exercise improves passive avoidance memory in morphine-exposed rats.

    PubMed

    Saadipour, K; Sarkaki, A; Alaei, H; Badavi, M; Rahim, F

    2009-09-01

    The aim of this study was to investigate the effect of short-term forced exercise protocol on passive avoidance retention in morphine-exposed rats. Effects of morphine on acquisition and retrieval of retention have been proven in the avoidance paradigms. Twenty four male Wistar rats weighing 250-300 g were used in this study. Animals were randomly divided into four groups including: (1) non-morphine-exposed without exercise (nA.nE) (2) non-morphine-exposed with exercise (nA.E) (3) morphine-exposed without exercise (A.nE) and (4) morphine-exposed with exercise (A.E). Rats ran as forced exercise on the motorized treadmill 1 h daily for ten days. Morphine-exposed animals received intraperitoneal morphine during first 5 days of the exercise period and their dependence to morphine was confirmed by naloxane admistration (10 mg kg(-1), i.p.) and withdrawal test. After 10 days of forced exercise, step down latency was tested and Inflexion Ratio (IR) was evaluated in each rat. Baseline step down latencies before any morphine exposing or exercise have shown no significant alteration in all groups. Inflexion Ratio (IR) ofnA.E group has increased significantly (p<0.001) at 1, 3, 7 and 14 days after receiving shock (learning) compared to nA.nE and A.E groups. Our data showed that short-term forced exercise on treadmill improved retention in both morphine-exposed and non morphine-exposed rats at least up to 7 days and more than 14 days, respectively. Alteration in retention between exercised groups may attribute the release of adrenal stress hormones such as epinephrine and corticosterone because of the emotional arousal.

  9. [Morphine by external route, prescribed to Heinrich Heine by David Gruby].

    PubMed

    Chast, F

    1998-01-01

    The exhibition held in Paris commemorating the bicentenial of Heinrich Heine showed three prescriptions by Dr. D. Gruby, through which morphine was prescribed for the poet by external route. The use of morphine was justified in a patient with unrelieved pain caused by neurosyphilis during the last twelve years of his life. This way of morphine administration (endemic method) was quite popular between 1830 and 1860. The process consisted in stripping the derm with the help of a vesicant and in applying directly on it morphine salts crystals. Several authors commented the interest of this way of administration rather uncomfortable for the patient but apparently very effective. PMID:11625475

  10. Combined morphine-bupivacaine caudals for reconstructive penile surgery in children: systemic absorption of morphine and postoperative analgesia.

    PubMed

    Wolf, A R; Hughes, D; Hobbs, A J; Prys-Roberts, C

    1991-02-01

    We wished to determine if the addition of a small dose of morphine (0.05 mg.kg-1) to a caudal solution of 0.25% bupivacaine could extend the duration of analgesia after major reconstructive penile surgery and also to measure the systemic absorption of morphine after caudal injection. Thirty children undergoing reconstructive penile surgery received a caudal injection of 0.25% bupivacaine 0.75 ml.kg-1 with or without morphine 0.05 mg.kg-1. All patients awoke pain-free, but eight of the fifteen patients receiving bupivacaine alone required supplementary injections of opioid postoperatively, whereas none of the patients receiving the bupivacaine-morphine mixture required additional opioids. The incidence of side-effects was similar for the two groups. Morphine was absorbed rapidly after caudal injection to reach a peak plasma level of 21.2 (+/- 4.8) ng.ml-1 at ten minutes and then fell to 10.1 (+/- 3.8) ng.ml-1 at one hour and 4.1 (+/- 2.6) ng.ml-1 at three hours. These levels are low compared with plasma levels associated with systemic analgesia. We conclude that the extended duration of analgesia from morphine 0.05 mg/kg given caudally is due at least in part to specific spinal analgesia. PMID:2012289

  11. Tissue-Sparing Effect of X-ray Microplanar Beams Particulary in the CNS: Is a Bystander Effect Involved?

    SciTech Connect

    Dilmanian,A.; Qu, Y.; Feinendegen, L.; Pena, L.; Bacarian, T.; Henn, F.; Kalef-Ezra, J.; Liu, S.; Zhong, Z.; McDonald, J.

    2007-01-01

    Normal tissues, including the central nervous system, tolerate single exposures to narrow planes of synchrotron-generated x-rays (microplanar beams; microbeams) up to several hundred Gy. The repairs apparently involve the microvasculature and the glial system. We evaluate a hypothesis on the involvement of bystander effects in these repairs.

  12. A randomized, controlled study to evaluate the steroid sparing effect of essential fatty acid supplementation in the treatment of canine atopic dermatitis.

    PubMed

    Saevik, Bente K; Bergvall, Kerstin; Holm, Birgit R; Saijonmaa-Koulumies, Leena E; Hedhammar, Ake; Larsen, Stig; Kristensen, Flemming

    2004-06-01

    A randomized, double blind, placebo-controlled multicentre clinical trial of 12 weeks' duration was undertaken in 60 dogs with atopic dermatitis to evaluate the steroid sparing effect of essential fatty acid supplementation. The dogs were randomly assigned to receive either a combination of borage seed oil and fish oil or a placebo, in addition to prednisolone tablets. All dogs received a standardized basal diet. Owners of the dogs recorded pruritus daily using a 10 cm visual analog scale and the dosage of prednisolone was established based on the pruritus score, according to written instructions. The dosage of prednisolone and the use of any concurrent treatment (shampoo and/or ear-cleanser) were recorded by the owner on a daily basis. The investigators graded the skin lesions at days 0, 42 and 84. The use of prednisolone during the test period was lower in the active group, but the difference was not statistically significant (P = 0.32). The test period was sequentially divided into 43-84, 50-84, 57-84, 64-84, 71-84 and 78-84 days. On day 64, the difference between the active group and the placebo group reached statistical significance (P = 0.04) with an increasing difference towards the end of the study. A statistically significant reduction in the pruritus scores and the total clinical scores from day 0 to day 84 was apparent in both groups (P < 0.0001). At the end of the study, both the pruritus score and the total clinical score were lower in the active group. Our findings indicate a steroid sparing effect of essential fatty acid supplementation in canine atopic dermatitis and, furthermore, that there is a time lag before the effect is attained.

  13. A randomized, controlled study to evaluate the steroid sparing effect of essential fatty acid supplementation in the treatment of canine atopic dermatitis.

    PubMed

    Saevik, Bente K; Bergvall, Kerstin; Holm, Birgit R; Saijonmaa-Koulumies, Leena E; Hedhammar, Ake; Larsen, Stig; Kristensen, Flemming

    2004-06-01

    A randomized, double blind, placebo-controlled multicentre clinical trial of 12 weeks' duration was undertaken in 60 dogs with atopic dermatitis to evaluate the steroid sparing effect of essential fatty acid supplementation. The dogs were randomly assigned to receive either a combination of borage seed oil and fish oil or a placebo, in addition to prednisolone tablets. All dogs received a standardized basal diet. Owners of the dogs recorded pruritus daily using a 10 cm visual analog scale and the dosage of prednisolone was established based on the pruritus score, according to written instructions. The dosage of prednisolone and the use of any concurrent treatment (shampoo and/or ear-cleanser) were recorded by the owner on a daily basis. The investigators graded the skin lesions at days 0, 42 and 84. The use of prednisolone during the test period was lower in the active group, but the difference was not statistically significant (P = 0.32). The test period was sequentially divided into 43-84, 50-84, 57-84, 64-84, 71-84 and 78-84 days. On day 64, the difference between the active group and the placebo group reached statistical significance (P = 0.04) with an increasing difference towards the end of the study. A statistically significant reduction in the pruritus scores and the total clinical scores from day 0 to day 84 was apparent in both groups (P < 0.0001). At the end of the study, both the pruritus score and the total clinical score were lower in the active group. Our findings indicate a steroid sparing effect of essential fatty acid supplementation in canine atopic dermatitis and, furthermore, that there is a time lag before the effect is attained. PMID:15214949

  14. Testosterone is required for corticosteroid-binding globulin upregulation by morphine to be fully manifested.

    PubMed

    Nock, B; Wich, M; Cicero, T J; O'Connor, L H

    2000-09-01

    We previously reported that morphine increases the concentration of corticosteroid-binding globulin (CBG) in blood of male, but not female, rats. This pronounced sexual dimorphism suggested that CBG upregulation by morphine might be androgen-dependent. In the current studies, we found that castration, whether performed just before or just after puberty or in adulthood, increased the concentration of CBG in adult male rats. Naltrexone did not prevent this increase and, therefore, it does not appear to be attributable to the release of endogenous opioids. Exposure to morphine for 1 week in adulthood increased ( approximately 100%) the concentration of CBG in intact, i.e., sham-castrated, males. The CBG levels of castrated rats treated with morphine did not differ from those of intact rats treated with morphine. However, because castration increased the concentration of CBG, the difference between the placebo and morphine groups decreased with time after castration. At 4 weeks after castration, the difference between the morphine and placebo groups (19%) was no longer statistically significant. Testosterone replacement prevented the rise in CBG levels following castration and maintained the magnitude of the difference between placebo and morphine-treated rats within the normal range. Thus, testosterone appears necessary for morphine effects on CBG to be fully manifested. PMID:11113500

  15. Prefrontal cortex gates acute morphine action on dopamine neurons in the ventral tegmental area.

    PubMed

    Liu, Changliang; Fang, Xing; Wu, Qianqian; Jin, Guozhang; Zhen, Xuechu

    2015-08-01

    Morphine excites dopamine (DA) neurons in the ventral tegmental area (VTA), an effect mediated by both local and systemic mechanisms. While the importance of the prefrontal cortex (PFC) - VTA circuit in opiate addiction is well established, little is known about how the PFC regulates the activity of VTA DA neurons upon morphine stimulation. One major challenge is that VTA DA neurons are highly heterogeneous in terms of projection and regulation, making their responses to PFC manipulations variable. Our previous work has identified a subgroup of VTA DA neurons exhibiting significant slow oscillation in their firing sequence, and demonstrated that most of these neurons are functionally connected with the PFC. In the present study, we focus our efforts only on VTA DA neurons expressing strong slow oscillation, and report that blocking the neuronal activity in the PFC remarkably attenuates the morphine-induced excitation of these neurons. Using in vivo microdialysis, we find that inactivation of the PFC also reduces the morphine-induced elevation of DA levels in the nucleus accumbens (NAc). Furthermore, 24 h after only single morphine exposure, PFC-inactivation failed to prevent subsequent morphine challenge from exciting VTA DA neurons, which is paralleled by altered response of PFC pyramidal neurons to morphine stimulation. Our results indicate that the PFC gates acute morphine action on a subset of VTA DA neurons, which is highly plastic and can be functionally remodeled by morphine exposure.

  16. 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.

  17. Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice.

    PubMed

    Neelakantan, Harshini; Tallarida, Ronald J; Reichenbach, Zachary W; Tuma, Ronald F; Ward, Sara J; Walker, Ellen A

    2015-04-01

    Cannabinoid and opioid agonists can display overlapping behavioral effects and the combination of these agonists is known to produce enhanced antinociception in several rodent models of acute and chronic pain. The present study investigated the antinociceptive effects of the nonpsychoactive cannabinoid, cannabidiol (CBD) and the µ-opioid agonist morphine, both alone and in combination, using three behavioral models in mice, to test the hypothesis that combinations of morphine and CBD would produce synergistic effects. The effects of morphine, CBD, and morphine/CBD combinations were assessed in the following assays: (a) acetic acid-stimulated stretching; (b) acetic acid-decreased operant responding for palatable food; and (c) hot plate thermal nociception. Morphine alone produced antinociceptive effects in all three models of acute nociception, whereas CBD alone produced antinociception only in the acetic acid-stimulated stretching assay. The nature of the interactions between morphine and CBD combinations were assessed quantitatively based on the principle of dose equivalence. Combinations of CBD and morphine produced synergistic effects in reversing acetic acid-stimulated stretching behavior, but subadditive effects in the hot plate thermal nociceptive assay and the acetic acid-decreased operant responding for palatable food assay. These results suggest that distinct mechanisms of action underlie the interactions between CBD and morphine in the three different behavioral assays and that the choice of appropriate combination therapies for the treatment of acute pain conditions may depend on the underlying pain type and stimulus modality.

  18. Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice.

