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Sample records for repeated opioid administration

  1. Population Pharmacokinetic Modeling After Repeated Administrations of RBP-6000, a New, Subcutaneously Injectable, Long-Acting, Sustained-Release Formulation of Buprenorphine, for the Treatment of Opioid Use Disorder.

    PubMed

    Laffont, Celine M; Gomeni, Roberto; Heidbreder, Christian; Jones, J P; Nasser, Azmi F

    2016-07-01

    RBP-6000 is a novel sustained-release formulation of buprenorphine for the treatment of opioid use disorder, which has been designed for once-monthly (28 days) subcutaneous (SC) injections. A population pharmacokinetic (PK) model was developed to describe the time course of buprenorphine plasma concentrations after repeated SC injections of RBP-6000 at 50 mg, 100 mg, 200 mg, or 300 mg in treatment-seeking opioid-dependent subjects previously on sublingual buprenorphine (Subutex(®) ) treatment. The μ-opioid receptor occupancy was predicted using a previously developed PK/PD Emax model. The results of the population PK analysis jointly with the predicted level of μ-opioid receptor occupancy provided quantitative criteria for clinical dose selection for RBP-6000: the dose of 300 mg every 28 days seems appropriate for immediately achieving an effective exposure after the first SC injection and to maintain effective levels of exposure during chronic treatment. Furthermore, simulations conducted to evaluate the potential impact of a holiday in drug intake indicated that in the unexpected event of a 2-week holiday, levels of μ-opioid receptor occupancy remained consistently above 70% with no significant loss of drug efficacy. This analysis indicated that RBP-6000 has the potential for becoming an effective treatment for opioid-dependent subjects by addressing compliance issues associated with the current once-a-day treatments.

  2. Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain.

    PubMed

    Araldi, Dioneia; Ferrari, Luiz F; Levine, Jon D

    2015-09-01

    The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNFα, NGF, or IL-6 receptor) or direct activation of protein kinase Cε (PKCε), the pronociceptive effects of PGE2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKCε, dependence; (3) prolongation of hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-positive nociceptor. These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the nociceptor. Significance statement: The current study demonstrates the molecular mechanisms involved in the sensitization of nociceptors produced by repeated activation of mu-opioid receptors and contributes to our understanding of the painful condition observed in patients submitted to chronic use of opioids. PMID:26354917

  3. Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain

    PubMed Central

    Araldi, Dioneia; Ferrari, Luiz F.

    2015-01-01

    The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNFα, NGF, or IL-6 receptor) or direct activation of protein kinase Cε (PKCε), the pronociceptive effects of PGE2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKCε, dependence; (3) prolongation of hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-positive nociceptor. These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the nociceptor. SIGNIFICANCE STATEMENT The current study demonstrates the molecular mechanisms involved in the sensitization of nociceptors produced by repeated activation of mu-opioid receptors and contributes to our understanding of the painful condition observed in patients submitted to chronic use of opioids. PMID:26354917

  4. Repeated activation of delta opioid receptors counteracts nerve injury-induced TNF-α up-regulation in the sciatic nerve of rats with neuropathic pain

    PubMed Central

    Vicario, Nunzio; Parenti, Rosalba; Aricò, Giuseppina; Turnaturi, Rita; Scoto, Giovanna Maria; Chiechio, Santina

    2016-01-01

    Despite mu opioid receptor agonists are the cornerstones of moderate-to-severe acute pain treatment, their effectiveness in chronic pain conditions is controversial. In contrast to mu opioid receptor agonists, a number of studies have reported the effectiveness of delta opioid receptor agonists on neuropathic pain strengthening the idea that delta opioid receptors gain importance when chronic pain develops. Among other effects, it has been shown that delta opioid receptor activation in optic nerve astrocytes inhibits tumor necrosis factor-α-mediated inflammation in response to severe hypoxia. Considering the involvement of tumor necrosis factor-α in the development and maintenance of neuropathic pain, with this study we sought to correlate the effect of delta opioid receptor agonist on the development of mechanical allodynia to tumor necrosis factor-α expression at the site of nerve injury in rats subjected to chronic constriction injury of the sciatic nerve. To this aim, we measured the levels of tumor necrosis factor-α in the sciatic nerve of rats with neuropathic pain after repeated injections with a delta opioid receptor agonist. Results obtained demonstrated that repeated administrations of the delta opioid receptor agonist SNC80 (10 mg/kg, i.p. for seven consecutive days) significantly inhibited the development of mechanical allodynia in rats with neuropathic pain and that the improvement of neuropathic symptom was timely related to the reduced expression of tumor necrosis factor-α in the rat sciatic nerve. We demonstrated also that when treatment with the delta opioid receptor agonist was suspended both allodynia and tumor necrosis factor-α up-regulation in the sciatic nerve of rats with neuropathic pain were restored. These results show that persistent delta opioid receptor activation significantly attenuates neuropathic pain and negatively regulates sciatic nerve tumor necrosis factor-α expression in chronic constriction injury rats. PMID:27590071

  5. Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing.

    PubMed

    Ingman, Kimmo; Hagelberg, Nora; Aalto, Sargo; Någren, Kjell; Juhakoski, Auni; Karhuvaara, Sakari; Kallio, Antero; Oikonen, Vesa; Hietala, Jarmo; Scheinin, Harry

    2005-12-01

    The opioid antagonist nalmefene offers an alternative to traditional pharmacological treatments for alcoholism. The present study was designed to investigate the relationship between nalmefene plasma concentration and central mu-opioid receptor occupancy after a clinically effective dose (20 mg, orally). Pharmacokinetics and mu-opioid receptor occupancy of nalmefene after single and repeated dosing over 7 days was studied in 12 healthy subjects. Serial blood samples were obtained after both dosings, and pharmacokinetic parameters for nalmefene and main metabolites were determined. Central mu-opioid receptor occupancy of nalmefene was measured with positron emission tomography (PET) and [(11)C]carfentanil at four time points (3, 26, 50, 74 h) after both dosings. Nalmefene was rapidly absorbed in all subjects. The mean t(1/2) of nalmefene was 13.4 h after single and repeated dosing. The accumulation of nalmefene and its main metabolites in plasma during the repeated dosing period was as expected for a drug with linear pharmacokinetics, and steady-state was reached for all analytes. Both nalmefene dosings resulted in a very high occupancy at mu-opioid receptors (87-100%), and the decline in the occupancy was similar after both dosings but clearly slower than the decline in the plasma concentration of nalmefene or metabolites. High nalmefene occupancy (83-100%) persisted at 26 h after the dosings. The prolonged mu-opioid receptor occupancy by nalmefene indicates slow dissociation of the drug from mu-opioid receptors. These results support the rational of administering nalmefene when needed before alcohol drinking, and they additionally suggest that a high mu-opioid receptor occupancy can be maintained when nalmefene is taken once daily.

  6. Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors

    PubMed Central

    Hipólito, Lucia; Wilson-Poe, Adrianne; Campos-Jurado, Yolanda; Zhong, Elaine; Gonzalez-Romero, Jose; Virag, Laszlo; Whittington, Robert; Comer, Sandra D.; Carlton, Susan M.; Walker, Brendan M.; Bruchas, Michael R.

    2015-01-01

    Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbic DA transmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbic MOR function suggested by DA microdialysis. Consistent with the reduction in low dose FR heroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss of MOR function in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes. SIGNIFICANCE STATEMENT This study provides critical new insights that show that inflammatory pain alters heroin intake through a desensitization of MORs located within the VTA. These findings expand our knowledge of the interactions between

  7. Opioid-induced hyperalgesia and rapid opioid detoxification after tacrolimus administration.

    PubMed

    Siniscalchi, Antonio; Piraccini, Emanuele; Miklosova, Zuzana; Taddei, Stefania; Faenza, Stefano; Martinelli, Gerardo

    2008-02-01

    Opioids can induce central sensitization and hyperalgesia, referred to as "opioid-induced hyperalgesia." Our report describes a patient who underwent intestinal transplant followed by immunosuppressant-related neuropathic pain. Her pain was treated with limited success over the course of 3 yr with different therapies, including i.v. morphine. She developed opioid-induced hyperalgesia, which was successfully treated with rapid detoxification under general anesthesia. Detoxification improved her quality of life, including the ability to resume physiotherapy. Six months after treatment, she remained opioid free. Our experience suggests that rapid detoxification under general anesthesia may be an effective treatment for opioid-induced hyperalgesia and merits comparison to traditional detoxification methods.

  8. 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.

  9. Patterns of opioid use for chronic noncancer pain in the Veterans Health Administration from 2009 to 2011.

    PubMed

    Edlund, Mark J; Austen, Mark A; Sullivan, Mark D; Martin, Bradley C; Williams, James S; Fortney, John C; Hudson, Teresa J

    2014-11-01

    Although opioids are frequently prescribed for chronic noncancer pain (CNCP) among Veterans Health Administration (VHA) patients, little has been reported on national opioid prescribing patterns in the VHA. Our objective was to better characterize the dosing and duration of opioid therapy for CNCP in the VHA. We analyzed national VHA administrative and pharmacy data for fiscal years 2009 to 2011. For individuals with CNCP diagnoses and any opioid use in the fiscal year, we calculated the distribution of individual mean daily opioid dose, individual total days covered with opioids in a year, and individual total opioid dose in a year. We also investigated the factors associated with being in the top 5% of individuals for total opioid dose in a year, which we term receipt of high-volume opioids. About half of the patients with CNCP received opioids in a given fiscal year. The median daily dose was 21 mg morphine equivalents. Approximately 4.5% had a mean daily dose higher than 120 mg morphine equivalents. The median days covered in a year was 115 to 120 days in these years for those receiving opioids. Fifty-seven percent had at least 90 days covered with opioids per year. Major depression and posttraumatic stress disorder were positively associated with receiving high-volume opioids, but nonopioid substance use disorders were not. Among VHA patients with CNCP, chronic opioid therapy occurs frequently, but for most patients, the average daily dose is modest. Doses and duration of therapy were unchanged from 2009 to 2011.