    PubMed

    Neelakantan, Harshini; Tallarida, Ronald J; Reichenbach, Zachary W; Tuma, Ronald F; Ward, Sara J; Walker, Ellen A

    2015-04-01

    Cannabinoid and opioid agonists can display overlapping behavioral effects and the combination of these agonists is known to produce enhanced antinociception in several rodent models of acute and chronic pain. The present study investigated the antinociceptive effects of the nonpsychoactive cannabinoid, cannabidiol (CBD) and the µ-opioid agonist morphine, both alone and in combination, using three behavioral models in mice, to test the hypothesis that combinations of morphine and CBD would produce synergistic effects. The effects of morphine, CBD, and morphine/CBD combinations were assessed in the following assays: (a) acetic acid-stimulated stretching; (b) acetic acid-decreased operant responding for palatable food; and (c) hot plate thermal nociception. Morphine alone produced antinociceptive effects in all three models of acute nociception, whereas CBD alone produced antinociception only in the acetic acid-stimulated stretching assay. The nature of the interactions between morphine and CBD combinations were assessed quantitatively based on the principle of dose equivalence. Combinations of CBD and morphine produced synergistic effects in reversing acetic acid-stimulated stretching behavior, but subadditive effects in the hot plate thermal nociceptive assay and the acetic acid-decreased operant responding for palatable food assay. These results suggest that distinct mechanisms of action underlie the interactions between CBD and morphine in the three different behavioral assays and that the choice of appropriate combination therapies for the treatment of acute pain conditions may depend on the underlying pain type and stimulus modality. PMID:25485642

  19. Superior analgesic effect of H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA), a multifunctional opioid peptide, compared to morphine in a rat model of neuropathic pain.

    PubMed

    Shimoyama, Megumi; Schiller, Peter W; Shimoyama, Naohito; Toyama, Satoshi; Szeto, Hazel H

    2012-11-01

    H-Dmt-D-Arg-Phe-Lys-NH(2) ([Dmt(1)]DALDA) is a synthetic tetrapeptide with extraordinary selectivity for the mu-opioid receptor and is an extremely potent analgesic. [Dmt(1) ]DALDA is unusual in the way that the greater part of its analgesic potency appears to be produced by its actions in the spinal cord. Furthermore, [Dmt(1) ]DALDA inhibits norepinephrine re-uptake and is a mitochondria-targeted antioxidant. Such characteristics may make [Dmt(1)]DALDA particularly effective against neuropathic pain. The present study was designed to compare the effects of [Dmt(1)]DALDA and morphine on thermal hyperalgesia in an experimental neuropathic pain model. Neuropathic pain was induced in rats by surgical ligation of the L5 spinal nerve, and thermal pain thresholds were assessed by latencies of paw withdrawal to radiant heat. The increase in paw withdrawal latency was greater after the administration of [Dmt(1) ]DALDA than that of morphine in neuropathic rats at doses that were equianalgesic in naïve animals. We conclude that [Dmt(1)]DALDA is more effective than morphine against thermal hyperalgesia in this experimental model of neuropathic pain.

  20. 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.

  1. Skin-sparing mastectomy

    PubMed Central

    Rancati, Alberto O.

    2015-01-01

    The surgical treatment of breast cancer has evolved rapidly in recent decades. Conservative treatment was adopted in the late 1970s, with rates above 70%, and this was followed by a period during which the indications for surgical intervention were expanded to those patients at high risk for BRCA1, BRCA2 mutations, and also due to new staging standards and use of nuclear magnetic resonance. This increase in the indications for mastectomy coincided with the availability of immediate breast reconstruction as an oncologically safe and important surgical procedure for prevention of sequelae. Immediate reconstruction was first aimed at correcting the consequences of treatment, and almost immediately, the challenge of the technique became the achievement of a satisfactory breast appearance and shape, as well as normal consistency. The skin-sparing mastectomy (SSM) in conservation first and nipple-areola complex (NAC) later was a result of this shift that occurred from the early 1990s to the present. The objective of this review is to present all these developments specifically in relation to SSM and analyze our personal experience as well as the experience of surgeons worldwide with an emphasis on the fundamental aspects, indications, surgical technique, complications, oncological safety, and cosmetic results of this procedure. PMID:26645008

  2. Morphine Protects Spinal Cord Astrocytes from Glutamate-Induced Apoptosis via Reducing Endoplasmic Reticulum Stress

    PubMed Central

    Zhang, Chao; Wang, Chendan; Ren, Jianbo; Guo, Xiangjie; Yun, Keming

    2016-01-01

    Glutamate is not only a neurotransmitter but also an important neurotoxin in central nervous system (CNS). Chronic elevation of glutamate induces both neuronal and glial cell apoptosis. However, its effect on astrocytes is complex and still remains unclear. In this study, we investigated whether morphine, a common opioid ligand, could affect glutamate-induced apoptosis in astrocytes. Primary cultured astrocytes were incubated with glutamate in the presence/absence of morphine. It was found that morphine could reduce glutamate-induced apoptosis of astrocytes. Furthermore, glutamate activated Ca2+ release, thereby inducing endoplasmic reticulum (ER) stress in astrocytes, while morphine attenuated this deleterious effect. Using siRNA to reduce the expression of κ-opioid receptor, morphine could not effectively inhibit glutamate-stimulated Ca2+ release in astrocytes, the protective effect of morphine on glutamate-injured astrocytes was also suppressed. These results suggested that morphine could protect astrocytes from glutamate-induced apoptosis via reducing Ca2+ overload and ER stress pathways. In conclusion, this study indicated that excitotoxicity participated in the glutamate mediated apoptosis in astrocytes, while morphine attenuated this deleterious effect via regulating Ca2+ release and ER stress. PMID:27783050

  3. Morphine Self-Administration following Spinal Cord Injury

    PubMed Central

    Malik, Jamal S.; Aceves, Miriam; Hook, Michelle A.

    2014-01-01

    Abstract Neuropathic pain develops in up to two-thirds of people following spinal cord injury (SCI). Opioids are among the most effective treatments for this pain and are commonly prescribed. There is concern surrounding the use of these analgesics, however, because use is often associated with the development of addiction. Previous data suggests that this concern may not be relevant in the presence of neuropathic pain. Yet, despite the common prescription of opioids for the treatment of SCI-related pain, there has been only one previous study examining the addictive potential of morphine following spinal injury. To address this, the present study used a self-administration paradigm to examine the addictive potential of morphine in a rodent model of SCI. Animals were placed into self-administration chambers 24 h, 14 d, or 35 d following a moderate spinal contusion injury. They were placed into the chambers for seven 12-hour sessions with access to 1.5 mg morphine/lever depression (up to 30 mg/d). In the acute phase of SCI, contused animals self-administered significantly less morphine than their sham counterparts, as previously shown. However, contused animals showing signs of neuropathic pain did not self-administer less morphine than their sham counterparts when administration began 14 or 35 d after injury. Instead, these animals administered nearly the full amount of morphine available each session. This amount of morphine did not affect recovery of locomotor function but did cause significant weight loss. We suggest caution is warranted when prescribing opioids for the treatment of neuropathic pain resulting from SCI, as the addictive potential is not reduced in this model. PMID:24827476

  4. Harpagophytum procumbens extract potentiates morphine antinociception in neuropathic rats.

    PubMed

    Parenti, Carmela; Aricò, Giuseppina; Pennisi, Marzio; Venditti, Alessandro; Scoto, Giovanna M

    2016-06-01

    The association of opioids and non-steroidal anti-inflammatory drugs, to enhance pain relief and reduce the development of side effects, has been demonstrated. Given many reports concerning the antinociceptive and anti-inflammatory effects of Harpagophytum procumbens extracts, the aim of our study was to investigate the advantage of a co-administration of a subanalgesic dose of morphine preceded by a low dose of H. procumbens to verify this therapeutically useful association in a neuropathic pain model. Time course, registered with the association of the natural extract, at a dose that does not induce an antinociceptive effect, followed by a subanalgesic dose of morphine showed a well-defined antiallodynic and antihyperalgesic effect, suggesting a synergism as a result of the two-drug association. H. procumbens cooperates synergistically with morphine in resolving hyperalgesia and allodynia, two typical symptoms of neuropathic pain. The results support the strategy of using an adjuvant drug to improve opioid analgesic efficacy. PMID:26189616

  5. Intrathecal rapamycin attenuates morphine-induced analgesic tolerance and hyperalgesia in rats with neuropathic pain

    PubMed Central

    Xu, Ji-Tian; Sun, Linlin; Lutz, Brianna Marie; Bekker, Alex; Tao, Yuan-Xiang

    2015-01-01

    Repeated and long-term administration of opioids is often accompanied by the initiation of opioid-induced analgesic tolerance and hyperalgesia in chronic pain patients. Our previous studies showed that repeated intrathecal morphine injection activated the mammalian target of rapamycin complex 1 (mTORC1) in spinal dorsal horn neurons and that blocking this activation prevented the initiation of morphine-induced tolerance and hyperalgesia in healthy rats. However, whether spinal mTORC1 is required for morphine-induced tolerance and hyperalgesia under neuropathic pain conditions remains elusive. We here observed the effect of intrathecal infusion of rapamycin, a specific mTORC1 inhibitor, on morphine-induced tolerance and hyperalgesia in a neuropathic pain model in rats induced by the fifth lumbar spinal nerve ligation (SNL). Continuous intrathecal infusion of morphine for one week starting on day 8 post-SNL led to morphine tolerance demonstrated by morphine-induced reduction in maximal possible analgesic effect (MPAE) to tail heat stimuli and ipsilateral paw withdrawal threshold (PWT) to mechanical stimuli in SNL rats. Such reduction was attenuated by co-infusion of rapamycin. Co-infusion of rapamycin also blocked morphine tolerance demonstrated by attenuation of morphine-induced reduction in MPAE in sham rats and morphine-induced hyperalgesia demonstrated by the reverse of morphine-induced reduction in PWT on both sides of sham rats and on the contralateral side of SNL rats. The results suggest that mTORC1 inhibitors could serve as promising medications for use as adjuvants with opioids in clinical neuropathic pain management. PMID:26339682

  6. Proteome Analysis of Rat Hippocampus Following Morphine-induced Amnesia and State-dependent Learning

    PubMed Central

    Jafarinejad-Farsangi, Saeideh; Farazmand, Ali; Rezayof, Ameneh; Darbandi, Niloufar

    2015-01-01

    Morphine’s effects on learning and memory processes are well known to depend on synaptic plasticity in the hippocampus. Whereas the role of the hippocampus in morphine-induced amnesia and state-dependent learning is established, the biochemical and molecular mechanisms underlying these processes are poorly understood. The present study intended to investigate whether administration of morphine can change the expression level of rat hippocampal proteins during learning of a passive avoidance task. A step-through type passive avoidance task was used for the assessment of memory retention. To identify the complex pattern of protein expression induced by morphine, we compared rat hippocampal proteome either in morphine-induced amnesia or in state-dependent learning by two-dimensional gel electerophoresis and combined mass spectrometry (MS and MS/MS). Post-training administration of morphine decreased step-through latency. Pre-test administration of morphine induced state-dependent retrieval of the memory acquired under post-training morphine influence. In the hippocampus, a total of 18 proteins were identified whose MASCOT (Modular Approach to Software Construction Operation and Test) scores were inside 95% confidence level. Of these, five hippocampal proteins altered in morphine-induced amnesia and ten proteins were found to change in the hippocampus of animals that had received post-training and pre-test morphine. These proteins show known functions in cytoskeletal architecture, cell metabolism, neurotransmitter secretion and neuroprotection. The findings indicate that the effect of morphine on memory formation in passive avoidance learning has a morphological correlate on the hippocampal proteome level. In addition, our proteomicscreensuggests that morphine induces memory impairment and state-dependent learning through modulating neuronal plasticity. PMID:25901168

  7. Effects of Morphine on Temporal Discrimination and Color Matching: General Disruption of Stimulus Control or Selective Effects on Timing?

    ERIC Educational Resources Information Center

    Ward, Ryan D.; Odum, Amy L.

    2005-01-01

    Discrepant effects of drugs on behavior maintained by temporal-discrimination procedures make conclusive statements about the neuropharmacological bases of timing difficult. The current experiment examined the possible contribution of a general, drug-induced disruption of stimulus control. Four pigeons responded on a three-component multiple…

  8. Postoperative urinary retention in a dog following morphine with bupivacaine epidural analgesia.

    PubMed Central

    Herperger, L J

    1998-01-01

    Urinary retention, overflow incontinence, and subsequent detrusor atony were observed following surgery in which a morphine with bupivacaine epidural injection was used for perioperative analgesia. The premise that the urinary retention may have been due to the effects of the morphine component of the epidural is discussed, along with other possible causes. PMID:9789679

  9. Tolerance to intrathecal oxymetazoline-induced analgesia, with paradigm-dependent cross-tolerance to intrathecal morphine.

    PubMed

    Sherman, S E; Loomis, C W; Milne, B; Cervenko, F W

    1988-04-01

    Male, Sprague-Dawley rats, implanted with intrathecal (i.t.) catheters, were given repeated i.t. injections of morphine (40 nmol), oxymetazoline (100 nmol) or saline (10 microliter) at 12-h intervals for 3 days. Antinociception was determined 1 or 1.5 hr after each injection using the tail-flick and paw-pressure tests. Complete tolerance to i.t. morphine and oxymetazoline developed within 72 and 24 hr, respectively. Antinociception after i.t. oxymetazoline (100 nmol) in morphine-tolerant rats, and after i.t. morphine (20 nmol) in oxymetazoline-tolerant rats, was not significantly different from their respective effects in saline-pretreated rats. These data suggest an absence of cross-tolerance between morphine and oxymetazoline in the rat spinal cord. In a separate group of rats, the continuous i.t. infusion of morphine (26 nmol/hr) produced significant antinociception; tolerance to morphine developed within 36 hr. The antinociceptive effect of i.t. oxymetazoline (100 nmol) was significantly attenuated in rats pretreated with continuous i.t. morphine as compared to saline-pretreated rats. In rats pretreated with continuous i.t. oxymetazoline, cross-tolerance to morphine could not be determined due to severe adverse effects during oxymetazoline infusion. The results of this study suggest that functional cross-tolerance between morphine and alpha adrenoceptor agonists in the spinal cord cannot be excluded on the basis of repeated i.t. injection experiments alone.