  10. Patterns of opioid use for chronic noncancer pain in the Veterans Health Administration from 2009 to 2011.

    PubMed

    Edlund, Mark J; Austen, Mark A; Sullivan, Mark D; Martin, Bradley C; Williams, James S; Fortney, John C; Hudson, Teresa J

    2014-11-01

    Although opioids are frequently prescribed for chronic noncancer pain (CNCP) among Veterans Health Administration (VHA) patients, little has been reported on national opioid prescribing patterns in the VHA. Our objective was to better characterize the dosing and duration of opioid therapy for CNCP in the VHA. We analyzed national VHA administrative and pharmacy data for fiscal years 2009 to 2011. For individuals with CNCP diagnoses and any opioid use in the fiscal year, we calculated the distribution of individual mean daily opioid dose, individual total days covered with opioids in a year, and individual total opioid dose in a year. We also investigated the factors associated with being in the top 5% of individuals for total opioid dose in a year, which we term receipt of high-volume opioids. About half of the patients with CNCP received opioids in a given fiscal year. The median daily dose was 21 mg morphine equivalents. Approximately 4.5% had a mean daily dose higher than 120 mg morphine equivalents. The median days covered in a year was 115 to 120 days in these years for those receiving opioids. Fifty-seven percent had at least 90 days covered with opioids per year. Major depression and posttraumatic stress disorder were positively associated with receiving high-volume opioids, but nonopioid substance use disorders were not. Among VHA patients with CNCP, chronic opioid therapy occurs frequently, but for most patients, the average daily dose is modest. Doses and duration of therapy were unchanged from 2009 to 2011. PMID:25180008

  11. Opioid administration following spinal cord injury: implications for pain and locomotor recovery.

    PubMed

    Woller, Sarah A; Hook, Michelle A

    2013-09-01

    Approximately one-third of people with a spinal cord injury (SCI) will experience persistent neuropathic pain following injury. This pain negatively affects quality of life and is difficult to treat. Opioids are among the most effective drug treatments, and are commonly prescribed, but experimental evidence suggests that opioid treatment in the acute phase of injury can attenuate recovery of locomotor function. In fact, spinal cord injury and opioid administration share several common features (e.g. central sensitization, excitotoxicity, aberrant glial activation) that have been linked to impaired recovery of function, as well as the development of pain. Despite these effects, the interactions between opioid use and spinal cord injury have not been fully explored. A review of the literature, described here, suggests that caution is warranted when administering opioids after SCI. Opioid administration may synergistically contribute to the pathology of SCI to increase the development of pain, decrease locomotor recovery, and leave individuals at risk for infection. Considering these negative implications, it is important that guidelines are established for the use of opioids following spinal cord and other central nervous system injuries.

  12. Prescription Opioid Use Among Seriously Mentally Ill Veterans Nationally in the Veterans Health Administration.

    PubMed

    Mathew, Nickie; Rosenheck, Robert A

    2016-02-01

    Frequent prescription opioid use has been recognized as a growing problem but there have been no studies specifically among veterans with serious mental illness (SMI). National data from the Veterans Health Administration (VHA) during Fiscal Year 2012 show that VHA patients with SMI receive more opioid prescriptions than other veterans. Additionally, high numbers of opioid prescriptions is associated with greater use of anxiolytics/sedative-hypnotics, drug dependence and COPD-all of which pose an increased risk of respiratory depression and falls and warrant substantial caution and improved coordination between mental health and non-mental health prescribers to evaluate risk-benefit tradeoffs. PMID:26374435

  13. Central amygdala opioid transmission is necessary for increased high-fat intake following 24-h food deprivation, but not following intra-accumbens opioid administration.

    PubMed

    Parker, Kyle E; Johns, Howard W; Floros, Ted G; Will, Matthew J

    2014-03-01

    Previous research has demonstrated a dissociation of certain neural mediators that contribute to the increased consumption of a high-fat diet that follows intra-accumbens (Acb) administration of μ-opioid receptor agonists vs. 24-h food deprivation. These two models, both which induce rapid consumption of the diet, have been shown to involve a distributed corticolimbic circuitry, including the amygdala. Specifically, the central amygdala (CeA) has been shown to be involved in high-fat feeding within both opioid and food-deprivation driven models. The present experiments were conducted to examine the more specific role of CeA opioid transmission in mediating high-fat feeding driven by either intra-Acb administration of the μ-opioid agonist d-Ala2-NMe-Phe4-Glyol5-enkephalin (DAMGO) or 24-h home cage food deprivation. Injection of DAMGO into the Acb (0.25 μg/0.5 μl/side) increased consumption of the high-fat diet, but this feeding was unaffected by administration of opioid antagonist, naltrexone (5 μg/0.25 μl/side) administered into the CeA. In contrast, intra-CeA naltrexone administration attenuated high-fat intake driven by 24-h food deprivation, demonstrating a specific role for CeA opioid transmission in high-fat consumption. Intra-CeA naltrexone administration alone had no effect on baseline feeding levels within either feeding model. These findings suggest that CeA opioid transmission mediates consumption of a palatable high-fat diet driven by short-term negative-energy balance (24-h food deprivation), but not intra-Acb opioid receptor activation.

  14. Effects of fentanyl administration on locomotor response in horses with the G57C μ-opioid receptor polymorphism.

    PubMed

    Wetmore, Lois A; Pascoe, Peter J; Shilo-Benjamini, Yael; Lindsey, Jane C

    2016-08-01

    OBJECTIVE To determine the locomotor response to the administration of fentanyl in horses with and without the G57C polymorphism of the μ-opioid receptor. ANIMALS 20 horses of various breeds and ages (10 horses heterozygous for the G57C polymorphism and 10 age-, breed-, and sex-matched horses that did not have the G57C polymorphism). PROCEDURES The number of steps each horse took was counted over consecutive 2-minute periods for 20 minutes to determine a baseline value. The horse then received a bolus of fentanyl (20 μg/kg, IV), and the number of steps was again counted during consecutive 2-minute periods for 60 minutes. The mean baseline value was subtracted from each 2-minute period after fentanyl administration; step counts with negative values were assigned a value of 0. Data were analyzed by use of a repeated-measures ANOVA. RESULTS Data for 19 of 20 horses (10 horses with the G57C polymorphism and 9 control horses without the G57C polymorphism) were included in the analysis. Horses with the G57C polymorphism had a significant increase in locomotor activity, compared with results for horses without the polymorphism. There was a significant group-by-time interaction. CONCLUSIONS AND CLINICAL RELEVANCE Horses heterozygous for the G57C polymorphism of the μ-opioid receptor had an increased locomotor response to fentanyl administration, compared with the response for horses without this polymorphism. The clinical impact of this finding should be investigated. PMID:27463545

  15. Neonatal Administration of Thimerosal Causes Persistent Changes in Mu Opioid Receptors in the Rat Brain

    PubMed Central

    Olczak, Mieszko; Duszczyk, Michalina; Mierzejewski, Pawel; Bobrowicz, Teresa

    2010-01-01

    Thimerosal added to some pediatric vaccines is suspected in pathogenesis of several neurodevelopmental disorders. Our previous study showed that thimerosal administered to suckling rats causes persistent, endogenous opioid-mediated hypoalgesia. Here we examined, using immunohistochemical staining technique, the density of μ-opioid receptors (MORs) in the brains of rats, which in the second postnatal week received four i.m. injections of thimerosal at doses 12, 240, 1,440 or 3,000 μg Hg/kg. The periaqueductal gray, caudate putamen and hippocampus were examined. Thimerosal administration caused dose-dependent statistically significant increase in MOR densities in the periaqueductal gray and caudate putamen, but decrease in the dentate gyrus, where it was accompanied by the presence of degenerating neurons and loss of synaptic vesicle marker (synaptophysin). These data document that exposure to thimerosal during early postnatal life produces lasting alterations in the densities of brain opioid receptors along with other neuropathological changes, which may disturb brain development. PMID:20803069

  16. 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

  17. Repeated corticosterone administration sensitizes the locomotor response to amphetamine.

    PubMed

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

    1992-07-01

    Repeated exposures to stressful situations has been shown to increase individual reactivity to psychostimulants, although the biological factors involved in such stress-induced changes are still poorly understood. In this study, we investigated the role of corticosterone in the effects of stress on the response to psychostimulants. We found that repeated corticosterone administration (both 1.5 mg/kg, intraperitoneally and 50 micrograms/ml in drinking water, once per day for 15 days) increased the locomotor response to amphetamine (1.15 mg/kg, i.p.). At the doses used in these experiments, corticosterone administration induced similar increases in plasma levels of the hormone to those induced by stress. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress increases the behavioral responses to amphetamine. Since an enhanced reactivity to psychostimulants has been found to be an index of a propensity for drug self-administration and a model of certain psychopathological conditions, these findings point to a role for glucocorticoids in such abnormal states. PMID:1515947

  18. [Long-term administration of opioids for non-tumor pain - LONTS guideline provides an orientation].

    PubMed

    Petzke, Frank

    2015-10-01

    The long-term usage of opioid analgesics (> 3 months) for chronic, non-cancer related pain is critically discussed nationally and internationally. There are indications of under- and oversupply as well as misuse of opioids in Germany, but an "opioid epidemic" such as is evident in the USA cannot be detected at present.The S3-guideline LONTS (long-term usage of opioid analgesics for non-cancer related pain)serves as an orientation to improve provision of opioids and contains statements about the available evidence, indications and contraindications of use, as well as practical recommendations for managing a long-term opioid therapy.

  19. Two cases of intranasal naloxone self-administration in opioid overdose

    PubMed Central

    Green, Traci C.; Ray, Madeline; Bowman, Sarah E.; McKenzie, Michelle; Rich, Josiah D.