  10. Morphine suppression of ethanol withdrawal in mice.

    PubMed

    Blum, K; Wallace, J E; Schwerter, H A; Eubanks, J D

    1976-01-15

    The acute administration of morphine, alcohol or dopamine results in a pronounced suppression of the convulsions produced by alcohol in mice. The suppressive action of morphine on alcohol withdrawal in the mouse apparently is not a product of morphine intoxication, but rather to some other specific interaction between alcohol and morphine in the central nervous system. The conclusion suggest that dopamine may play a significant role as a modulator in convulsions produced during alcohol withdrawal.

  11. 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.

  12. Morphine protects SH-SY5Y human neuroblastoma cells against Dickkopf1-induced apoptosis.

    PubMed

    Wang, Kun-Peng; Bai, Yu; Wang, Jian; Zhang, Jin-Zhen

    2015-02-01

    Morphine is used to relieve pain in patients with cancer in terminal phases. Dickkopf‑1 (DKK1), a secreted protein, is a negative regulator of the Wnt/β‑catenin signaling pathway. Morphine and DKK1 are associated with tumorigenesis. However, to the best of our knowledge, there is no study evaluating the effects of these two factors simultaneously. In the present study, the effects of morphine and DKK1 on neuroblastoma cells in vivo and in vitro were evaluated. To establish the in vitro effects of DKK1 and morphine, human neuroblastoma SH‑SY5Y cells were transfected with a DKK1‑expressing plasmid and cell migration, apoptosis, migration and invasion were evaluated prior to and following morphine treatment. The results indicated that DKK1 induced apoptosis and inhibited the mobility of neuroblastoma cells and that morphine attenuated these DKK1‑induced effects. To evaluate the effects of DKK1 and morphine in vivo, a mouse model of neuroblastoma was established, where mice bearing tumors of native SH-SY5Y cells were injected with DKK1. Tumor size, spatial memory and survival rate were investigated in untreated, DKK1‑treated and DKK1+morphine‑treated mice. Water maze and T‑maze tests were performed, which revealed that DKK1‑treated mice exhibited a better memory than DKK1 + morphine‑treated mice. The expression of DKK1 in established xenografted tumors was associated with decreased tumor size and an increased survival rate, whereas morphine reversed these effects. Furthermore, it was confirmed that morphine and DKK1 take effect, at least in part, via the Wnt/β‑catenin signaling pathway. The results of the present study indicate that morphine may protect neuroblastoma cells and thus, it may be used in neuroblastoma patients.

  13. Pseudomonas aeruginosa virulence expression is directly activated by morphine and is capable of causing lethal gut derived sepsis in mice during chronic morphine administration

    PubMed Central

    Babrowski, Trissa; Holbrook, Christopher; Moss, Jonathan; Gottlieb, Lawrence; Valuckaite, Vesta; Zaborin, Alexander; Poroyko, Valeriy; Liu, Donald C.; Zaborina, Olga; Alverdy, John C.

    2011-01-01

    OBJECTIVE This study was designed to examine the effect of morphine administration on the intestinal mucus barrier and determine its direct effect on the virulence and lethality of Pseudomonas aeruginosa, one of the most frequent pathogens to colonize the gut of critically ill patients. SUMMARY BACKGROUND DATA Surgical injury is associated with significant exposure of host tissues to morphine from both endogenous release as well as its use as a potent analgesic agent. Morphine use in surgical patients exposed to extreme physiologic stress is well established to result in increased infection risk. Although morphine is a known immunosuppressant, whether it directly induces virulence expression and lethality in microbes that colonize the human gut remains unknown. METHODS Mice were implanted with a slow release morphine or placebo pellet with and without intestinal inoculation of P. aeruginosa created by direct cecal injection. Mucus production and epithelial integrity was assessed in cecal tissue via Alcian Blue staining and histological analysis. In vivo and in vitro P. aeruginosa virulence expression was examined using reporter strains tagged to the epithelial barrier disrupting protein PA-I lectin. P. aeruginosa chemotaxis toward morphine was also assayed in vitro. Finally the direct effect of morphine to induce PA-I lectin expression was determined in the absence and presence of methylnaltrexone, a mu opioid receptor antagonist. RESULTS Mice intestinally inoculated with P. aeruginosa and implanted with a morphine pellet demonstrated significant suppression of intestinal mucus, disrupted intestinal epithelium and enhanced mortality whereas exposure of mice to either systemic morphine or intestinal P. aeruginosa alone enhanced intestinal mucus without mortality suggesting a shift in P. aeruginosa during morphine exposure to a mucus suppressing, barrier disrupting, and lethal phenotype. Direct exposure of P. aeruginosa to morphine in vitro confirmed that morphine

  14. Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence.

    PubMed

    Kim, Joseph A; Bartlett, Selena; He, Li; Nielsen, Carsten K; Chang, Amy M; Kharazia, Viktor; Waldhoer, Maria; Ou, Chrissi J; Taylor, Stacy; Ferwerda, Madeline; Cado, Dragana; Whistler, Jennifer L

    2008-01-22

    Opioid drugs, such as morphine, are among the most effective analgesics available. However, their utility for the treatment of chronic pain is limited by side effects including tolerance and dependence. Morphine acts primarily through the mu-opioid receptor (MOP-R) , which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro, and in vivo. Receptor endocytosis serves at least two important functions in signal transduction. First, desensitization and endocytosis act as an "off" switch by uncoupling receptors from G protein. Second, endocytosis functions as an "on" switch, resensitizing receptors by recycling them to the plasma membrane. Thus, both the off and on function of the MOP-R are altered in response to morphine compared to endogenous ligands. To examine whether the low degree of endocytosis induced by morphine contributes to tolerance and dependence, we generated a knockin mouse that expresses a mutant MOP-R that undergoes morphine-induced endocytosis. Morphine remains an excellent antinociceptive agent in these mice. Importantly, these mice display substantially reduced antinociceptive tolerance and physical dependence. These data suggest that opioid drugs with a pharmacological profile similar to morphine but the ability to promote endocytosis could provide analgesia while having a reduced liability for promoting tolerance and dependence.

  15. Intrathecal morphine attenuates recovery of function after a spinal cord injury.

    PubMed

    Hook, Michelle A; Moreno, Georgina; Woller, Sarah; Puga, Denise; Hoy, Kevin; Balden, Robyn; Grau, James W

    2009-05-01

    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 microg) of intrathecal morphine 24 h after a moderate contusion injury. The 90-microg 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 microg 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

  16. Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery.

    PubMed

    Elkomy, Mohammed H; Drover, David R; Glotzbach, Kristi L; Galinkin, Jeffery L; Frymoyer, Adam; Su, Felice; Hammer, Gregory B

    2016-01-01

    The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3 days to 6 years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15 mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6 h after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6 months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites.

  17. Potentiation of morphine analgesia by subanesthetic doses of pentobarbital.

    PubMed

    Pontani, R B; Vadlamani, N L; Misra, A L

    1985-03-01

    Pentobarbital pretreatment reportedly either inhibits, enhances or has no effect on morphine analgesia. The effect of subanesthetic doses of sodium pentobarbital (8-12 mg kg-1, SC) delivered via a delivery system on analgesia of morphine (5 mg kg-1, SC or 1 mg kg-1, IV) acutely administered 45 min after the sodium pentobarbital pellet implantation was assessed using the warm water (55 degrees C)-induced tail-withdrawal reflex in male Wistar rats. Significant potentiation of morphine analgesia was observed in sodium pentobarbital as compared to the placebo-pelleted animals. Pharmacokinetic or dispositional factors were not involved in this potentiation, which was possibly due to the activation of the descending inhibitory control pathways of nociceptive spinal tail-withdrawal reflex by a combined interaction of two drugs at spinal and supraspinal sites of action, that mediate opiate antinociception. PMID:3991755

  18. Serum IL-10 involved in morphine tolerance development during adjuvant-induced arthritis.

    PubMed

    Zaringhalam, Jalal; Hormozi, Asef; Tekieh, Elaheh; Razavi, Jafar; Khanmohammad, Ramin; Golabi, Sahar

    2014-06-01

    Opioid receptors play an important role in modulation of hyperalgesia in inflamed tissues, but chronic morphine application induces such side effects as tolerance. There is near communications between cytokines and mu opioid receptor expression. This study was aimed to assess the role of serum IL-10 in morphine tolerance development during adjuvant-induced arthritis. Adjuvant arthritis (AA) was induced on day 0 by single injection of Complete Freund's Adjuvant (CFA) into the rats' hindpaw. Hyperalgesia, edema, and spinal mu opioid receptor (mOR) variations were assessed on 0, 7, 14, and 21 days of the study. For assessment of the morphine tolerance development, morphine effective dose (4 mg/kg) was administered from the 14th day after CFA injection and continued until the morphine post-dose paw withdrawal latency (PWL); it did not significantly differ from the baseline. For assessment of the effects of IL-10 on tolerance induction, a neutralizing dose (ND50) of anti-IL-10 was administered daily during different stages of the study. AA induction in the right hindpaw of rats resulted in unilateral inflammation and hyperalgesia within 21 days of the study. Anti-IL-10 antibody administration in the AA rats induced marked elevation of hyperalgesia compared to the AA control group. Our data also indicated that morphine effective anti-hyperalgesic dose significantly decreased in the AA rats compared to the control group, which this symptom was aligned with spinal mu opioid receptor (mOR) expression increase during AA. Moreover, there was a significant difference in morphine tolerance induction between the AA and control rats, and our results also demonstrated that IL-10 played an important role in tolerance-induction process. It can be concluded that morphine tolerance slowly progressed when administered morphine effective dose was reduced during AA chronic inflammation. On the other hand, it seems that increased level of serum IL-10 may affect morphine tolerance

  19. 47 CFR 80.866 - Spare antenna.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Spare antenna. 80.866 Section 80.866... Spare antenna. A spare transmitting antenna completely assembled for immediate erection must be provided. If the installed transmitting antenna is suspended between supports, this spare antenna must be...

  20. 47 CFR 80.866 - Spare antenna.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Spare antenna. 80.866 Section 80.866... Spare antenna. A spare transmitting antenna completely assembled for immediate erection must be provided. If the installed transmitting antenna is suspended between supports, this spare antenna must be...

  1. 47 CFR 80.866 - Spare antenna.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Spare antenna. 80.866 Section 80.866... Spare antenna. A spare transmitting antenna completely assembled for immediate erection must be provided. If the installed transmitting antenna is suspended between supports, this spare antenna must be...

  2. 47 CFR 80.866 - Spare antenna.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Spare antenna. 80.866 Section 80.866... Spare antenna. A spare transmitting antenna completely assembled for immediate erection must be provided. If the installed transmitting antenna is suspended between supports, this spare antenna must be...

  3. 47 CFR 80.866 - Spare antenna.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Spare antenna. 80.866 Section 80.866... Spare antenna. A spare transmitting antenna completely assembled for immediate erection must be provided. If the installed transmitting antenna is suspended between supports, this spare antenna must be...

  4. The analgesic and toxic effects of nornicotine enantiomers alone and in interaction with morphine in rodent models of acute and persistent pain

    PubMed Central

    Holtman, Joseph R.; Crooks, Peter A.; Johnson-Hardy, Jaime K.; Wala, Elzbieta P.

    2009-01-01

    Neuronal nicotinic acetylcholinic receptors (nAChR) are promising targets for the development of novel analgesics. Nicotine and other nAChR-agonists produce profound analgesia in rodent models of acute and persistent pain. However, significant side-effects are of concern. Nornicotine (N-desmethyl-nicotine) appears to activate different nAChR subtypes, has a better pharmacokinetic profile, and produces less toxicity than nicotine. Little is known about its analgesic properties. In the present study, the S(−)- and R(+)- enantiomers of nornicotine were characterized with regard to analgesia and side-effects profile. Efficacy was demonstrated in rat models of pain where central sensitization is involved: i.e. the chronic constriction nerve injury model of peripheral neuropathy and the formalin model of tonic inflammatory pain. The desirable (analgesic) properties resided predominantly in the S(−)- rather than the R(+)- enantiomer. In contrast, undesirable effects (motor in-coordination, reduced locomotor activity, ataxia) were more pronounced with the R(+)- enantiomer. This is an interesting finding, which may suggest separation of toxicity from analgesia by utilization of S(−)-enantiomer of nornicotine. Maximum analgesic effectiveness without significant side-effects was achieved when S(−)-nornicotine (sub-analgesic dose) was combined with a low-dose of the μ-opioid, morphine. These preclinical data suggest that S(−)-nornicotine may be of value, either alone or in combination with an opioid, for treatment of a broad-spectrum of pain (i.e. nociceptive, neuropathic, mixed pain). PMID:19800911

  5. 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.