    2013-01-01

    Background Overdose is a leading cause of death for former prisoners, exacting its greatest toll during the first 2 weeks post-release. Protective effects have been observed with training individuals at high risk of overdose and prescribing them naloxone, an opioid antagonist that reverses the effects of the opioid-induced respiratory depression that causes death. Cases We report two people with opiate use histories who self-administered intranasal naloxone to treat their own heroin overdoses following release from prison. Patient A is a 34-year-old male, who reported having experienced an overdose on heroin the day after he was released from incarceration. Patient B is a 29-year-old female, who reported an overdose on her first injection of heroin, 17 days post release from incarceration. Both patients self-administered the medication but were assisted at some point during the injury by a witness whom they had personally instructed in how to prepare and administer the medication. Neither patient experienced withdrawal symptoms following exposure to naloxone. Discussion Self-administration of naloxone should not be a goal of overdose death prevention training. A safer, more reliable approach is to prescribe naloxone to at-risk patients and train and also equip members of their household and social or drug using networks in overdose prevention and response. PMID:24821348

  20. μ Opioid Receptor Expression after Morphine Administration Is Regulated by miR-212/132 Cluster.

    PubMed

    Garcia-Concejo, Adrian; Jimenez-Gonzalez, Ada; Rodríguez, Raquel E

    2016-01-01

    Since their discovery, miRNAs have emerged as a promising therapeutical approach in the treatment of several diseases, as demonstrated by miR-212 and its relation to addiction. Here we prove that the miR-212/132 cluster can be regulated by morphine, through the activation of mu opioid receptor (Oprm1). The molecular pathways triggered after morphine administration also induce changes in the levels of expression of oprm1. In addition, miR-212/132 cluster is actively repressing the expression of mu opioid receptor by targeting a sequence in the 3' UTR of its mRNA. These findings suggest that this cluster is closely related to opioid signaling, and function as a post-transcriptional regulator, modulating morphine response in a dose dependent manner. The regulation of miR-212/132 cluster expression is mediated by MAP kinase pathway, CaMKII-CaMKIV and PKA, through the phosphorylation of CREB. Moreover, the regulation of both oprm1 and of the cluster promoter is mediated by MeCP2, acting as a transcriptional repressor on methylated DNA after prolonged morphine administration. This mechanism explains the molecular signaling triggered by morphine as well as the regulation of the expression of the mu opioid receptor mediated by morphine and the implication of miR-212/132 in these processes. PMID:27380026

  1. μ Opioid Receptor Expression after Morphine Administration Is Regulated by miR-212/132 Cluster

    PubMed Central

    Garcia-Concejo, Adrian; Jimenez-Gonzalez, Ada; Rodríguez, Raquel E.

    2016-01-01

    Since their discovery, miRNAs have emerged as a promising therapeutical approach in the treatment of several diseases, as demonstrated by miR-212 and its relation to addiction. Here we prove that the miR-212/132 cluster can be regulated by morphine, through the activation of mu opioid receptor (Oprm1). The molecular pathways triggered after morphine administration also induce changes in the levels of expression of oprm1. In addition, miR-212/132 cluster is actively repressing the expression of mu opioid receptor by targeting a sequence in the 3’ UTR of its mRNA. These findings suggest that this cluster is closely related to opioid signaling, and function as a post-transcriptional regulator, modulating morphine response in a dose dependent manner. The regulation of miR-212/132 cluster expression is mediated by MAP kinase pathway, CaMKII-CaMKIV and PKA, through the phosphorylation of CREB. Moreover, the regulation of both oprm1 and of the cluster promoter is mediated by MeCP2, acting as a transcriptional repressor on methylated DNA after prolonged morphine administration. This mechanism explains the molecular signaling triggered by morphine as well as the regulation of the expression of the mu opioid receptor mediated by morphine and the implication of miR-212/132 in these processes. PMID:27380026

  2. Use of infusion devices for epidural or intrathecal administration of spinal opioids.

    PubMed

    Kwan, J W

    1990-08-01

    The use of infusion devices for epidural or intrathecal administration of spinal opioids is described. The risks of infection and mechanical catheter complications, the need for escalating doses, reservoir volume, drug stability, and cost are practical considerations associated with use of both external and internal infusion systems. Use of patient criteria to identify suitable candidates for intraspinal administration of pain medication helps ensure successful management. The criteria for intraspinal delivery pumps are safety, accuracy, reliability, ease of management by the patient and the health-care professional, and compatibility of the drug with the pump components. The primary factors to consider when comparing pumps to be used for intraspinal delivery of pain medication are the volume and flow rate requirements of the devices. External portable infusion devices are classified according to the mechanism of operation into three primary groups: syringe pumps, peristaltic mechanisms, and elastomeric reservoir pumps. Portable patient-controlled analgesia pumps that have syringes, flexible reservoir bags, and elastomeric reservoirs have been developed. Implanted systems with flow rates that are preset at the factory make pain management more difficult when the patient requires changes or escalations in doses over time. A programmable implanted pump is available. Two advantages of continuous epidural or intrathecal infusion are (1) the peaks and valleys of pain relief with bolus injections are eliminated and (2) the need for multiple injections is reduced. Patient-controlled analgesia (PCA) pumps enhance the efficacy of continuous infusions by allowing the patient to administer bolus doses to control acute pain. PMID:2202209

  3. Impact of Intraoperative Acetaminophen Administration on Postoperative Opioid Consumption in Patients Undergoing Hip or Knee Replacement

    PubMed Central

    Vaughan, Cathy; McGee, Ann

    2014-01-01

    Abstract Background: Opioid utilization for acute pain has been associated with numerous adverse events, potentially resulting in longer inpatient stays and increased costs. Objective: To examine the effect of intravenous (IV) acetaminophen administered intraoperatively on postoperative opioid consumption in adult subjects who underwent hip or knee replacement. Methods: This retrospective cohort study evaluated postoperative opioid consumption in 176 randomly selected adult subjects who underwent hip or knee replacement at Duke University Hospital (DUH). Eighty-eight subjects received a single, intraoperative, 1 g dose of IV acetaminophen. The other subjects did not receive any IV acetaminophen. This study evaluated mean opioid consumption (in oral morphine equivalents) during the 24-hour postoperative period in the 2 groups. Other endpoints included length of stay in the postanesthesia care unit (PACU), incidence of oversedation, need for acute opioid reversal, and adjunctive analgesic utilization. Results: Subjects who were given a single dose of intraoperative acetaminophen received an average of 149.3 mg of oral morphine equivalents during the 24 hours following surgery compared to 147.2 mg in participants who were not exposed to IV acetaminophen (P = .904). The difference in average length of PACU stay between the IV acetaminophen group (163 minutes) and those subjects not exposed to IV acetaminophen (169 minutes) was not statistically significant (P = .588). No subjects in the study experienced oversedation or required acute opioid reversal. Conclusion: There was not a statistically significant difference in postoperative opioid consumption between patients receiving and not receiving IV acetaminophen intraoperatively. PMID:25673891

  4. Nicotine effects and the endogenous opioid system.

    PubMed

    Kishioka, Shiroh; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro

    2014-01-01

    Nicotine (NIC) is an exogenous ligand of the nicotinic acetylcholine receptor (nAChR), and it influences various functions in the central nervous system. Systemic administration of NIC elicits the release of endogenous opioids (endorphins, enkephalins, and dynorphins) in the supraspinal cord. Additionally, systemic NIC administration induces the release of methionine-enkephalin in the spinal dorsal horn. NIC has acute neurophysiological actions, including antinociceptive effects, and the ability to activate the hypothalamic-pituitary-adrenal (HPA) axis. The endogenous opioid system participates in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception is mediated by α4β2 and α7 nAChRs, while NIC-induced HPA axis activation is mediated by α4β2, not α7, suggesting that the effects of NIC on the endogenous opioid system are mediated by α7, not α4β2. NIC has substantial physical dependence liability. The opioid-receptor antagonist naloxone (NLX) elicits NIC withdrawal after repeated NIC administration, and NLX-induced NIC withdrawal is inhibited by concomitant administration of an opioid-receptor antagonist. NLX-induced NIC withdrawal is also inhibited by concomitant administration of an α7 antagonist, but not an α4β2 antagonist. Taken together, these findings suggest that NIC-induced antinociception and the development of physical dependence are mediated by the endogenous opioid system, via the α7 nAChR.

  5. Nicotine effects and the endogenous opioid system.

    PubMed

    Kishioka, Shiroh; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro

    2014-01-01

    Nicotine (NIC) is an exogenous ligand of the nicotinic acetylcholine receptor (nAChR), and it influences various functions in the central nervous system. Systemic administration of NIC elicits the release of endogenous opioids (endorphins, enkephalins, and dynorphins) in the supraspinal cord. Additionally, systemic NIC administration induces the release of methionine-enkephalin in the spinal dorsal horn. NIC has acute neurophysiological actions, including antinociceptive effects, and the ability to activate the hypothalamic-pituitary-adrenal (HPA) axis. The endogenous opioid system participates in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception is mediated by α4β2 and α7 nAChRs, while NIC-induced HPA axis activation is mediated by α4β2, not α7, suggesting that the effects of NIC on the endogenous opioid system are mediated by α7, not α4β2. NIC has substantial physical dependence liability. The opioid-receptor antagonist naloxone (NLX) elicits NIC withdrawal after repeated NIC administration, and NLX-induced NIC withdrawal is inhibited by concomitant administration of an opioid-receptor antagonist. NLX-induced NIC withdrawal is also inhibited by concomitant administration of an α7 antagonist, but not an α4β2 antagonist. Taken together, these findings suggest that NIC-induced antinociception and the development of physical dependence are mediated by the endogenous opioid system, via the α7 nAChR. PMID:24882143

  6. Erasure of a spinal memory trace of pain by a brief, high-dose opioid administration.

    PubMed

    Drdla-Schutting, Ruth; Benrath, Justus; Wunderbaldinger, Gabriele; Sandkühler, Jürgen

    2012-01-13

    Painful stimuli activate nociceptive C fibers and induce synaptic long-term potentiation (LTP) at their spinal terminals. LTP at C-fiber synapses represents a cellular model for pain amplification (hyperalgesia) and for a memory trace of pain. μ-Opioid receptor agonists exert a powerful but reversible depression at C-fiber synapses that renders the continuous application of low opioid doses the gold standard in pain therapy. We discovered that brief application of a high opioid dose reversed various forms of activity-dependent LTP at C-fiber synapses. Depotentiation involved Ca(2+)-dependent signaling and normalization of the phosphorylation state of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This also reversed hyperalgesia in behaving animals. Opioids thus not only temporarily dampen pain but may also erase a spinal memory trace of pain.

  7. Life-threatening adverse events following therapeutic opioid administration in adults: Is pharmacogenetic analysis useful?

    PubMed Central

    Madadi, Parvaz; Sistonen, Johanna; Silverman, Gregory; Gladdy, Rebecca; Ross, Colin J; Carleton, Bruce C; Carvalho, Jose C; Hayden, Michael R; Koren, Gideon

    2013-01-01

    BACKGROUND: Systemic approaches are needed to understand how variations in the genes associated with opioid pharmacokinetics and response can be used to predict patient outcome. The application of pharmacogenetic analysis to two cases of life-threatening opioid-induced respiratory depression is presented. The usefulness of genotyping in the context of these cases is discussed. METHODS: A panel of 20 functional candidate polymorphisms in genes involved in the opioid biotransformation pathway (CYP2D6, UGT2B7, ABCB1, OPRM1, COMT) were genotyped in these two patients using commercially available genotyping assays. RESULTS: In case 1, the patient experienced adverse outcomes when administered codeine and morphine, but not hydromorphone. Genetic test results suggested that this differential response may be due to an inherent propensity to generate active metabolites from both codeine and morphine. These active metabolites are not generated with hydromorphone. In case 2, the patient experienced severe respiratory depression during postoperative recovery following standard doses of morphine. The patient was found to carry genetic variations that result in decreased morphine efflux transporter activity at the blood-brain barrier and increased sensitivity to opioids. CONCLUSIONS: Knowledge of the relative contribution of pharmacogenetic biomarkers and their influence on opioid response are continually evolving. Pharmacogenetic analysis, together with clinical history, has the potential to provide mechanistic insight into severe respiratory depressive events in patients who receive opioids at therapeutic doses. PMID:23748253

  8. Effects of Acute and Repeated Administration of Oxycodone and Naloxone-Precipitated Withdrawal on Intracranial Self-Stimulation in Rats.

    PubMed

    Wiebelhaus, Jason M; Walentiny, D Matthew; Beardsley, Patrick M

    2016-01-01

    Incidence of prescription opioid abuse and overdose, often led by oxycodone, continues to increase, producing twice as many overdose deaths as heroin. Surprisingly, preclinical reports relevant to oxycodone's abuse-related effects are relatively sparse considering its history and patient usage. The goal of this study was to characterize dose- and time-dependent effects of acute and repeated oxycodone administration in a frequency-rate intracranial self-stimulation (ICSS) procedure, an assay often predictive of drug-related reinforcing effects, in male Sprague-Dawley rats. We hypothesized that oxycodone would produce a biphasic profile of rate-increasing and rate-decreasing effects maintained by ICSS similar to μ-opioid receptor agonists. Oxycodone (0.03, 0.3, 1, and 3 mg/kg, s.c.) produced dose- and time-dependent alterations on ICSS, with the predicted biphasic profile of rate-increasing effects at lower stimulation frequencies followed by rate-decreasing effects at higher frequencies. Peak effects were observed between 30 and 60 minutes, which were reversed by naloxone pretreatment (30 minutes). Tolerance to rate-decreasing effects was observed over a 5-day period when rats were treated with 1 mg/kg oxycodone twice a day. Subsequently, the dosing regimen was increased to 3 mg/kg twice a day over 10 days, although further marked tolerance did not develop. When then challenged with 10 mg/kg naloxone, a significant suppression below baseline levels of ICSS-maintained responding occurred indicative of dependence that recovered to baseline within 5 hours. The results of this study provide the first report of acute and chronic effects of oxycodone on responding maintained by ICSS presentation and the use of ICSS-maintained responding to characterize its tolerance and dependence effects.

  9. Mu-opioid receptor activation in the medial shell of nucleus accumbens promotes alcohol consumption, self-administration and cue-induced reinstatement.

    PubMed

    Richard, Jocelyn M; Fields, Howard L

    2016-09-01

    Endogenous opioid signaling in ventral cortico-striatal-pallidal circuitry is implicated in elevated alcohol consumption and relapse to alcohol seeking. Mu-opioid receptor activation in the medial shell of the nucleus accumbens (NAc), a region implicated in multiple aspects of reward processing, elevates alcohol consumption while NAc opioid antagonists reduce it. However, the precise nature of the increases in alcohol consumption, and the effects of mu-opioid agonists on alcohol seeking and relapse are not clear. Here, we tested the effects of the mu-opioid agonist [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin (DAMGO) in rat NAc shell on lick microstructure in a free-drinking test, alcohol seeking during operant self-administration, extinction learning and expression, and cue-reinforced reinstatement of alcohol seeking. DAMGO enhanced the number, but not the size of drinking bouts. DAMGO also enhanced operant alcohol self-administration and cue-induced reinstatement, but did not affect extinction learning or elicit reinstatement in the absence of cues. Our results suggest that mu-opioid agonism in NAc shell elevates alcohol consumption, seeking and conditioned reinforcement primarily by enhancing the incentive motivational properties of alcohol and alcohol-paired cues, rather than by modulating palatability, satiety, or reinforcement. PMID:27089981

  10. Antinociception induced by acute oral administration of sweet substance in young and adult rodents: the role of endogenous opioid peptides chemical mediators and μ(1)-opioid receptors.

    PubMed

    de Freitas, Renato Leonardo; Kübler, João Marcus Lopes; Elias-Filho, Daoud Hibraim; Coimbra, Norberto Cysne

    2012-04-01

    The present work aimed to investigate the effects of acute sucrose treatment on the perception of painful stimuli. Specifically, we sought to determine the involvement of the endogenous opioid peptide-mediated system as well as the role of the μ(1)-opioid receptor in antinociception organisation induced by acute sucrose intake. Nociception was assessed with the tail-flick test in rats (75, 150 and 250 g) of different ages acutely pre-treated with 500 μL of a sucrose solution (25, 50, 150 and 250 g/L) or tap water. Young and Adult rats (250 g) showed antinociception after treatment with 50 g/L (during 5 min) and 150 g/L and 250 g/L (during 20 min) sucrose solutions. Surprisingly, this antinociception was more consistent in mature adult rodents than in pups. To evaluate the role of opioid systems, mature adult rodents were pre-treated with different doses (0.25, 1 or 4 mg/kg) of the non-selective opioid receptor antagonist naloxone, the selective μ(1)-opioid receptor antagonist naloxonazine or vehicle followed by 250 g/L sucrose solution treatment. Sucrose-induced antinociception was reduced by pre-treatment with both naloxone and naloxonazine. The present findings suggest that sweet substance-induced hypo-analgesia is augmented by increasing sucrose concentrations in young and adult rodents. Acute oral sucrose treatment inhibits pain in laboratory animal by mediating endogenous opioid peptide and μ(1)-opioid receptor actions.

  11. Repeated administration of fresh garlic increases memory retention in rats.

    PubMed

    Haider, Saida; Naz, Nosheen; Khaliq, Saima; Perveen, Tahira; Haleem, Darakhshan J

    2008-12-01

    Garlic (Allium sativum) is regarded as both a food and a medicinal herb. Increasing attention has focused on the biological functions and health benefits of garlic as a potentially major dietary component. Chronic garlic administration has been shown to enhance memory function. Evidence also shows that garlic administration in rats affects brain serotonin (5-hydroxytryptamine [5-HT]) levels. 5-HT, a neurotransmitter involved in a number of physiological functions, is also known to enhance cognitive performance. The present study was designed to investigate the probable neurochemical mechanism responsible for the enhancement of memory following garlic administration. Sixteen adult locally bred male albino Wistar rats were divided into control (n = 8) and test (n = 8) groups. The test group was orally administered 250 mg/kg fresh garlic homogenate (FGH), while control animals received an equal amount of water daily for 21 days. Estimation of plasma free and total tryptophan (TRP) and whole brain TRP, 5-HT, and 5-hydroxyindole acetic acid (5-HIAA) was determined by high-performance liquid chromatography with electrochemical detection. For assessment of memory, a step-through passive avoidance paradigm (electric shock avoidance) was used. The results showed that the levels of plasma free TRP significantly increased (P < .01) and plasma total TRP significantly decreased (P < .01) in garlic-treated rats. Brain TRP, 5-HT, and 5-HIAA levels were also significantly increased following garlic administration. A significant improvement in memory function was exhibited by garlic-treated rats in the passive avoidance test. Increased brain 5-HT levels were associated with improved cognitive performance. The present results, therefore, demonstrate that the memory-enhancing effect of garlic may be associated with increased brain 5-HT metabolism in rats. The results further support the use of garlic as a food supplement for the enhancement of memory. PMID:19053859

  12. Synthesis of mixed MOR/KOR efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration.

    PubMed

    Perlikowska, Renata; Piekielna, Justyna; Gentilucci, Luca; De Marco, Rossella; Cerlesi, Maria Camilla; Calo, Girolamo; Artali, Roberto; Tömböly, Csaba; Kluczyk, Alicja; Janecka, Anna

    2016-02-15

    Cyclic pentapeptide Tyr-c[D-Lys-Phe-Phe-Asp]NH2, based on the structure of endomorphin-2 (EM-2), which shows high affinity to the μ-opioid receptor (MOR) and a very strong antinociceptive activity in mice was used as a parent compound for the structure-activity relationship studies. In this report we synthesized analogs of a general sequence Dmt-c[D-Lys-Xaa-Yaa-Asp]NH2, with D-1- or D-2-naphthyl-3-alanine (D-1-Nal or D-2-Nal) in positions 3 or 4. In our earlier papers we have indicated that replacing a phenylalanine residue by the more extended aromatic system of naphthylalanines may result in increased bioactivities of linear analogs. The data obtained here showed that only cyclopeptides modified in position 4 retained the sub-nanomolar MOR and nanomolar κ-opioid receptor (KOR) affinity, similar but not better than that of a parent cyclopeptide. In the in vivo mouse hot-plate test, the most potent analog, Dmt-c[D-Lys-Phe-D-1-Nal-Asp]NH2, exhibited higher than EM-2 but slightly lower than the cyclic parent peptide antinociceptive activity after peripheral (ip) and also central administration (icv). Conformational analyses in a biomimetic environment and molecular docking studies disclosed the structural determinants responsible for the different pharmacological profiles of position 3- versus position 4-modified analogs. PMID:26785295

  13. Association of Opioids and Sedatives with Increased Risk of In-Hospital Cardiopulmonary Arrest from an Administrative Database

    PubMed Central

    Overdyk, Frank J.; Dowling, Oonagh; Marino, Joseph; Qiu, Jiejing; Chien, Hung-Lun; Erslon, Mary; Morrison, Neil; Harrison, Brooke; Dahan, Albert; Gan, Tong J.