  6. Reinforcer interactions under concurrent schedules of food, water, and intravenous morphine.

    PubMed

    Dworkin, S I; Guerin, G F; Goeders, N E; Cherek, D R; Lane, J D; Smith, J E

    1984-01-01

    Responding by six rats was maintained under a concurrent chained fixed-ratio 1, fixed-ratio 9 schedule (conc chain FR1 FR9 ) of food, water, and morphine presentations. The subjects had continuous access to the schedule contingencies on a reversed 12-h light-dark cycle. Local rates and temporal patterns were very similar for responding maintained by the three reinforcers with food and water intake occurring predominantly during the dark cycle, while morphine infusions were evenly distributed. Food and water extinction (24-h duration) decreased the number of ratios completed on both the food and water levers. Moreover, food extinction resulted in a large increase in I.V. morphine self-administration. Morphine extinction increased responding on the morphine lever while almost eliminating responding on the water lever. Changes in the dose of morphine (2.5-40 mg/kg/injection) did not significantly affect food and water intake, but were inversely related to responding on the morphine lever. Saline substitutions resulted in effects similar to those observed during morphine extinction. The schedule used in this study provides a method for examining the specificity of a number of pharmacological and neurochemical manipulations.

  7. Study on the interaction of morphine chloride with deoxyribonucleic acid by fluorescence method

    NASA Astrophysics Data System (ADS)

    Li, J. F.; Dong, C.

    2009-01-01

    The mode and mechanism of the interaction of morphine chloride, an important alkaloid compound to calf thymus deoxyribonucleic acid (ct DNA) was investigated from absorption and fluorescence titration techniques. Hypochromic effect was founded in the absorption spectra of morphine when concentration of DNA increased. The decreased fluorescence study revealed non-cooperative binding of the morphine to DNA with an affinity of 3.94 × 10 3 M -1, and the stoichiometry of binding was characterized to be about one morphine molecule per nucleotide. Stern-Volmer plots at different temperatures proved that the quenching mechanism was static. Ferrocyanide quenching study showed that the magnitude of KSV of the bound morphine was lower than that of the free one. In addition, it was found that ionic strength could affect the binding of morphine and DNA. Fluorescence polarization and denatured DNA studies also applied strong evidences that morphine molecule was partially intercalated between every alternate base pairs of ct DNA. As observed from above experiments, intercalation was well supported as the binding mode of morphine and ct DNA.

  8. 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.

  9. Morphine Analgesia Modification in Normotensive and Hypertensive Female Rats after Repeated Fluoxetine Administration.

    PubMed

    Kosiorek-Witek, Anna; Makulska-Nowak, Helena Elżbieta

    2016-01-01

    The purpose of this investigation was to determine through the use of fluoxetine the effect of administering a serotonin reuptake inhibitor over several days on the antinociceptive action of μ-morphine type opioid receptor agonist. Investigations were performed on rats of both sexes, both the WKY normotensive strains as well as on the SHR genetically conditioned hypertensive strains. Results showed that the efficacy of morphine analgesia is higher in the SHR strain compared to normotensive rats (WKY). Surprisingly, repeated administration of fluoxetine reduced morphine analgesia, with the weakening of opioid antinociceptive action comparable to the duration of serotonin reuptake inhibitor administration. It was also concluded that the antinociceptive action of morphine in female rats and the alteration of its efficacy as a result of fluoxetine premedication for several days depend on oestrus cycle phase. The highest sensitivity of female rats to morphine was reported in the dioestrus and oestrus phases; much lower values were reported for the metoestrus phase.

  10. 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.

  11. BK channels in microglia are required for morphine-induced hyperalgesia

    PubMed Central

    Hayashi, Yoshinori; Morinaga, Saori; Zhang, Jing; Satoh, Yasushi; Meredith, Andrea L.; Nakata, Takahiro; Wu, Zhou; Kohsaka, Shinichi; Inoue, Kazuhide; Nakanishi, Hiroshi

    2016-01-01

    Although morphine is a gold standard medication, long-term opioid use is associated with serious side effects, such as morphine-induced hyperalgesia (MIH) and anti-nociceptive tolerance. Microglia-to-neuron signalling is critically involved in pain hypersensitivity. However, molecules that control microglial cellular state under chronic morphine treatment remain unknown. Here we show that the microglia-specific subtype of Ca2+-activated K+ (BK) channel is responsible for generation of MIH and anti-nociceptive tolerance. We find that, after chronic morphine administration, an increase in arachidonic acid levels through the μ-opioid receptors leads to the sole activation of microglial BK channels in the spinal cord. Silencing BK channel auxiliary β3 subunit significantly attenuates the generation of MIH and anti-nociceptive tolerance, and increases neurotransmission after chronic morphine administration. Therefore, microglia-specific BK channels contribute to the generation of MIH and anti-nociceptive tolerance. PMID:27241733

  12. BK channels in microglia are required for morphine-induced hyperalgesia.

    PubMed

    Hayashi, Yoshinori; Morinaga, Saori; Zhang, Jing; Satoh, Yasushi; Meredith, Andrea L; Nakata, Takahiro; Wu, Zhou; Kohsaka, Shinichi; Inoue, Kazuhide; Nakanishi, Hiroshi

    2016-05-31

    Although morphine is a gold standard medication, long-term opioid use is associated with serious side effects, such as morphine-induced hyperalgesia (MIH) and anti-nociceptive tolerance. Microglia-to-neuron signalling is critically involved in pain hypersensitivity. However, molecules that control microglial cellular state under chronic morphine treatment remain unknown. Here we show that the microglia-specific subtype of Ca(2+)-activated K(+) (BK) channel is responsible for generation of MIH and anti-nociceptive tolerance. We find that, after chronic morphine administration, an increase in arachidonic acid levels through the μ-opioid receptors leads to the sole activation of microglial BK channels in the spinal cord. Silencing BK channel auxiliary β3 subunit significantly attenuates the generation of MIH and anti-nociceptive tolerance, and increases neurotransmission after chronic morphine administration. Therefore, microglia-specific BK channels contribute to the generation of MIH and anti-nociceptive tolerance.

  13. Combination of morphine with nortriptyline for neuropathic pain.

    PubMed

    Gilron, Ian; Tu, Dongsheng; Holden, Ronald R; Jackson, Alan C; DuMerton-Shore, Deborah

    2015-08-01

    First-line neuropathic pain drugs, including tricyclic antidepressants, are not always effective, and opioids have been recommended as second line. This trial evaluates a nortriptyline-morphine combination, compared with each monotherapy. In this randomized, double-blind crossover trial, patients with neuropathic pain were enrolled at 1 site between January 25, 2010, and May 22, 2014, and randomized in a 1:1:1 ratio using a balanced Latin square design to receive oral nortriptyline, morphine, and their combination. During each of three 6-week periods, doses were titrated toward maximal tolerated dose (MTD). The primary outcome was average daily pain at MTD, and secondary outcomes included other pain, mood and quality of life measures, and adverse effects. Sixty-two patients were screened, 52 enrolled, and 39 completed at least 2 treatment periods. Average daily pain (0-10) at baseline was 5.3 and at MTD was 2.6 for combination vs 3.1 for nortriptyline (P = 0.046) and 3.4 for morphine (P = 0.002). Brief Pain Inventory scores for average and present pain were also significantly lower for combination vs each monotherapy. Combination treatment resulted in moderate-severe constipation in 43% vs 46% with morphine (P = 0.82) and 5% with nortriptyline (P < 0.0001). Combination treatment resulted in moderate-severe dry mouth in 58% vs 49% with nortriptyline (P = 0.84) and 13% with morphine (P < 0.0001). This trial suggests superior efficacy of a nortriptyline-morphine combination over either monotherapy with constipation, dry mouth, and somnolence as the most frequent adverse effects.

  14. EMA- EISENBERGER-MAIOCCO ALGORITHM FOR SPARES PROVISIONING

    NASA Technical Reports Server (NTRS)

    Eisenberger, I.

    1994-01-01

    The Eisenberger-Maiocco algorithm (EMA) is an efficient Markov sparing algorithm to aid in the provisioning of spare parts. There are two calculations performed by EMA: 1) forecasting the availability of a system with a given spare parts pool, and 2) determining the most cost effective spares package. EMA was used in NASA's Deep Space Network project to calculate the probability that a system would be up and operational with the spares available at each location. The system to be analyzed is defined in terms of modules, which are any pieces of equipment which may fail, be repaired, or be replaced. A module can be in one of three states: working, spare, or failed and waiting for repair. For each module type in the system configuration, there is an actual number in use by the system, and a minimum number for the system to be operational. A module type is considered 'down' when there are fewer than the required minimum number working, and there are no spares in the stockpile. Input to EMA includes module data such as mean time between failure, mean time to repair, number of spares, and cost of the item. EMA determines the overall system availability, or uptime ratio, as the probability the system will be operational during a given time. EMA can also calculate the most cost effective spares package for a given range of uptime ratios. EMA is written in interpreter PC-BASIC and is for interactive execution. It has been implemented on an IBM PC series computer operating under DOS 2.0 with a central memory requirement of approximately 64K of 8 bit bytes. This program was developed in 1978.

  15. Potentiation of morphine analgesia by caffeine.

    PubMed Central

    Misra, A. L.; Pontani, R. B.; Vadlamani, N. L.

    1985-01-01

    Significant potentiation of morphine (5 mg kg-1 s.c. or 1 mg kg-1 i.v.) analgesia (tail-withdrawal reflex at 55 degrees C) was observed in caffeine-treated (100 mg kg-1 i.p.) rats as compared to the control group and lower doses of caffeine (2mg kg-1 i.p.) did not show this effect. Potentiated analgesia was reversed by naloxone. Pharmacokinetic or dispositional factors appear to be involved in part in this potentiation. PMID:4005485

  16. Potentiation of morphine analgesia by caffeine.

    PubMed

    Misra, A L; Pontani, R B; Vadlamani, N L

    1985-04-01

    Significant potentiation of morphine (5 mg kg-1 s.c. or 1 mg kg-1 i.v.) analgesia (tail-withdrawal reflex at 55 degrees C) was observed in caffeine-treated (100 mg kg-1 i.p.) rats as compared to the control group and lower doses of caffeine (2mg kg-1 i.p.) did not show this effect. Potentiated analgesia was reversed by naloxone. Pharmacokinetic or dispositional factors appear to be involved in part in this potentiation. PMID:4005485

  17. 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.

  18. Photoaffinity labeling of rat liver microsomal morphine UDP-glucuronosyltransferase by ( sup 3 H)flunitrazepam

    SciTech Connect

    Thomassin, J.; Tephly, T.R. )

    1990-09-01

    Benzodiazepines have been shown to competitively inhibit morphine glucuronidation in rat and human hepatic microsomes. Flunitrazepam exerted a potent competitive inhibition of rat hepatic morphine UDP-glucuronosyltransferase (UDPGT) activity (Ki = 130 microM). It has no effect on the activity of p-nitrophenol, 17 beta-hydroxysteroid, 3 alpha-hydroxysteroid, or 4-hydroxybiphenyl UDPGTs. Because flunitrazepam is an effective photoaffinity label for benzodiazepine receptors, studied were performed in solubilized rat hepatic microsomes and with partially purified preparations of morphine UDPGT to determine the enhancement of flunitrazepam inhibition and binding to morphine UDPGT promoted by exposure to UV light. Under UV light, flunitrazepam inhibition was markedly enhanced. UV light exposure also led to a marked increase in binding of (3H)flunitrazepam to microsomal protein, which was protected substantially by preincubation with morphine. Testosterone, androsterone, and UDP-glucuronic acid did not protect against UV-enhanced flunitrazepam binding, and morphine did not reverse flunitrazepam binding once binding had occurred. As morphine UDPGT was purified, a good correlation was found between the increases in specific activity of morphine UDPGT and flunitrazepam binding to protein. Chromatofocusing chromatography showed that flunitrazepam bound only to fractions containing active morphine UDPGT, and no binding to 4-hydroxybiphenyl UDPGT was observed. Fluorography of a sodium dodecyl sulfate-polyacrylamide electrophoresis gel of solubilized hepatic microsomes that had been treated with (3H) flunitrazepam under UV light revealed a band with a monomeric molecular weight between 54,000 and 58,000. This monomeric molecular weight compares favorably with the reported monomeric molecular weight of homogeneous morphine UDPGT (56,000).