    2016-01-01

    Background While opioid use confers a known risk for respiratory depression, the incremental risk of in-hospital cardiopulmonary arrest, respiratory arrest, or cardiopulmonary resuscitation (CPRA) has not been studied. Our aim was to investigate the prevalence, outcomes, and risk profile of in-hospital CPRA for patients receiving opioids and medications with central nervous system sedating side effects (sedatives). Methods A retrospective analysis of adult inpatient discharges from 2008–2012 reported in the Premier Database. Patients were grouped into four mutually exclusive categories: (1) opioids and sedatives, (2) opioids only, (3) sedatives only, and (4) neither opioids nor sedatives. Results Among 21,276,691 inpatient discharges, 53% received opioids with or without sedatives. A total of 96,554 patients suffered CPRA (0.92 per 1000 hospital bed-days). Patients who received opioids and sedatives had an adjusted odds ratio for CPRA of 3.47 (95% CI: 3.40–3.54; p<0.0001) compared with patients not receiving opioids or sedatives. Opioids alone and sedatives alone were associated with a 1.81-fold and a 1.82-fold (p<0.0001 for both) increase in the odds of CPRA, respectively. In opioid patients, locations of CPRA were intensive care (54%), general care floor (25%), and stepdown units (15%). Only 42% of patients survived CPRA and only 22% were discharged home. Opioid patients with CPRA had mean increased hospital lengths of stay of 7.57 days and mean increased total hospital costs of $27,569. Conclusions Opioids and sedatives are independent and additive risk factors for in-hospital CPRA. The impact of opioid sparing analgesia, reduced sedative use, and better monitoring on CPRA incidence deserves further study. PMID:26913753

  14. An unusual case of homicide by use of repeated administration of organophosphate insecticides.

    PubMed

    De Letter, E A; Cordonnier, J A C M; Piette, M H A

    2002-03-01

    We present an unusual murder case by use of repeated administration of organophosphate insecticides. A 49-year-old woman suffering from mental retardation, epileptic fits and acromegaly was poisoned by her husband. At first, her death was considered as a 'sudden and unexpected' natural death. Abdominal abscesses of pancreatic origin found at autopsy were compatible with repeated administration of pesticides with anticholinergic action. In her medical history at least one episode consistent with an organophosphate intoxication was retrieved. Thorough inquiry revealed that the victim had ingested phosphamidon and/or omethoate orally. Organophosphate intoxication should be considered when unexplained neurological symptoms are associated with pancreatic disturbances.

  15. Alterations in serum osmolality, sodium, and potassium levels after repeated mannitol administration.

    PubMed

    Seo, WhaSook; Oh, HyunSoo

    2010-08-01

    This study was undertaken to evaluate whether significant alterations in serum osmolality, [Na+], and [K+] occur after the repeated dosing of mannitol and whether these imbalances increased accordingly with the progress of mannitol application. This study was conducted by performing a retrospective medical record review of brain injury patients who were admitted to the neurological intensive care units of a university hospital located in Incheon, South Korea. Data on intracranial pressure and serum [Na+], [K+], and osmolality levels were collected from the first to the seventh day of mannitol administration. Our results showed that the highest rate of hyperosmolality occurred on the first day of mannitol administration and that subsequently its rate reduced, although it still maintained high (70-77%). Regarding the serum [Na+], hypernatremia was observed in 10% of the subjects on the first day of mannitol administration and in 10-21% throughout the 7-day mannitol administration period. In this study, hyponatremia was observed in 12.2% of our subjects on the first day of mannitol administration and in 9-24% throughout the 7-day period. In addition, no statistical differences were found between changes in the rates of hypernatremia and hyponatremia throughout the 7-day administration period. The most notable finding was the high rates of hypokalemia observed during mannitol administration. Hypokalemia was observed in 22% of subjects on the first day and continuously increased to 52.3%, and this increase was significant. On the other hand, the rate of hyperkalemia was almost negligible. Our findings appear to provide clear evidence of electrolyte imbalances after repeated mannitol administration. Accordingly, careful monitoring of electrolyte status is essential when repeated doses of mannitol are given. We recommend that the practice of administering repeated dose of mannitol for prophylactic purposes be reevaluated.

  16. ACCUMULATION AND METABOLISM OF ARSENIC IN MICE AFTER REPEATED ADMINISTRATION OF ARSENATE

    EPA Science Inventory

    Accumulation and metabolism of arsenic in mice after repeated oral administration of arsenate, Hughes, M. F., Kenyon, E. M., Edwards, B. C., Mitchell, C. T., Del Razo, L. M., and Thomas,
    D. J.

    The human carcinogen inorganic arsenic (iAs) is a pervasive environmental ...

  17. COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE

    EPA Science Inventory

    COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE
    Michael F. Hughes*1, Elaina M. Kenyon1, Brenda C. Edwards1, Carol T. Mitchell1, Luz Maria Del Razo2 and David J. Thomas1
    1US EPA, ORD, NHEERL, ETD, PKB, Research Triangle Pa...

  18. Repeated Post- or Presession Cocaine Administration: Roles of Dose and Fixed-Ratio Schedule

    ERIC Educational Resources Information Center

    Pinkston, Jonathan W.; Branch, Marc N.

    2004-01-01

    Effects of repeated administration of cocaine to animals behaving under operant contingencies have depended on when the drug is given. Moderate doses given presession have generally led to a decrease in the drug's effect, an outcome usually referred to as tolerance. When these same doses have been given after sessions, the usual result has been no…

  19. The macrocyclic tetrapeptide [D-Trp]CJ-15,208 produces short-acting κ opioid receptor antagonism in the CNS after oral administration

    PubMed Central

    Eans, Shainnel O; Ganno, Michelle L; Reilley, Kate J; Patkar, Kshitij A; Senadheera, Sanjeewa N; Aldrich, Jane V; McLaughlin, Jay P

    2013-01-01

    Background and Purpose Cyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic κ opioid receptor (KOR)-selective antagonist [D-Trp]CJ-15,208 would demonstrate antagonist activity after systemic, that is, s.c. and oral (per os, p. o.), administration. Experimental Approach C57BL/6J mice were pretreated with [D-Trp]CJ-15,208 s.c. or p.o. before administration of the KOR-selective agonist U50,488 and the determination of antinociception in the warm-water tail-withdrawal assay. The locomotor activity of mice treated with [D-Trp]CJ-15,208 was determined by rotorod testing. Additional mice demonstrating cocaine conditioned place preference and subsequent extinction were pretreated daily with vehicle or [D-Trp]CJ-15,208 and then exposed to repeated forced swim stress or a single additional session of cocaine place conditioning before redetermining place preference. Key Results Pretreatment with [D-Trp]CJ-15,208 administered s.c. or p.o. dose-dependently antagonized the antinociception induced by i.p. administration of U50,488 in mice tested in the warm-water tail-withdrawal assay for less than 12 and 6 h respectively. [D-Trp]CJ-15,208 also produced limited (<25%), short-duration antinociception mediated through KOR agonism. Orally administered [D-Trp]CJ-15,208 dose-dependently antagonized centrally administered U50,488-induced antinociception, and prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine-seeking behaviour, consistent with its KOR antagonist activity, without affecting locomotor activity. Conclusions and Implications The macrocyclic tetrapeptide [D-Trp]CJ-15,208 is a short-duration KOR antagonist with weak KOR agonist activity that is active after oral administration and demonstrates blood–brain barrier permeability. These data validate the use of systemically active peptides such as [D-Trp]CJ-15,208 as potentially useful

  20. The effects of repeated parenteral administration of chelating agents on the distribution and excretion of uranium

    SciTech Connect

    Domingo, J.L.; Ortega, A.; Llobet, J.M.; Paternain, J.L.; Corbella, J.

    1989-04-01

    The effects of repeated ip administration of gallic acid, 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron), diethylenetriaminepentaacetic acid (DTPA), and 5-aminosalicylic acid (5-AS) on the distribution and excretion of uranium were assessed in male Swiss mice. Only Tiron significantly increased the amount of uranium excreted into urine and feces. A significant decrease in the concentration of uranium in liver, spleen and bone was observed after administration of Tiron, whereas injection of gallic acid or DTPA resulted in a significant decrease in the concentration of the metal in the liver. The results show that Tiron was consistently the most effective chelator of those tested in the treatment of uranium poisoning after repeated daily administration of the metal.