  19. Regional dependence of morphine-induced mu-opiate receptor down-regulation in perinatal rat brain.

    PubMed

    Hammer, R P; Seatriz, J V; Ricalde, A R

    1991-12-17

    The effect of perinatal morphine administration was examined in various brain regions using in vitro receptor autoradiography. Morphine was administered by continuous s.c. infusion of 10 mg/kg per day; brains of offspring were examined at five days of age. Morphine exposure reduced mu-receptor binding density in the preoptic area of hypothalamus, but not in the primary somatosensory cortex. mu-Receptor density was greater in the medial preoptic area of females than males, and in superficial layers of cortex in males than females. The results suggest that morphine has selective regional effects on mu-receptor ontogeny in rat brain. PMID:1665797

  20. Morphine Inhibits Sleep-Promoting Neurons in the Ventrolateral Preoptic Area Via Mu Receptors and Induces Wakefulness in Rats

    PubMed Central

    Wang, Qin; Yue, Xiao-Fang; Qu, Wei-Min; Tan, Rong; Zheng, Ping; Urade, Yoshihiro; Huang, Zhi-Li

    2013-01-01

    Morphine is the most efficacious and widely prescribed treatment for pain. However, it decreases the total amount of deep sleep and rapid eye movement sleep in humans. Acute morphine administration at low doses causes wakefulness in animal models. To clarify the mechanism by which morphine affects sleep–wake behavior, we investigated the effects of morphine on the sleep-promoting neurons of the ventrolateral preoptic area (VLPO), a putative sleep-active nucleus, using in vitro brain slices by the patch-clamp technique. We also examined the effects of morphine on sleep–wake profiles after administration of opioid receptor antagonist to the VLPO using EEG and electromyogram recordings in freely moving rats. The results showed that morphine inhibited the firing rate of sleep-promoting neurons and hyperpolarized their membrane potentials without affecting interneurons in the VLPO. Morphine-induced hyperpolarization of membrane potentials could be reversed by, D-Phe-Cys-Thr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), a mu receptor antagonist, in the presence of tetrodotoxin. However, after the mu receptors were blocked by CTOP, morphine still suppressed the firing of the sleep-promoting neurons. This effect was antagonized by nor-BIN, a kappa receptor antagonist. Activation of kappa receptor by U50488H inhibited the firing of the sleep-promoting neurons. These results indicate that morphine could inhibit the activity of sleep-promoting neurons in the VLPO through mu and kappa receptors. EEG recordings revealed that morphine injected subcutaneously induced arousal in a dose-dependent manner. CTOP microinjected into VLPO antagonized the arousal effects of morphine, but nor-BIN did not. However, CTOP alone was not associated with any changes in the physiological sleep–wake cycle. Taken together, these findings clearly indicate that morphine inhibits sleep-promoting neurons in the VLPO by affecting mu receptors and so induces wakefulness in rats. PMID:23303062

  1. Morphine with adjuvant ketamine versus higher dose of morphine alone for acute pain: a meta-analysis

    PubMed Central

    Ding, Xibing; Jin, Shuqing; Niu, Xiaoyin; Wang, Tingting; Zhao, Xiang; Ren, Hao; Tong, Yao; Li, Quan

    2014-01-01

    Purpose: Ketamine is currently the N-methyl-D-aspartate receptor channel blocker in clinical use. Morphine in pain management is usually limited by adverse effect such as nausea and vomiting. Adjuvant treatment with ketamine may be value in giving better analgesia with fewer adverse effects. The purpose of this meta-analysis was to evaluate the differences when patients received morphine with adjuvant ketamine (MK) compared with higher dose of morphine (MO) for acute pain. Methods: The PubMed, EMBASE and the Cochrane Library databases were searched (Last search performed on July 1, 2014) by two reviewers independently. Data were extracted independently by the same two individuals who searched the studies. Results: A total of 7 trials involving 492 patients were included in the current analysis. We found pain scores were lower in the MK group compared to the MO group [MD 2.19, 95% CI (1.24, 3.13) P<0.00001]. And more patients in the MO required diclofenac [OR 1.97, 95% CI (1.06, 3.67) P=0.03]. Furthermore, morphine plus ketamine can reduced post-operative nausea and vomiting (PONV) [OR 3.71, 95% CI (2.37, 5.80) P<0.00001]. Importantly, the wakefulness scores for the MK group were consistently and significantly better than those for the MO group [MD -1.53, 95% CI (-2.67, -0.40) P=0.008]. Conclusion: The use of ketamine plus 1/4~2/3 the dose of morphine is better than higher dose of morphine alone in reducing pain scores, and rescuing analgesic requirement. It also improved PONV and wakefulness. PMID:25356103

  2. Morphine Increases Acetylcholine Release in the Trigeminal Nuclear Complex

    PubMed Central

    Zhu, Zhenghong; Bowman, Heather R.; Baghdoyan, Helen A.; Lydic, Ralph

    2008-01-01

    Study Objectives: The trigeminal nuclear complex (V) contains cholinergic neurons and includes the principal sensory trigeminal nucleus (PSTN) which receives sensory input from the face and jaw, and the trigeminal motor nucleus (MoV) which innervates the muscles of mastication. Pain associated with pathologies of V is often managed with opioids but no studies have characterized the effect of opioids on acetylcholine (ACh) release in PSTN and MoV. Opioids can increase or decrease ACh release in brainstem nuclei. Therefore, the present experiments tested the 2-tailed hypothesis that microdialysis delivery of opioids to the PSTN and MoV significantly alters ACh release. Design: Using a within-subjects design and isoflurane-anesthetized Wistar rats (n = 53), ACh release in PSTN during microdialysis with Ringer's solution (control) was compared to ACh release during dialysis delivery of the sodium channel blocker tetrodotoxin, muscarinic agonist bethanechol, opioid agonist morphine, mu opioid agonist DAMGO, antagonists for mu (naloxone) and kappa (nor-binaltorphimine; nor-BNI) opioid receptors, and GABAA antagonist bicuculline. Measurements and Results: Tetrodotoxin decreased ACh, confirming action potential-dependent ACh release. Bethanechol and morphine caused a concentration-dependent increase in PSTN ACh release. The morphine-induced increase in ACh release was blocked by nor-BNI but not by naloxone. Bicuculline delivered to the PSTN also increased ACh release. ACh release in the MoV was increased by morphine, and this increase was not blocked by naloxone or nor-BNI. Conclusions: These data comprise the first direct measures of ACh release in PSTN and MoV and suggest synaptic disinhibition as one possible mechanism by which morphine increases ACh release in the trigeminal nuclei. Citation: Zhu Z; Bowman HR; Baghdoyan HA; Lydic R. Morphine increases acetylcholine release in the trigeminal nuclear complex. SLEEP 2008;31(12):1629–1637. PMID:19090318

  3. The offset of morphine tolerance in rats and mice.

    PubMed

    Cox, B M; Ginsburg, M; Willis, J

    1975-03-01

    1. In rats and mice made tolerant to morphine by pretreatment with the drug, the shift to the right of the log dose/analgesic response line for in naive animals occurs without significant change in slope provided that sufficient time is allowed for elimination of pretreatment drug. 2. Responsiveness to the analgesic effects of morphine, given together with cycloheximide to prevent reinforcement of tolerance, was measured in rats (paw pressure method) and mice (hot plate method) at intervals during 1-23 days following cessation of a variety of regimens of tolerance-inducing drug treatments. 3. A biphasic pattern of recovery of responsiveness was observed, which was independent of the regimen or the drug (morphine, methadone or diamorphine) used to induce tolerance. Estimates of the rates of the first, fast phase are imprecise but the rate of the second phase of offset, from 4th day after cessation of pretreatment had, in rats, a mean half-time of 13.2 plus or minus 0.53 days-for all pretreatments combined, there being no significant differences between the various pretreatment regimens employed. In mice, similarly, a biphasic recovery of analgesic responsiveness was seen after morphine pretreatment, the mean half-time of the slower phase being 17.4 days. 4. Precipitation of an acute withdrawal syndrome in rats by naloxone HCl given 6 h after the final injection of a tolerance-inducing treatment with morphine did not affect the subsequent rate of recovery from tolerance. 5. During the period following a tolerance-inducing pretreatment with morphine in mice, the rate of attenuation of the naloxone-evoked jumping response was faster than the rate of offset of tolerance. PMID:1169082

  4. Serotonin syndrome probably triggered by a morphine-phenelzine interaction.

    PubMed

    Mateo-Carrasco, Hector; Muñoz-Aguilera, Eva María; García-Torrecillas, Juan Manuel; Abu Al-Robb, Hiba

    2015-06-01

    Serotonin syndrome is a potentially life-threatening condition caused by excessive central and peripheral stimulation of serotonin brainstem receptors, usually triggered by inadvertent interactions between agents with serotonergic activity. Evidence supporting an association between nonserotonergic opiates, such as oxycodone or morphine, and serotonin syndrome is very limited and even contradictory. In this case report, we describe a patient who developed serotonergic-adverse effects likely precipitated by an interaction between morphine and phenelzine. A 57-year-old woman presented to the emergency department with complaints of increasing visual hallucinations, restlessness, photophobia, dizziness, neck stiffness, occipital headache, confusion, sweating, tachycardia, and nausea over the previous week. On admission, her blood pressure was 185/65 mm Hg, and clonus was noted in the lower extremities. The patient was hospitalized 10 days earlier for cellulitis of the left breast secondary to a left mastectomy 5 months earlier, and a short course of oral morphine was prescribed for pain control. Her routine medications consisted of aspirin, atorvastatin, bisoprolol, clopidogrel, gabapentin, omeprazole, phenelzine, and ramipril. Supportive measures were initiated on admission. Phenelzine and morphine were discontinued immediately, leading to a progressive resolution of symptoms over the next 48 hours. Phenelzine was restarted on discharge without further complications. Use of the Drug Interaction Probability Scale indicated a probable relationship (score of 6) between the patient's development of serotonin syndrome and the combination of morphine and phenelzine. The mechanism underlying this interaction, however, remains unclear and warrants further investigation. Clinicians should carefully weigh the risk and benefits of initiating morphine in patients taking monoamine oxidase inhibitors or any other serotonin-enhancing drugs.

  5. Design of controlled-release morphine suppositories containing polyglycerol ester of fatty acid.

    PubMed

    Takatori, Toshihito; Yamamoto, Kazumitsu; Yamaguchi, Toshikazu; Higaki, Kazutaka; Kimura, Toshikiro

    2005-08-01

    Controlled-release morphine suppositories were prepared by utilizing polyglycerol ester of fatty acid (PGEF). The addition of PGEF to fatty suppository base Witepsol H15 resulted in a decrease of morphine release rate from suppositories. Among PGEFs examined, decaglycerol heptabehenate (HB750) was the most effective additive for the controlled-release of morphine from fatty suppositories. The apparent viscosity of suppository bases increased with the increase in HB750 content, and good correlation was observed between the apparent viscosity of suppository bases at 37 degrees C and the amount of HB750 added in the mixed base. The in vitro release rate of morphine was decreased by the addition of HB750 and the release rate constant (Higuchi's rate constant) for morphine release was significantly correlated with the HB750 content in the mixed bases as well as the apparent viscosity of mixed bases, indicating that the release of morphine from the mixed bases could be regulated by the HB750 content in the mixed bases. After rectal administration of Witepsol H-15-HB750 mixed suppositories to dogs, plasma concentrations of morphine did not increase rapidly at early time periods, but relatively high levels of morphine in plasma were sustained for longer time periods. Mean residence time of morphine was considerably prolonged without changing relative bioavailability in the case of the mixed base suppositories containing 15-17% HB750, compared with the Witepsol H15 suppository, clearly indicating that the mixed bases containing HB750 are expected to be useful for the design of controlled-release morphine suppositories.

  6. 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

  7. Eating behavior reveals rats' preference for morphine.

    PubMed

    Yanaura, S; Suzuki, T; Kawai, T

    1980-04-01

    Using an automatic food intake measuring apparatus ("food intakometer"), we recorded the approach behavior to food, eating behavior and food intake of morphine dependent rats and examined the relationship among these factors and morphine dependence. Morphine dependent rats were produced by the drug-admixed food (DAF) method. In the choice trial of free feeding group, morphine dependent rats showed only the approach behavior both to drug-free diet and to morphine-admixed food, then ate the morphine-admixed food and approached the drug-free diet at the same period. Eating behavior in the case of morphine-admixed food was observed not only at night but also during thee feeding group, morphine dependent rats showed only the approach behavior both to drug-free diet and to morphine-admixed food, then ate the morphine-admixed food and approached the drug-free diet at the same period. Eating behavior in the case of morphine-admixed food was observed not only at night but also during the day time in the morphine dependent rats. In the choice trial of the limited feeding group, preference for morphine rapidly increased in every choice trial of each session and the preference rate became stable at about 60%. Eating patterns of these rats were similar to these in the free feeding group. When these rats were given morphine prior to the choice trial, eating behavior of those on the morphine-admixed food was inhibited dose-dependently, while eating behavior of these on the drug-free diet was enhanced dose-dependently. When these rats were allowed free access to drug-free diet for 1 hour previously to the choice trial, eating behavior of the rats on the morphine-admixed food in the choice trial was markedly enhanced. Thus, the rats clearly showed drug-seeking behavior and seemed to be able to distinguish between the need for morphine and satisfaction without it. Morphine dependent rats apparently can control their required maintenance dose.

  8. Differences in the morphine-induced inhibition of small and large intestinal transit: Involvement of central and peripheral μ-opioid receptors in mice.

    PubMed

    Matsumoto, Kenjiro; Umemoto, Hiroyuki; Mori, Tomohisa; Akatsu, Ryuya; Saito, Shinichiro; Tashima, Kimihito; Shibasaki, Masahiro; Kato, Shinichi; Suzuki, Tsutomu; Horie, Syunji

    2016-01-15

    Constipation is the most common side effect of morphine. Morphine acts centrally and on peripheral sites within the enteric nervous system. There are a few comprehensive studies on morphine-induced constipation in the small and large intestine by the activation of central and peripheral μ-opioid receptors. We investigated the differences in the inhibition of the small and large intestinal transit in normal and morphine-tolerant mice. Morphine reduced the geometric center in the fluorescein isothiocyanate-dextran assay and prolonged the bead expulsion time in a dose-dependent manner. The inhibitory effects of morphine were blocked by μ-opioid antagonist β-funaltrexamine, but not by δ- and κ-opioid antagonists. The peripheral opioid receptor antagonist, naloxone methiodide, partially blocked morphine's effect in the small intestine and completely blocked its effect in the large intestine. The intracerebroventricular administration of naloxone significantly reversed the delay of small intestinal transit but did not affect morphine-induced inhibition of large intestinal transit. Naloxone methiodide completely reversed the inhibition of large intestinal transit in normal and morphine-tolerant mice. Naloxone methiodide partially reversed the morphine-induced inhibition of small intestinal transit in normal mice but completely reversed the effects of morphine in tolerant mice. Chronic treatment with morphine results in tolerance to its inhibitory effect on field-stimulated contraction in the isolated small intestine but not in the large intestine. These results suggest that peripheral and central opioid receptors are involved in morphine-induced constipation in the small and large intestine during the early stage of treatment, but the peripheral receptors mainly regulate constipation during long-term morphine treatment.

  9. Chronic exposure to cadmium attenuates behavioral sensitization to morphine.

    PubMed

    Nation, J R; Miller, D K; Livermore, C L

    1997-06-01

    The purpose of this investigation was to assess the impact of dietary cadmium on morphine-induced changes in locomotor activity. Adult male rats were exposed ad libitum to an adulterated food supply containing 100 ppm added cadmium chloride, or an identical diet containing no added cadmium, for 45 days prior to testing for the locomotor activating effects of successive daily morphine administration (0, 5, 10, or 20 mg/kg per session) on locomotor activity. On day 1 of testing, increasing doses of morphine produced a dose-related suppression of activity, and this sedative effect was greater in control than in cadmium-exposed animals. Repeated morphine administration resulted in tolerance to the sedative effects of the drug, and a systematic elevation of locomotor activity over the 14-day testing period was observed, with the augmentation (sensitization) effect more pronounced in control than cadmium-exposed animals. There was no indication that conditioning (context) events played a role in the effects observed here.

  10. Chronic Morphine Reduces Surface Expression of δ-Opioid Receptors in Subregions of Rostral Striatum.

    PubMed

    Leah, Paul M; Heath, Emily M L; Balleine, Bernard W; Christie, Macdonald J

    2016-03-01

    The delta opioid receptor (DOPr), whilst not the primary target of clinically used opioids, is involved in development of opioid tolerance and addiction. There is growing evidence that DOPr trafficking is involved in drug addiction, e.g., a range of studies have shown increased plasma membrane DOPr insertion during chronic treatment with opioids. The present study used a transgenic mouse model in which the C-terminal of the DOPr is tagged with enhanced-green fluorescence protein to examine the effects of chronic morphine treatment on surface membrane expression in striatal cholinergic interneurons that are implicated in motivated learning following both chronic morphine and morphine sensitization treatment schedules in male mice. A sex difference was noted throughout the anterior striatum, which was most prominent in the nucleus accumbens core region. Incontrast with previous studies in other neurons, chronic exposure to a high dose of morphine for 6 days had no effect, or slightly decreased (anterior dorsolateral striatum) surface DOPr expression. A morphine sensitization schedule produced similar results with a significant decrease in surface DOPr expression in nucleus accumbens shell. These results suggest that chronic morphine and morphine sensitisation treatment may have effects on instrumental reward-seeking behaviours and learning processes related to drug addiction, via effects on striatal DOPr function.

  11. Repeated experience with naloxone facilitates acute morphine withdrawal: potential role for conditioning processes in acute opioid dependence.

    PubMed

    Schulteis, Gery; Morse, Andrew C; Liu, Jian

    2003-12-01

    Single injections with morphine can induce a state of acute opioid dependence in humans and animals, typically measured as precipitated withdrawal when an antagonist such as naloxone is administered 4-24 h after morphine. Repeated treatment with morphine at 24-h intervals can result in a progressive shift in potency of naloxone to produce such acute withdrawal signs, including suppression of operant responding for food reward. The current study characterized fully both morphine and naloxone dose-effect functions in an effort to establish the relative contributions of repeated morphine vs. repeated naloxone (Nal) experience to these potency shifts. Rats trained on an FR15 schedule for food received four vehicle or morphine injections (0.56-5.6 mg/kg sc), spaced 24 h apart. Four hours after each morphine pretreatment (Repeat Nal), or 4 h after the fourth and final morphine pretreatment only (Single Nal), a cumulative dose-effect function for naloxone-induced suppression of responding was determined. Vehicle-pretreated (Morphine Naive) rats showed little change in the naloxone dose effect function even after four cumulative dose-effect determinations. By contrast, a progressive increase in naloxone potency was observed following successive pretreatments with morphine under Repeat Nal conditions, and the magnitude of naloxone potency shift was morphine dose dependent. At a morphine dose of 5.6 mg/kg, repeated naloxone experience in the presence of morphine was not an absolute requirement to produce an increase in naloxone potency across days, but repeated naloxone could potentiate the magnitude of the observed shift, indicating both experience-independent and experience-dependent processes at work. At lower doses of morphine (1.0 and 3.3 mg/kg) no shift in naloxone potency was observed across days of morphine treatment in the absence of repeated naloxone experience (Single Nal conditions), indicating an increasing contribution of naloxone experience-dependent processes

  12. Oral administration of morphine versus ibuprofen to manage postfracture pain in children: a randomized trial

    PubMed Central

    Poonai, Naveen; Bhullar, Gina; Lin, Kangrui; Papini, Adam; Mainprize, David; Howard, Jocelyn; Teefy, John; Bale, Michelle; Langford, Cindy; Lim, Rodrick; Stitt, Larry; Rieder, Michael J.; Ali, Samina

    2014-01-01

    Background: Recent warnings from Health Canada regarding codeine for children have led to increased use of nonsteroidal anti-inflammatory drugs and morphine for common injuries such as fractures. Our objective was to determine whether morphine administered orally has superior efficacy to ibuprofen in fracture-related pain. Methods: We used a parallel group, randomized, blinded superiority design. Children who presented to the emergency department with an uncomplicated extremity fracture were randomly assigned to receive either morphine (0.5 mg/kg orally) or ibuprofen (10 mg/kg) for 24 hours after discharge. Our primary outcome was the change in pain score using the Faces Pain Scale — Revised (FPS-R). Participants were asked to record pain scores immediately before and 30 minutes after receiving each dose. Results: We analyzed data from 66 participants in the morphine group and 68 participants in the ibuprofen group. For both morphine and ibuprofen, we found a reduction in pain scores (mean pre–post difference ± standard deviation for dose 1: morphine 1.5 ± 1.2, ibuprofen 1.3 ± 1.0, between-group difference [δ] 0.2 [95% confidence interval (CI) −0.2 to 0.6]; dose 2: morphine 1.3 ± 1.3, ibuprofen 1.3 ± 0.9, δ 0 [95% CI −0.4 to 0.4]; dose 3: morphine 1.3 ± 1.4, ibuprofen 1.4 ± 1.1, δ −0.1 [95% CI −0.7 to 0.4]; and dose 4: morphine 1.5 ± 1.4, ibuprofen 1.1 ± 1.2, δ 0.4 [95% CI −0.2 to 1.1]). We found no significant differences in the change in pain scores between morphine and ibuprofen between groups at any of the 4 time points (p = 0.6). Participants in the morphine group had significantly more adverse effects than those in the ibuprofen group (56.1% v. 30.9%, p < 0.01). Interpretation: We found no significant difference in analgesic efficacy between orally administered morphine and ibuprofen. However, morphine was associated with a significantly greater number of adverse effects. Our results suggest that ibuprofen remains safe and effective

  13. Neuroprotection of donepezil against morphine-induced apoptosis is mediated through Toll-like receptors.

    PubMed

    Shafie, Alireza; Moradi, Farshid; Izadpanah, Esmael; Mokarizadeh, Aram; Moloudi, Mohammad Raman; Nikzaban, Mehrnoush; Hassanzadeh, Kambiz

    2015-10-01

    Previously, we had shown that donepezil provides anti-apoptotic effects associated with the prevention of morphine tolerance to the analgesic effect. In this regard, the present study aimed to evaluate the molecular mechanisms involved in this effect considering the possible role of Toll-like receptor (TLR) 2,4, and the balance between pre-apoptotic and anti-apoptotic Bcl family proteins. To this end, male Wistar rats received daily morphine in combination with either normal saline or donepezil (0.5, 1, or 1.5 mg/kg, ip). The analgesic effect was assessed by the plantar test apparatus. The latency was recorded when the animal responded to the light stimulus. On the 15th day, when no significant difference was observed between morphine and saline groups in terms of analgesia, the frontal cortex and lumbar spinal cord of the animals were dissected. Then, TLR2 and 4, Bcl2, and Bax mRNA fold changes were calculated using Real-time PCR method. The results indicated no significant analgesic effect in the morphine group compared with the saline treated animals after 15 days of injection, while daily co-administration of donepezil with morphine preserved significant analgesia. Moreover, Quantitative PCR showed that morphine significantly increased TLRs and Bax gene expressions and decreased the anti-apoptotic Bcl2. In contrast, donepezil prevented these morphine induced changes in the mentioned gene expressions. Taken together, the results suggest that the neuroprotective effects of donepezil in attenuating morphine-induced tolerance and apoptosis are mediated by preventing morphine-induced changes in TLR2 and 4 gene expressions.

  14. [Altered expression of transporter and analgesic of morphine in neuropathic pain mice].

    PubMed

    Ochiai, Wataru; Sugiyama, Kiyoshi

    2015-01-01

    It is known that morphine is less effective for patients with neuropathic pain, accounting for approximately 70% of cancer patients with severe pain. One of the causes of the decline is reported as a decreased function of the μ-opioid receptor, which binds to the active metabolites of morphine in the mesencephalic ventral tegmental area. However, the details of this mechanism are not understood. We hypothesized that a decrease in the concentration of morphine in the brain reduces its analgesic effect on neuropathic pain, and found that the analgesic effect of morphine was correlated with its concentration in the brain. We examined the reason for the decreased concentration of morphine in the brain in case of neuropathic pain. We discovered increased P-glycoprotein (P-gp) expression in the small intestine, increased expression and activity of UGT2B in the liver, and increased P-gp expression in the brain under conditions of neuropathic pain. In this symposium, we argue that low brain morphine concentration is considered one of the causes of lower sensitivity to morphine in neuropathic pain patients.

  15. Sex differences in the Nociceptin/Orphanin FQ system in rat spinal cord following chronic morphine treatment

    PubMed Central

    Zhang, Yong; Donica, Courtney L.; Standifer, Kelly M.

    2016-01-01

    Nociceptin/Orphanin FQ (N/OFQ) appears to contribute to the development of morphine tolerance, as blockade of its actions will block or reverse the process. To better understand the contribution of N/OFQ to the development of morphine tolerance, this study examined the effect of chronic morphine treatment on levels of N/OFQ and levels and activity of the N/OFQ peptide (NOP) receptor in spinal cord (SC) from male and female rats. Both male and female Wistar rats showed less responsiveness to morphine after subcutaneous injection of escalating doses of morphine (10, 20, 40, 60 and 80 mg/kg, respectively) twice daily for five consecutive days. Male rats were more tolerant to the antinociceptive actions of morphine than females. The N/OFQ content of SC extracts was higher in females than in males, regardless of treatment; following chronic morphine treatment the difference in N/OFQ levels between males and females was more pronounced. N/OFQ content in cerebrospinal fluid (CSF) was reduced 40% in male and 16% in female rats with chronic morphine exposure, but increased in periaqueductal grey of both sexes. Chronic morphine treatment increased NOP receptor levels 173% in males and 137% in females, while decreasing affinity in both. Chronic morphine increased the efficacy of N/OFQ-stimulated [35S]GTPγS binding to SC membranes from male rats, consistent with increased receptor levels. Taken together, these findings demonstrate sex differences in N/OFQ–NOP receptor expression and NOP receptor activity following chronic morphine treatment. They also suggest interplay between endogenous N/OFQ and chronic morphine treatment that results in nociceptive modulation. PMID:22575074

  16. Effectiveness of early initiation of protease inhibitor-sparing antiretroviral regimen in human immunodeficiency virus-1 vertically infected infants.