  1. Repeated post- or presession cocaine administration: roles of dose and fixed-ratio schedule.

    PubMed Central

    Pinkston, Jonathan W; Branch, Marc N

    2004-01-01

    Effects of repeated administration of cocaine to animals behaving under operant contingencies have depended on when the drug is given. Moderate doses given presession have generally led to a decrease in the drug's effect, an outcome usually referred to as tolerance. When these same doses have been given after sessions, the usual result has been no change or an increase in the drug's effects, with the latter usually referred to as sensitization. In the present study, repeated postsession administration of a relatively small dose of cocaine (3.0 or 5.6 mg/kg) to pigeons responding under a multiple fixed-ratio 5, fixed-ratio 100 schedule of food presentation generally resulted in tolerance to the rate-decreasing effects of the drug. When the same dose was given before sessions, little additional tolerance was observed, although some subjects showed further tolerance in the small-ratio component. A regimen of repeated postsession injection of larger (10.0-23.0 mg/kg) doses suppressed key pecking during the session; responding resumed following discontinuation of postsession administrations. Effects of postsession administration of cocaine, therefore, depended on the dose, with smaller doses leading to tolerance and larger ones to suppression of behavior during the session. Effects of postsession drug administration of either small or large doses were not related to whether effects of postsession drug were experienced mainly in the operant test chamber or in the pigeon's home cage. The results with large postsession doses are compatible with a view that the drug acted as a Pavlovian unconditional stimulus, with the session-related stimuli acting as a long-duration Pavlovian conditional stimulus. Tolerance following postsession administration of the smaller doses challenges the view that it depended on experiencing the drug's effects while the arranged reinforcement contingencies were in effect. PMID:15239491

  2. Elimination of progressive mammary cancer by repeated administrations of chimeric antigen receptor-modified T cells.

    PubMed

    Globerson-Levin, Anat; Waks, Tova; Eshhar, Zelig

    2014-05-01

    Continuous oncogenic processes that generate cancer require an on-going treatment approach to eliminate the transformed cells, and prevent their further development. Here, we studied the ability of T cells expressing a chimeric antibody-based receptor (CAR) to offer a therapeutic benefit for breast cancer induced by erbB-2. We tested CAR-modified T cells (T-bodies) specific to erbB-2 for their antitumor potential in a mouse model overexpressing a human erbB-2 transgene that develops mammary tumors. Comparing the antitumor reactivity of CAR-modified T cells under various therapeutic settings, either prophylactic, prior to tumor development, or therapeutically. We found that repeated administration of CAR-modified T cells is required to eliminate spontaneously developing mammary cancer. Systemic, as well as intratumoral administered CAR-modified T cells accumulated at tumor sites and eventually eliminated the malignant cells. Interestingly, within a few weeks after a single CAR T cells' administration, and rejection of primary lesion, tumors usually relapsed both in treated mammary gland and at remote sites; however, repeated injections of CAR-modified T cells were able to control the secondary tumors. Since spontaneous tumors can arise repeatedly, especially in the case of syndromes characterized by specific susceptibility to cancer, multiple administrations of CAR-modified T cells can serve to control relapsing disease.

  3. The pharmacological basis of opioids.

    PubMed

    Ghelardini, Carla; Di Cesare Mannelli, Lorenzo; Bianchi, Enrica

    2015-01-01

    An opioid is a chemical that binds to opioid receptors, which are widely distributed in the central and peripheral nervous system and gastrointestinal tract. The different effects elicited by activation of these receptors are due to their specific neuronal and extraneuronal distribution. The painkiller effect of opioids is induced by the synergy of the two events, namely reduction of pain threshold and emotional detachment from pain. The opioid effects transcending analgesia include sedation, respiratory depression, constipation and a strong sense of euphoria. There are opioid-like substances endogenously produced by the body. Naturally occurring peptides, called enkephalins, have opioid-like activities but are not derived from opium and exert opioid-like effects by interacting with opioid receptors on cell membranes. Yet, animals do contain the same morphine precursors and metabolites as opium poppy and are able to synthesize endogenous morphine alkaloid. Experimental and clinical studies show that opioids, at doses comparable to those of endogenous opioids, can activate pronociceptive systems, leading to pain hypersensitivity and short-term tolerance, a phenomenon encountered in postoperative pain management by acute opioid administration. Whether endogenous opioids play a role in the acute pain necessary to the survival of the individual, remains an open question. PMID:26811699

  4. Pharmacogenomic considerations in opioid analgesia

    PubMed Central

    Vuilleumier, Pascal H; Stamer, Ulrike M; Landau, Ruth

    2012-01-01

    Translating pharmacogenetics to clinical practice has been particularly challenging in the context of pain, due to the complexity of this multifaceted phenotype and the overall subjective nature of pain perception and response to analgesia. Overall, numerous genes involved with the pharmacokinetics and dynamics of opioids response are candidate genes in the context of opioid analgesia. The clinical relevance of CYP2D6 genotyping to predict analgesic outcomes is still relatively unknown; the two extremes in CYP2D6 genotype (ultrarapid and poor metabolism) seem to predict pain response and/or adverse effects. Overall, the level of evidence linking genetic variability (CYP2D6 and CYP3A4) to oxycodone response and phenotype (altered biotransformation of oxycodone into oxymorphone and overall clearance of oxycodone and oxymorphone) is strong; however, there has been no randomized clinical trial on the benefits of genetic testing prior to oxycodone therapy. On the other hand, predicting the analgesic response to morphine based on pharmacogenetic testing is more complex; though there was hope that simple genetic testing would allow tailoring morphine doses to provide optimal analgesia, this is unlikely to occur. A variety of polymorphisms clearly influence pain perception and behavior in response to pain. However, the response to analgesics also differs depending on the pain modality and the potential for repeated noxious stimuli, the opioid prescribed, and even its route of administration. PMID:23226064

  5. Repeated REM sleep deprivation after chronic haloperidol administration in the rat.

    PubMed

    Salín-Pascual, R J; García-Ferreiro, R; Moro-López, M L; Blanco-Centurión, C; Drucker-Colín, R

    1997-06-01

    Repeated haloperidol administration produces up-regulation of dopamine (DA) receptors. REM sleep deprivation (REMSD) does also, but in addition, has been shown to produce REM sleep rebound. Should DA receptor up-regulation play a role in REM sleep rebound, haloperidol could conceivably have effects similar to those observed following REMSD. This is the central question investigated in this study. Male Wistar rats were prepared for sleep recordings. They were randomly assigned to the following groups: group 1, REMSD by small platforms (40 h REMSD + 8 h recording); group 2, was the large platform control group (40 h in large platforms + 8 h of recording); group 3, received 2-week daily administration of haloperidol (3 mg/kg, i.p.) plus REMSD (40 h REMSD + 8 h of recording); group 4, 2-week administration of haloperidol (3 mg/kg) without sleep manipulation and at the end 40 h were allowed to elapse, following which 8 h of sleep recordings was carried out. In each group the sleep manipulation and/or sleep recordings were repeated five consecutive times. Repeated REMSD produced increases of REM sleep time after each recovery in group 1. Large platforms did not produce increases of REM sleep during the recovery trials. The 2-week administration of haloperidol plus REMSD prevented REM sleep rebound (group 3). The 2-week administration of haloperidol without sleep manipulation (group 4) produced a REM sleep reduction. Dopamine modulation seems not to be important for REM sleep rebound. Hypersensitivity of DA receptors developed after REMSD may be an epiphenomenon associated with this sleep manipulation, but seems not to participate in REM sleep enhancement after REMSD.

  6. 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

  7. Prescription Opioids. IV: Disposition of Hydrocodone in Oral Fluid and Blood Following Single-Dose Administration.

    PubMed

    Cone, Edward J; DePriest, Anne Z; Heltsley, Rebecca; Black, David L; Mitchell, John M; LoDico, Charles; Flegel, Ron

    2015-09-01

    The Substance Abuse and Mental Health Services Administration (SAMHSA) is currently evaluating hydrocodone (HC) for inclusion in the Mandatory Guidelines for Federal Workplace Drug Testing Programs. This study evaluated the time course of HC, norhydrocodone (NHC), dihydrocodeine (DHC) and hydromorphone (HM) in paired oral fluid and whole blood specimens by liquid chromatography-tandem mass spectrometry (limit of quantitation = 1 ng/mL of oral fluid, 5 ng/mL of blood) over a 52-h period. A single dose of HC bitartrate, 20 mg, was administered to 12 subjects. Analyte prevalence was as follows: oral fluid, HC > NHC > DHC; and blood, HC > NHC. HM was not detected in any specimen. HC was frequently detected within 15 min in oral fluid and 30 min in blood. Mean oral fluid to blood (OF : BL) ratios and correlations were 3.2 for HC (r = 0.73) and 0.7 for NHC (r = 0.42). The period of detection for oral fluid exceeded blood at all evaluated thresholds. At a 1-ng/mL threshold for oral fluid, mean detection time was 30 h for HC and 18 h for NHC and DHC. This description of HC and metabolite disposition in oral fluid following single-dose administration provides valuable interpretive guidance of HC test results.

  8. Prescription Opioids. IV: Disposition of Hydrocodone in Oral Fluid and Blood Following Single-Dose Administration.

    PubMed

    Cone, Edward J; DePriest, Anne Z; Heltsley, Rebecca; Black, David L; Mitchell, John M; LoDico, Charles; Flegel, Ron

    2015-09-01

    The Substance Abuse and Mental Health Services Administration (SAMHSA) is currently evaluating hydrocodone (HC) for inclusion in the Mandatory Guidelines for Federal Workplace Drug Testing Programs. This study evaluated the time course of HC, norhydrocodone (NHC), dihydrocodeine (DHC) and hydromorphone (HM) in paired oral fluid and whole blood specimens by liquid chromatography-tandem mass spectrometry (limit of quantitation = 1 ng/mL of oral fluid, 5 ng/mL of blood) over a 52-h period. A single dose of HC bitartrate, 20 mg, was administered to 12 subjects. Analyte prevalence was as follows: oral fluid, HC > NHC > DHC; and blood, HC > NHC. HM was not detected in any specimen. HC was frequently detected within 15 min in oral fluid and 30 min in blood. Mean oral fluid to blood (OF : BL) ratios and correlations were 3.2 for HC (r = 0.73) and 0.7 for NHC (r = 0.42). The period of detection for oral fluid exceeded blood at all evaluated thresholds. At a 1-ng/mL threshold for oral fluid, mean detection time was 30 h for HC and 18 h for NHC and DHC. This description of HC and metabolite disposition in oral fluid following single-dose administration provides valuable interpretive guidance of HC test results. PMID:25962610

  9. Pharmacokinetics of marbofloxacin after single intravenous and repeat oral administration to cats.

    PubMed

    Albarellos, G A; Montoya, L; Landoni, M F

    2005-09-01

    The pharmacokinetic properties of marbofloxacin, a third generation fluoroquinolone, were investigated in six cats after single intravenous (IV) and repeat oral (PO) administration at a daily dose of 2 mg/kg. Marbofloxacin serum concentration was analysed by microbiological assay using Klebsiella pneumoniae ATCC 10031 as micro-organism test. Serum marbofloxacin disposition was best described by bicompartmental and mono-compartmental open models with first-order elimination after IV and oral dosing respectively. After IV administration, distribution was rapid (T(1/2(d)) 0.23+/-0.24 h) and wide, as reflected by the steady-state volume of distribution of 1.01+/-0.15 L/kg. Elimination from the body was slow with a body clearance of 0.09+/-0.02 L/h kg and a T(1/2) of 7.98+/-0.57 h. After repeat oral administration, absorption half-life was 0.86+/-1.59 h and T(max) of 1.94+/-2.11 h. Bioavailability was almost complete (99+/-29%) with a peak plasma concentration at the steady-state of 1.97+/-0.61 mug/mL. Drug accumulation was not significant after six oral administrations. Calculation of efficacy predictors showed that marbofloxacin has good therapeutic profile against Gram-negative and Gram-positive bacteria with a MIC(50) value <0.25 microg/mL.

  10. Effect of repeated oral administration on taurocholate on hepatic excretory function in the rat.

    PubMed

    Watkins, J B; Klaassen, C D

    1981-07-01

    The effect of repeated administration of taurocholate on bile acid pool size, biliary composition and biliary excretory capacity for bile acids and two xenobiotics was determined. The bile acid pool was increased 50 to 60% by oral administration of sodium taurocholate (300--900 mg/kg, 10 ml/kg) every 12 hr for 2 days to male Sprague-Dawley rats. Bile flow, biliary excretion of bile acids, cholesterol and phospholipid and the concentrations of phospholipid and bile acids in bile were increased in rats treated with 750 mg of taurocholate per kg. No effect was observed on Na+,K+ or Cl- levels. The biliary transport maximum for taurocholate was increased by 30% in rats treated with 750 mg/kg. In contrast, the plasma disappearance and biliary excretion of phenol-3,6-dibromphthalein and ouabain were not affected by taurocholate administration.

  11. Varenicline impairs extinction and enhances reinstatement across repeated cycles of nicotine self-administration in rats.

    PubMed

    Macnamara, Claire L; Holmes, Nathan M; Westbrook, R Fred; Clemens, Kelly J

    2016-06-01

    Varenicline is a partial nicotine receptor agonist widely prescribed as a smoking cessation medication. Repeated (or long-term) use of varenicline has been proposed as a treatment option for tobacco addiction. However the effect of repeated varenicline use on motivation for nicotine is unknown. Here the intravenous nicotine self-administration paradigm in rats was used to model the consequences of varenicline treatment across repeated cycles of administration, extinction and reinstatement. Rats acquired nicotine self-administration across 20 days before undergoing 6 days of extinction, where each extinction session was preceded by a single injection of varenicline or saline. This was followed by a single varenicline-free nicotine-primed reinstatement test. All rats then reacquired nicotine self-administration for 10 days followed by a second cycle of extinction. Across this period, rats either received a second cycle of varenicline (VAR-VAR) or saline (SAL-SAL), or the alternative treatment (SAL-VAR, VAR-SAL), followed by a final reinstatement test. Treatment with varenicline increased responding across the first cycle of extinction, but did not affect responding in the reinstatement test. Across the second cycle, varenicline again increased responding across extinction, and critically, rats treated with varenicline across cycle 1 and saline across cycle 2 (Group VAR-SAL) exhibited more reinstatement than rats in any other group. The effect of VAR on nicotine seeking was not due to its effects on locomotor activity. Instead, the results suggest that a history of VAR can increase vulnerability to reinstatement/relapse when its treatment is discontinued. The possible mechanisms of this increased vulnerability are discussed.

  12. Sex differences in behavioral and PKA cascade responses to repeated cocaine administration.

    PubMed

    Zhou, Luyi; Sun, Wei-Lun; Weierstall, Karen; Minerly, Ana Christina; Weiner, Jan; Jenab, Shirzad; Quinones-Jenab, Vanya

    2016-10-01

    Previous studies have shown sex different patterns in behavioral responses to cocaine. Here, we used between-subject experiment design to study whether sex differences exist in the development of behavioral sensitization and tolerance to repeated cocaine, as well as the role of protein kinase A (PKA) signaling cascade in this process. Ambulatory and rearing responses were recorded in male and female rats after 1 to 14 days of administration of saline or cocaine (15 mg/kg; ip). Correspondent PKA-associated signaling in the nucleus accumbens (NAc) and caudate-putamen (CPu) was measured at each time point. Our results showed that females exhibited higher cocaine-induced behavioral responses and developed behavioral sensitization and tolerance faster than males. Whereas females developed behavioral sensitization to cocaine after 2 days and tolerance after 14 days, male rats developed sensitization after 5 days. In addition, cocaine induced a sexual dimorphic pattern in the progression of neuronal adaptations on the PKA cascade signaling in region (NAc vs. CPu) and time (days of cocaine administration)-dependent manners. In general, more PKA signaling cascade changes were found in the NAc of males on day 5 and in the CPu of females with repeated cocaine injection. In addition, in females, behavioral activities positively correlated with FosB levels in the NAc and CPu and negatively correlated with Cdk5 and p35 in the CPu, while no correlation was observed in males. Our studies suggest that repeated cocaine administration induced different patterns of behavioral and molecular responses in the PKA cascade in male and female rats. PMID:27553823

  13. Effect of repeated administration of Annona diversifolia Saff. (ilama) extracts and palmitone on rat amygdala kindling.

    PubMed

    González-Trujano, Ma Eva; López-Meraz, Leonor; Reyes-Ramírez, Adelfo; Aguillón, Miguel; Martínez, Adrián

    2009-12-01

    Annonas are consumed as fresh fruits, but, because of their effects on the central nervous system, are also used in folk medicine. The effect on rat amygdala kindling of repeated administration of Annona diversifolia hexane (100mg/kg IP or PO) and ethanol (100mg/kg, PO) leaf extracts and palmitone (10mg/kg, IP) was determined. Electrographic and/or behavioral changes were monitored during kindling-induced seizures 60minutes after treatments. Antiepileptic efficacy was evaluated with respect to afterdischarge (AD) duration, spike frequency, and/or behavioral seizure activity. Oral administration of both extracts significantly decreased spike frequency, whereas intraperitoneally administered hexane extract and palmitone only reduced AD duration. Hexane extract and palmitone exhibited anticonvulsant properties and delayed establishment of a kindling state as observed with diazepam (0.3mg/kg IP). These results reinforce the anticonvulsant properties of this plant, and palmitone and other constituents are responsible for the pharmacological effects. PMID:19836312

  14. Brexpiprazole Alters Monoaminergic Systems following Repeated Administration: an in Vivo Electrophysiological Study

    PubMed Central

    Mansari, Mostafa El; Bundgaard, Christoffer; Blier, Pierre

    2016-01-01

    Background: Brexpiprazole was recently approved as adjunctive therapy for depression and treatment of schizophrenia in adults. To complement results from a previous study in which its acute effects were characterized, the present study assessed the effect of repeated brexpiprazole administration on monoaminergic systems. Methods: Brexpiprazole (1mg/kg, subcutaneous) or vehicle was administered once daily for 2 and 14 days. Single-unit electrophysiological recordings from noradrenaline neurons in the locus coeruleus, serotonin neurons in the dorsal raphe nucleus, dopaminergic neurons in the ventral tegmental area, and pyramidal neurons in the hippocampus CA3 region were obtained in adult male Sprague-Dawley rats under chloral hydrate anesthesia within 4 hours after final dosing. Results: Brexpiprazole blunted D2 autoreceptor responsiveness, while firing activity of ventral tegmental area dopaminergic neurons remained unaltered. Brexpiprazole increased the firing rate of locus coeruleus noradrenaline neurons and increased noradrenaline tone on α2-adrenergic receptors in the hippocampus. Administration of brexpiprazole for 2 but not 14 days increased the firing rate of serotonin neurons in the dorsal raphe nucleus. In the hippocampus, serotonin1A receptor blockade significantly disinhibited pyramidal neurons after 2- and 14-day brexpiprazole administration. In contrast, no significant disinhibition occurred after 24-hour washout or acute brexpiprazole. Conclusions: Repeated brexpiprazole administration resulted in a marked occupancy of D2 autoreceptors, while discharge activity of ventral tegmental area dopaminergic neurons remained unaltered. Brexpiprazole enhanced serotonergic and noradrenergic tone in the hippocampus, effects common to antidepressant agents. Together, these results provide further insight in the neural mechanisms by which brexpiprazole exerts antidepressant and antipsychotic effects. PMID:26428352

  15. Opioid Analgesics.

    PubMed

    Jamison, Robert N; Mao, Jianren

    2015-07-01

    Chronic pain is an international health issue of immense importance that is influenced by both physical and psychological factors. Opioids are useful in treating chronic pain but have accompanying complications. It is important for clinicians to understand the basics of opioid pharmacology, the benefits and adverse effects of opioids, and related problematic issues of tolerance, dependence, and opioid-induced hyperalgesia. In this article, the role of psychiatric comorbidity and the use of validated assessment tools to identify individuals who are at the greatest risk for opioid misuse are discussed. Additionally, interventional treatment strategies for patients with chronic pain who are at risk for opioid misuse are presented. Specific behavioral interventions designed to improve adherence with prescription opioids among persons treated for chronic pain, such as frequent monitoring, periodic urine screens, opioid therapy agreements, opioid checklists, and motivational counseling, are also reviewed. Use of state-sponsored prescription drug monitoring programs is also encouraged. Areas requiring additional investigation are identified, and the future role of abuse-deterrent opioids and innovative technology in addressing issues of opioid therapy and pain are presented.