    PubMed

    Van der Linden, Dimitri; Hainaut, Marc; Goetghebuer, Tessa; Haelterman, Edwige; Schmitz, Véronique; Maes, Philip; Peltier, Alexandra; Levy, Jack

    2007-04-01

    Each of the 17 vertically infected infants born to HIV-1-infected mothers in Belgian HIV reference centers since 1996 was treated with a combination of 3 reverse transcription inhibitors as soon as the diagnosis was established. Treatment was initiated in all patients before 66 days of life. Twelve patients, including 11/13 infants treated with the combination of zidovudine, lamivudine and nevirapine, experienced a complete viral suppression (<50 copies/mL) with their first drug regimen. At last follow-up, 12 patients were asymptomatic, 2 were CDC stage A and 3 were stage B; 15 had HIV-1 RNA levels of <50 copies/mL and 14 had >or=25% CD4 lymphocytes. These results suggest that early initiation of treatment with 3 reverse transcription inhibitors is highly effective to inhibit viral replication and to prevent clinical and immunologic progression of HIV infection in vertically infected infants.

  17. Postoperative analgesia after paediatric orchidopexy: evaluation of a bupivacaine-morphine mixture.

    PubMed

    Wolf, A R; Hughes, D; Wade, A; Mather, S J; Prys-Roberts, C

    1990-04-01

    The value of combining morphine with bupivacaine for caudal analgesia was investigated. Thirty children, undergoing orchidopexy, received a caudal block of 0.125% bupivacaine with or without morphine 0.05 mg kg-1. Analgesia, side-effects, ventilatory frequency and oxygen saturation (SaO2) were recorded after operation. None of the 15 patients receiving the bupivacaine-morphine mixture required post-operative opioids, whereas eight of 15 patients receiving bupivacaine alone needed additional opioid analgesia. The incidence of side effects after surgery was similar for the two groups and there was no detectable difference in ventilatory frequency or SaO2.

  18. Postoperative analgesia after paediatric orchidopexy: evaluation of a bupivacaine-morphine mixture.

    PubMed

    Wolf, A R; Hughes, D; Wade, A; Mather, S J; Prys-Roberts, C

    1990-04-01

    The value of combining morphine with bupivacaine for caudal analgesia was investigated. Thirty children, undergoing orchidopexy, received a caudal block of 0.125% bupivacaine with or without morphine 0.05 mg kg-1. Analgesia, side-effects, ventilatory frequency and oxygen saturation (SaO2) were recorded after operation. None of the 15 patients receiving the bupivacaine-morphine mixture required post-operative opioids, whereas eight of 15 patients receiving bupivacaine alone needed additional opioid analgesia. The incidence of side effects after surgery was similar for the two groups and there was no detectable difference in ventilatory frequency or SaO2. PMID:1970738

  19. 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. PMID:26052274

  20. Activation of CXCL10/CXCR3 signaling attenuates morphine analgesia: involvement of Gi protein.

    PubMed

    Ye, Dawei; Bu, Huilian; Guo, Genhua; Shu, Bin; Wang, Wei; Guan, Xuehai; Yang, Hui; Tian, Xuebi; Xiang, Hongbing; Gao, Feng

    2014-08-01

    Morphine is a potent agonist of μ-opioid receptor and is widely used to relieve severe pain, including cancer pain. Some chemokines, for example, CX3CL1 and CCL2, participate in the regulation of opioid santinociception. In our previous study, we found overexpression of chemokine CXCL10/CXCR3 in spinal cord participated in the development of cancer-induced bone pain, so we supposed that CXCL10 may have influence in morphine analgesia in cancer pain relief. In this study, we found that a single dose of morphine could transiently increase the expression of CXCL10 in spinal cord. Blocking the function of CXCL10 enhanced morphine antinociception in cancer-induced bone pain rats. However, overexpression of CXCL10 induced acute algesia and decreased the analgesic effect of morphine in normal mice. The algesic effect of CXCL10 was blocked by inhibition of CXCR3 and Gi protein. These results suggested that CXCL10 in spinal cord serves as a novel negative regulator of morphine analgesia and provided evidence that activation of CXCL10/CXCR3 in spinal cord may attenuate antinociceptive potency of morphine in cancer pain relief.

  1. Urethral Sparing Histotripsy of the Prostate in a Canine Model

    PubMed Central

    Schade, George R.; Hall, Timothy L.; Roberts, William W.

    2012-01-01

    Objective To evaluate the feasibility and healing response to urethral sparing prostate histotripsy a canine model of benign prostatic hypertrophy. Methods Histotripsy was performed on 10 canines using a 750 kHz piezoelectric ultrasound transducer targeting the prostatic parenchyma while avoiding the urethra. Periprocedure prostatic urethral integrity was evaluated with serial cystourethroscopy. Evolution of histotripsy treatment effect and subjects’ response to urethral sparing was evaluated with serial ultrasound and laboratory evaluation, respectively. Subjects were euthanized acutely or chronically and findings were confirmed histologically. Results Bilateral treatment was possible in 8/10 subjects while unilateral treatment was performed in 2/10. Failure to spare the urethra was observed in 2/18 treatments; one acutely and one chronically despite normal cystourethroscopy for the first week. Modest prostatic volume reduction was seen in subjects survived to 8 weeks post-histotripsy. Laboratory studies revealed transient perioperative increases in mean white-blood cell count, C-reactive protein, and lactate dehydrogenase. On histology, 80% of successful urethral sparing treatment cavities were completely epithelialized, containing simple fluid with minimal cellular debris at 8 weeks despite no communication with the urethra. Conclusions Urethral sparing histotripsy of the prostate is feasible and well tolerated in a canine model, resulting in modest volume reduction and prompt resorption of homogenized tissue debris. Human studies to evaluate the clinical utility and symptomatic response of urethral sparing are needed. PMID:22840869

  2. ANDROGENS AND OPIATES: TESTOSTERONE INTERACTION WITH MORPHINE SELF-ADMINISTRATION IN MALE RATS

    PubMed Central

    Cooper, Sarah E.; Wood, Ruth I.

    2016-01-01

    Abuse of anabolic-androgenic steroids (AAS) and opioids intersect in athletics. Evidence from humans and animals suggests that AAS may act in the brain via opioidergic mechanisms, and may potentiate effects of opioids. To determine if AAS enhance motivation for opioid intake, this study treated male rats chronically for 6 weeks with high levels of testosterone (7.5 mg/kg) or vehicle s.c. and tested them for morphine self-administration under fixed (FR) and progressive ratio (PR) schedules. Initially, rats received chronic morphine infusion (16.8–50 mg/kg/day) over 7 days. Subsequently, rats were tested for morphine self-administration (3.2 mg/kg) 6h/day for 3 days under an FR1 schedule, and for 7 days under a PR 9-4 schedule. With FR1, controls self-administered more morphine (95.9±8.5 mg/kg), compared with testosterone-treated rats (63.2±7.2 mg/kg, p<0.05). Under PR, there was no effect of testosterone on morphine intake or operant responding (26.7±5.7 responses vs 30.9±5.9 responses for vehicle; n.s.). To determine if testosterone enhances morphine sedation, additional rats were treated with testosterone or vehicle and evaluated for locomotor behavior and rearing activity over 30 min in response to saline or 10 mg/kg morphine. Morphine inhibited locomotor activity and rearing; testosterone selectively reduced rearing behavior, but did not alter locomotor behavior. These results suggest that testosterone does not increase motivation for morphine. PMID:24488032

  3. 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.

  4. Quantitative analysis of naloxone antagonism of the discriminative stimulus properties of morphine in the pigeon.

    PubMed

    Wessinger, W D; McMillan, D E

    1986-07-01

    Pigeons were trained to discriminate morphine (5.0 mg/kg) from saline under a second-order fixed ratio 10 (fixed-ratio 5) color-tracking schedule for food reinforcement. After reliable stimulus control was established, cumulative graded doses of morphine (0.3-30.0 mg/kg) were tested and resulted in dose-dependent increases in morphine-appropriate key pecking and decreases in response rate. Cumulative doses of naloxone (0.1-10.0 mg/kg) or consecutive injections of saline did not elicit morphine-appropriate responding or affect response rate. Pre-treatment with naloxone (0.1-1.0 mg/kg) before determination of cumulative dose-effect curves for morphine caused the morphine generalization curves to be shifted, in a parallel manner, rightward. Dose-ratio analysis of naloxone antagonism of morphine generalization, using a Schild plot with the slope constrained to -1, gave an apparent pA2 value (95% confidence limits) of 6.53 (6.18-6.89).

  5. Morphine Modulates Interleukin-4- or Breast Cancer Cell-induced Pro-metastatic Activation of Macrophages.

    PubMed

    Khabbazi, Samira; Goumon, Yannick; Parat, Marie-Odile

    2015-01-01

    Interactions between cancer cells and stromal cells in the tumour microenvironment play a key role in the control of invasiveness, metastasis and angiogenesis. Macrophages display a range of activation states in specific pathological contexts and alternatively activated (M2) macrophages can promote tumour aggressiveness. Opioids are able to modulate tumour growth and metastasis. We tested whether morphine modulates the activation of macrophages induced by (i) interleukin-4 (IL-4), the prototypical M2 polarization-inducing cytokine, or (ii) coculture with breast cancer cells. We showed that IL-4 causes increased MMP-9 production and expression of the alternative activation markers arginase-1 and MRC-1. Morphine prevented IL-4-induced increase in MMP-9 in a naloxone- and methylnaltrexone-reversible fashion. Morphine also prevented IL-4-elicited alternative activation of RAW264.7 macrophages. Expression of MMP-9 and arginase-1 were increased when RAW264.7 were subjected to paracrine activation by 4T1 cells, and this effect was prevented by morphine via an opioid receptor-mediated mechanism. Morphine further decreased 4T1 breast cancer cell invasion elicited by co-culture with RAW264.7. Reduction of MMP-9 expression and alternative activation of macrophages by morphine was confirmed using mouse bone marrow-derived macrophages. Taken together, our results indicate that morphine may modulate tumour aggressiveness by regulating macrophage protease production and M2 polarization within the tumour microenvironment.

  6. Treadmill exercise reduces self-administration of morphine in male rats.

    PubMed

    Hosseini, Mahmoud; Alaei, Hojjat Allah; Naderi, Asieh; Sharifi, Mohammad Reza; Zahed, Reza

    2009-06-01

    Exercise can activate the same pathways as morphine. The aim of the present study was to clarify the effect of short-term and mid-term exercises on the self-administration of morphine in rats. Male Wistar rats were initially trained to receive small pellets of food by pressing the active lever in self-administration apparatus. Rats were divided into 4 groups: Saline, Morphine, Exercise 1 (11 days) and Exercise 2 (30 days). Their jugular vein was cannulated. The animals were placed in self-administration apparatus and allowed to self-administer morphine (0.5mg per infusion all test groups) or saline (Saline group) during consecutive days, for 2h/sessions. In the group 1 the rats were running before each session of self-administration and of group Exercise 2, 30 days before surgery as well as before each session. The pressing numbers of active and passive levers in each group and among different groups were compared. The number of active lever pressing of Morphine group was significantly higher than Saline group (p<0.001). In Exercise 1 and Exercise 2 groups, the number of active lever pressing was significantly lower than Morphine group (p<0.001). As exercise can activate many neurotransmitter systems involved in the addiction process and increase the release of endorphins, it is likely that could decrease the morphine self-administration in this experimental setup. PMID:19131225

  7. 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.

  8. An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury.

    PubMed

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

    2011-02-01

    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 h 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 h 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

  9. Morphine attenuates cholinergic nerve activity in human isolated colonic muscle.

    PubMed Central

    Burleigh, D. E.; Trout, S. J.

    1986-01-01

    The action of morphine on cholinergic nerves in human sigmoid taenia coli muscle strips (taenia) was investigated using a radiolabelling technique. Basal release of tritiated material from taenia was increased by electrical field stimulation (EFS). This increase was tetrodotoxin (3.14 microM)-sensitive and calcium-dependent. Analysis of basal and stimulated release of tritiated material indicated that evoked release (i.e. stimulated minus basal) is almost entirely due to an increase in [3H]-acetylcholine ([3H]-ACh) output. Evoked release of [3H]-ACh was dependent on the current strength and could be greatly reduced by exposing taenia to hemicholinium (34.8, 87.0 microM) before and during incubation with [3H]-choline (4 microCi ml-1, 15 Ci mmol-1). Spontaneous activity, muscle tone and the motor response of taenia to EFS were unaffected by morphine. Evoked, but not basal, release of tritiated material was inhibited by morphine (1.32-13.20 microM) in a concentration-dependent manner. The inhibition of release was frequency-dependent and naloxone (0.28 microM)-sensitive. The possible relationship between the effects of morphine on cholinergic nerves in taenia muscle and its actions in vivo are discussed. PMID:2873856

  10. Use of morphine in cholescintigraphy for obstructive cholecystitis

    SciTech Connect

    Kim, E.E.; Nguyen, M.; Pjura, G.; Pollack, M.; Gobuty, A.

    1985-05-01

    Non-visualization of the gallbladder (GB) during the first hour of cholescintigraphy is observed in cystic duct obstruction (e.g. in acute cholecystitis) but may also occur in chronic cholecystitis, hepatocellular disease, alcoholism and prolonged total parenteral nutrition. Low dose morphine is shown to improve the specificity of the diagnosis of acute cholecystitis (from 85% to 100%) with no loss in sensitivity (98%) at a small cost in terms of additional study time. The authors reviewed 27 selected cholescintigraphic examinations augmented by intravenous (IV) morphine (0.04 mg/Kg). Of the 16 cases with persistent nonvisualization of the GB, ultrasound revealed gallstones in 5 cases, sludge in 4, acalculous cholecystitis in 3, one distended GB, one contracted GB and 2 normal GB's. Of the 4 patients taken to surgery, one with gallstones and one with acalculous cholecystitis were confirmed to have acute cholecystitis while another with gallstones had chronic cholecystitis and the final patient, who was sonographically normal, presented a single common duct stone. The authors conclude that the use of IV morphine is an effective adjunct to cholescintigraphy in the evaluation of gallbladder disease, especially when visualization post morphine rules out acute cholecystitis.

  11. Exposure of consumers to morphine from poppy seeds in Hungary.

    PubMed

    Zentai, A; Sali, J; Szeitzné-Szabó, M; Szabó, I J; Ambrus, Á

    2012-01-01

    Poppy seed-containing foods are popular dishes in Hungary and some other Central European countries. The alkaloids of poppy are used in the production of medicines. Poppy seeds used as food may also contain considerable amounts of alkaloids, which raises the question of food safety. Morphine, codeine, thebaine and noscapine concentrations of poppy seed samples from the period 2001-2010 and consumption data from two Hungarian surveys, carried out in 2003 and 2009, were evaluated. Exposure calculations were made for morphine intake by both point estimate and probabilistic methods, and the uncertainty of the calculated values was estimated. The point estimate for the acute consumer exposure, calculated using the 97.5th percentiles of morphine concentration and of poppy seed consumption and taking into account the reduction of morphine content by processing, was 78.64 µg (kg bw)⁻¹ day⁻¹ for adults, and 116.90 µg (kg bw)⁻¹ day⁻¹ for children. Based on probabilistic estimations, the 97.5th and 99th percentile exposures ranged between 18.3-25.4 and 25.6-47.4 µg (kg bw)⁻¹ day⁻¹ for adults, and between 32.9 and 66.4 µg (kg bw)⁻¹ day⁻¹ for children, respectively. As a no observed effect level (NOEL) had not been established, the significance of exposure could not be assessed.

  12. Morphine and gp120 toxic interactions in striatal neurons are dependent on HIV-1 strain

    PubMed Central

    Podhaizer, Elizabeth M.; Zou, Shiping; Fitting, Sylvia; Samano, Kimberly L.; El-Hage, Nazira; Knapp, Pamela E.; Hauser, Kurt F.

    2011-01-01

    A rigorously controlled, cell culture paradigm was used to assess the role of HIV-1 gp120 ± morphine in mediating opioid-HIV interactive toxicity in striatal neurons. Computerized time-lapse microscopy tracked the fate of individual neurons co-cultured with mixed-glia from mouse striata during opioid and gp120 exposure. Subpopulations of neurons and astroglia displayed μ-opioid receptor, CXCR4, and CCR5 immunoreactivity. While gp120 alone was or tended to be neurotoxic irrespective of whether X4-tropic gp120IIIB, R5-tropic gp120ADA, or dual-tropic gp120MN was administered, interactive toxicity with morphine differed depending on HIV-1 strain. For example, morphine only transiently exacerbated gp120IIIB-induced neuronal death; however, in combination with gp120MN, morphine caused sustained increases in the rate of neuronal death compared to gp120MN alone that were prevented by naloxone. Alternatively, gp120ADA significantly increased the rate of neuron death, which was unaffected by morphine. The transient neurotoxic interactions between morphine and gp120IIIB were abrogated in the absence of glia suggesting that glia contribute significantly to the interactive pathology with chronic opiate abuse and neuroAIDS. To assess how mixed-glia might contribute to the neurotoxicity, the effects of morphine and/or gp120 on the production of reactive oxygen species (ROS) and on glutamate buffering were examined. All gp120 variants, and to a lesser extent morphine, increased ROS and/or decreased glutamate buffering, but together failed to show any interaction with morphine. Our findings indicate that HIV-1 strain-specific differences in gp120 are critical determinants in shaping both the timing and pattern of neurotoxic interactions with opioid drugs. PMID:22101471

  13. Regulation of mammalian MOR-1 gene expression after chronic treatment with morphine

    PubMed Central

    PRENUS, ROSE V.; LUSCAR, EBENS; ZHU, ZHI-PING; BADISA, RAMESH B.; GOODMAN, CARL B.

    2012-01-01

    Morphine is an effective analgesic that acts by binding to the μ-opioid receptor (MOR) coded in the human by the OPRM1 gene. In the present study, we investigated the regulation of μ-opioid receptor (MOR-1) mRNA levels in all-trans-retinoic acid-differentiated SH-SY5Y human neuroblastoma cells under in vitro conditions with 10 μM morphine treatment for 24 h. In addition, we measured the MOR-1 levels in recombinant Chinese hamster ovary (CHO) cells, transfected with human μ-opioid receptor gene (hMOR) with 10 μM morphine treatment for 24 h. The isolated mRNA from these cells was subjected to real-time quantitative RT-PCR analysis to determine the regulation of μ-opioid receptor gene expression. It was observed that morphine treatment did not alter MOR-1 levels in undifferentiated SH-SY5Y cells compared to undifferentiated control cells. However, the MOR-1 levels in all-trans-retinoic acid-differentiated cells were significantly higher compared to the undifferentiated cells. Morphine treatment in differentiated SH-SY5Y cells caused significant downregulation of MOR-1 expression compared to the control cells. In the morphine-treated CHO cells, the hMOR-1 mRNA levels remained the same as the untreated control. Finally, pretreatment of SH-SY5Y cells with 10 μM naloxone, the antagonist of μ-opioid receptor, for 1 h significantly blocked the downregulation of MOR-1 mRNA levels with morphine treatment. These findings suggest that regulation of MOR-1 gene expression is cell-type specific after chronic morphine treatment and provide some evidence in the understanding of morphine tolerance. PMID:22992838

  14. Cochlea sparing effects of intensity modulated radiation therapy in head and neck cancers patients: a long-term follow-up study

    PubMed Central

    2014-01-01

    Background Radiation to the inner ear may lead to (irreversible) sensorineural hearing loss. The purpose of this study was to evaluate the long-term effect of radiotherapy on hearing in patients treated with Intensity Modulated Radiation Therapy (IMRT), sparing the inner ear from high radiation dose as much as possible. Methods Between 2003 and 2006, 101 patients with head and neck cancer were treated with IMRT. Audiometry was performed before, short-term, and long-term after treatment. Data were compared to normal hearing levels according to the International Organisation for Standardization (ISO). Statistical analysis was done using repeated measurements. None of the patients received chemotherapy. Results In 36 patients an audiogram at long-term follow-up (median 7.6 years) was available. The mean dose to the cochlea was 17.8 Gy (1.0-66.6 Gy). A hearing deterioration of 1.8 dB at Pure Tone Average (PTA) 0.5-1-2 kHz (p = 0.11), 2.3 dB at PTA 1-2-4 kHz (p = 0.02), and 4.4 dB at PTA 8-10-12.5 kHz (p = 0.01) was found. According to the ISO, the expected age-related hearing loss was 2.7, 4.8, and 8.8 dB at PTA 0.5-1-2 kHz, 1-2-4 kHz, and 8-10-12.5 kHz, respectively. Conclusions After IMRT with radiation dose constraint to the cochlea, potential long-term adverse effects of IMRT remained subclinical. The progressive hearing loss over time was mild and could be attributed to the natural effects of ageing. Therefore, we recommend that a dose constraint to the cochlea should be incorporated in the head and neck radiotherapy protocols. PMID:25095702

  15. D-serine in the midbrain periaqueductal gray contributes to morphine tolerance in rats

    PubMed Central

    Cao, Song; Sun, Mengjie; Li, Youyan

    2016-01-01

    Background The N-methyl-D-aspartate subtype of glutamate receptor plays a critical role in morphine tolerance. D-serine, a co-agonist of N-methyl-D-aspartate receptor, participates in many physiological and pathophysiological processes via regulating N-methyl-D-aspartate receptor activation. The purinergic P2X7 receptor activation can induce the D-serine release in the central nervous system. This study aimed to investigate the role of the ventrolateral midbrain periaqueductal gray D-serine in the mechanism of morphine tolerance in rats. The development of morphine tolerance was induced in normal adult male Sprague–Dawley rats through subcutaneous injection of morphine (10 mg/kg). The analgesic effect of morphine (5 mg/kg, i.p.) was assessed by measuring mechanical withdrawal thresholds in rats with an electronic von Frey anesthesiometer. The D-serine concentration and serine racemase expression levels in the ventrolateral midbrain periaqueductal gray were evaluated through enzyme-linked immunosorbent assay and Western blot analysis, respectively. The effects of intra-ventrolateral midbrain periaqueductal gray injections of the D-serine degrading enzyme D-amino acid oxidase and antisense oligodeoxynucleotide targeting the P2X7 receptor on chronic morphine-treated rats were also explored. Results We found that repeated morphine administrations decreased the antinociceptive potency of morphine evidenced by the percent changes in mechanical pain threshold in rats. By contrast, the D-serine contents and the expression levels of the serine racemase protein were upregulated in the ventrolateral midbrain periaqueductal gray in morphine-tolerant rats. The development of morphine tolerance was markedly alleviated by intra-ventrolateral midbrain periaqueductal gray injections of D-amino acid oxidase or antisense oligodeoxynucleotide targeting the P2X7 receptor. Conclusions Our data indicate that the development of antinociceptive tolerance to morphine is partially

  16. 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.

  17. Intensity-modulated radiation therapy after hysterectomy: Comparison with conventional treatment and sensitivity of the normal-tissue-sparing effect to margin size

    SciTech Connect

    Ahamad, Anesa; D'Souza, Warren; Salehpour, Mohammad; Iyer, Revathy; Tucker, Susan L.; Jhingran, Anuja; Eifel, Patricia J. . E-mail: peifel@mdanderson.org

    2005-07-15

    Purpose: To determine the influence of target-volume expansion on the reduction in small-bowel dose achieved with use of intensity-modulated radiation therapy (IMRT) vs. standard conformal treatment of the pelvis after hysterectomy, and to investigate the influence of patient body habitus on the normal-tissue sparing achieved with use of IMRT. Methods and Materials: A clinical target volume (CTV) was contoured on each of 10 planning computed tomography scans of patients who had been treated for cervical or endometrial cancer after a hysterectomy. Treatment planning was based on vaginal CTVs and regional nodal CTVs. To account for internal motion, margins were added to form an initial planning target volume (PTVA) as follows: 0.0 mm were added to the regional nodal CTV; 10 mm were added anteriorly to the vaginal CTV; and 5 mm were added to the vaginal CTV in all other directions. Two further PTVs (PTVB and PTVC) were produced by a 5-mm expansion of PTVA to give PTVB and a further 5-mm expansion to give PTVC. Treatment plans for all 3 PTVs were produced by use of 2 conformal fields (2FC), 4 conformal fields (4FC), or IMRT to deliver 45 Gy to more than 97% of the PTV. The primary goal of IMRT was to spare small bowel. The change in sparing that accompanied the increase in margin size was assessed by comparison of dose-volume histograms that resulted from PTVA, PTVB, and PTVC. Measured patient dimensions were correlated with bowel sparing. Results: Significantly less small bowel was irradiated by IMRT than by 2FC (p < 0.0001) or 4FC (p < 0.0001) for doses greater than 25 Gy. Significantly less rectum was irradiated by IMRT than by 2FC (p < 0.0001) or 4FC (p < 0.0001). Significantly less bladder was irradiated by IMRT than by 2FC (p < 0.0001). However, the magnitude of the sparing achieved by use of IMRT decreased as margins increased. In particular, the volume of small bowel spared by IMRT vs. 2FC or 4FC decreased as margin size increased (p = 0.0002 and p = 0.008 for

  18. Acute Morphine Treatments Alleviate Tremor in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Treated Monkeys

    PubMed Central

    Yan, Ting; Rizak, Joshua Dominic; Yang, ShangChuan; Li, Hao; Huang, BaiHui; Ma, YuanYe; Hu, XinTian

    2014-01-01

    Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder associated with decreased striatal dopamine levels. Morphine has been found to elevate dopamine levels, which indicates a potential therapeutic effect in PD treatment that has not been investigated previously. To evaluate this hypothesis, an investigation of the acute effects of morphine on PD symptoms was carried out in male rhesus PD monkeys that had been induced with MPTP. All MPTP induced monkeys displayed progressive and irreversible PD motor symptoms. The behavioral response of these animals to morphine and L-Dopa were quantified with the Kurlan scale. It was found that L-Dopa alleviated bradykinesia, but did not significantly improve tremor. In contrast, acute morphine alleviated tremor significantly. These results sugges