  16. Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models.

    PubMed

    Bourin, M; Hascoet, M; Mansouri, B; Colombel, M C; Bradwejn, J

    1992-06-01

    The behavioral and clinical profiles of various benzodiazepines after acute and chronic treatment are not well defined and may differ. The aim of this study was to evaluate the behavioral profiles of alprazolam, bromazepam, diazepam and lorazepam in mice after single and repeated (every half-life for seven half-lives) administrations using a stimulation-sedation test (actimeter), a myorelaxation test (rotarod), and an anxiolysis test ("four plates"). A dose range from 0.03 to 4 mg/kg was used. A single administration of alprazolam showed stimulating and anxiolytic effects which diminished after repeated administration. Lorezapam's sedative effect diminished but its anxiolytic effect increased upon repeated administration. Except for lorazepam, the myorelaxing effect of all four drugs increased after repeated treatment. These results suggest that the behavioral profile of benzodiazepines may not be identical during acute and chronic treatment. These differences may be present in clinical treatment and warrant investigation in humans.

  17. Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models.

    PubMed Central

    Bourin, M; Hascoet, M; Mansouri, B; Colombel, M C; Bradwejn, J

    1992-01-01

    The behavioral and clinical profiles of various benzodiazepines after acute and chronic treatment are not well defined and may differ. The aim of this study was to evaluate the behavioral profiles of alprazolam, bromazepam, diazepam and lorazepam in mice after single and repeated (every half-life for seven half-lives) administrations using a stimulation-sedation test (actimeter), a myorelaxation test (rotarod), and an anxiolysis test ("four plates"). A dose range from 0.03 to 4 mg/kg was used. A single administration of alprazolam showed stimulating and anxiolytic effects which diminished after repeated administration. Lorezapam's sedative effect diminished but its anxiolytic effect increased upon repeated administration. Except for lorazepam, the myorelaxing effect of all four drugs increased after repeated treatment. These results suggest that the behavioral profile of benzodiazepines may not be identical during acute and chronic treatment. These differences may be present in clinical treatment and warrant investigation in humans. PMID:1637802

  18. Alteration in metabolism and toxicity of acetaminophen upon repeated administration in rats.

    PubMed

    Kim, Sun J; Lee, Min Y; Kwon, Do Y; Kim, Sung Y; Kim, Young C

    2009-10-01

    Our previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity of APAP upon repeated administration. An intraperitoneal dose of APAP (500 mg/kg) alone did not increase aspartate aminotransferase, alanine aminotransferase, or sorbitol dehydrogenase activity in serum, but was significantly hepatotoxic when the rats had been pretreated with an identical dose of APAP 18 h earlier. The concentrations and disappearance of APAP and its metabolites in plasma were monitored for 8 h after the treatment. APAP pretreatment reduced the elevation of APAP-sulfate, but increased APAP-cysteine concentrations in plasma. APAP or APAP-glucuronide concentrations were not altered. Administration of a single dose of APAP 18 h before sacrifice increased microsomal CYP activities measured with p-nitrophenol, p-nitroanisole, and aminopyrine as probes. Expression of CYP2E1, CYP3A, and CYP1A proteins in the liver was also elevated significantly. The results suggest that administration of APAP at a subtoxic dose may result in an induction of hepatic CYP enzymes, thereby altering metabolism and toxicological consequences of various chemical substances that are substrates for the same enzyme system.

  19. Repeated ketamine administration redeems the time lag for citalopram's antidepressant-like effects.

    PubMed

    Zhang, G-F; Liu, W-X; Qiu, L-L; Guo, J; Wang, X-M; Sun, H-L; Yang, J-J; Zhou, Z-Q

    2015-06-01

    Current available antidepressants exhibit low remission rate with a long response lag time. Growing evidence has demonstrated acute sub-anesthetic dose of ketamine exerts rapid, robust, and lasting antidepressant effects. However, a long term use of ketamine tends to elicit its adverse reactions. The present study aimed to investigate the antidepressant-like effects of intermittent and consecutive administrations of ketamine on chronic unpredictable mild stress (CUMS) rats, and to determine whether ketamine can redeem the time lag for treatment response of classic antidepressants. The behavioral responses were assessed by the sucrose preference test, forced swimming test, and open field test. In the first stage of experiments, all the four treatment regimens of ketamine (10mg/kg ip, once daily for 3 or 7 consecutive days, or once every 7 or 3 days, in a total 21 days) showed robust antidepressant-like effects, with no significant influence on locomotor activity and stereotype behavior in the CUMS rats. The intermittent administration regimens produced longer antidepressant-like effects than the consecutive administration regimens and the administration every 7 days presented similar antidepressant-like effects with less administration times compared with the administration every 3 days. In the second stage of experiments, the combination of ketamine (10 mg/kg ip, once every 7 days) and citalopram (20 mg/kg po, once daily) for 21 days caused more rapid and sustained antidepressant-like effects than citalopram administered alone. In summary, repeated sub-anesthestic doses of ketamine can redeem the time lag for the antidepressant-like effects of citalopram, suggesting the combination of ketamine and classic antidepressants is a promising regimen for depression with quick onset time and stable and lasting effects. PMID:25795441

  20. Clenbuterol residues in pig muscle after repeat administration in a growth-promoting dose.

    PubMed

    Pleadin, Jelka; Vulić, Ana; Persi, Nina; Vahcić, Nada

    2010-11-01

    The aim of this study was to determine the level of clenbuterol residues in muscle tissue of pigs after repeat administration in a growth-promoting dose. An anabolic dose of clenbuterol (20 μg/kg body mass per day) was administered orally to experimental group (n=12) for 28 days, whereas control animals (n=3) were left untreated. Clenbuterol treated pigs were randomly sacrificed (n=3) on days 0, 3, 7 and 14 of treatment discontinuation and clenbuterol residues determined in muscle tissue. Determination of residual clenbuterol was by enzyme-linked immunosorbent assay (ELISA) as a screening method and liquid chromatography tandem mass spectrometry (LC-MS/MS) as a confirmation method. The highest clenbuterol content in the muscle of treated animals was recorded on day 0 of treatment cessation (4.40±0.37 ng/g) and significantly (p<0.05) exceeded the maximum residue limit (MRL) of 0.1 ng/g. On day 3 of withdrawal, it was 0.49±0.22 ng/g and on day 7 0.10±0.02 ng/g (at MRL); on day 14 of treatment discontinuation, clenbuterol content was below the limit of detection (<0.1 ng/g) in all samples. Administration of clenbuterol as a growth promoter in pig production could lead to residues in meat for human consumption up to 7 days after treatment discontinuation.

  1. Effects of exercise conditioning on thermoregulatory responses to repeated administration of chlorpyrifos.

    PubMed

    Rowsey, Pamela Johnson; Metzger, Bonnie L; Carlson, John; Gordon, Christopher J

    2003-05-01

    Little is known about the effects of physical activity (i.e., exercise training) on susceptibility to environmental toxicants. Chlorpyrifos (CHP), an organophosphate (OP) insecticide, affects thermoregulation, causing an acute period of hypothermia followed by a delayed fever. Since exercise conditioning alters the thermoregulatory responses of rodents, this study examined whether exercise training would alter the thermoregulatory response to repeated CHP administration in the female Sprague-Dawley rat. Core temperature (T(c)) and motor activity (MA) were monitored by radiotelemetry in rats housed at an ambient temperature (T(a)) of 22 degrees C. The rats either were provided with continuous access to running wheels (exercise group) or were housed in standard cages without wheels (sedentary group). The exercise group rats ran predominantly at night with an average of 7.6 km/24h. After 8 weeks the rats in both groups were gavaged daily with corn oil or 10mg/kg CHP (dissolved in corn oil) for 4 days. CHP induced an immediate hypothermic response followed by a delayed fever throughout the next day in the sedentary group rats after the first three doses of CHP. The exercise group rats showed no hypothermia after the first dose of CHP. However, they became hypothermic after the second and third doses of CHP. The exercise group rats developed a smaller daytime fever after each dose of CHP compared to the sedentary group rats. Overall, exercise training attenuated the hypothermic and febrile effects of repeated CHP. Thus, the data suggest that a sedentary lifestyle may increase the sensitivity to OP insecticides. Exercise training was also associated with a more rapid recovery of plasma cholinesterase activity. PMID:12706752

  2. Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers

    PubMed Central

    Ashare, R L; Kimmey, B A; Rupprecht, L E; Bowers, M E; Hayes, M R; Schmidt, H D

    2016-01-01

    Tobacco smoking remains the leading cause of preventable death worldwide and current smoking cessation medications have limited efficacy. Thus, there is a clear need for translational research focused on identifying novel pharmacotherapies for nicotine addiction. Our previous studies demonstrated that acute administration of an acetylcholinesterase inhibitor (AChEI) attenuates nicotine taking and seeking in rats and suggest that AChEIs could be repurposed for smoking cessation. Here, we expand upon these findings with experiments designed to determine the effects of repeated AChEI administration on voluntary nicotine taking in rats as well as smoking behavior in human smokers. Rats were trained to self-administer intravenous infusions of nicotine (0.03 mg kg−1 per 0.59 ml) on a fixed-ratio-5 schedule of reinforcement. Once rats maintained stable nicotine taking, galantamine or donepezil was administered before 10 consecutive daily nicotine self-administration sessions. Repeated administration of 5.0 mg kg−1 galantamine and 3.0 mg kg−1 donepezil attenuated nicotine self-administration in rats. These effects were reinforcer-specific and not due to adverse malaise-like effects of drug treatment as repeated galantamine and donepezil administration had no effects on sucrose self-administration, ad libitum food intake and pica. The effects of repeated galantamine (versus placebo) on cigarette smoking were also tested in human treatment-seeking smokers. Two weeks of daily galantamine treatment (8.0 mg (week 1) and 16.0 mg (week 2)) significantly reduced smoking rate as well as smoking satisfaction and reward compared with placebo. This translational study indicates that repeated AChEI administration reduces nicotine reinforcement in rats and smoking behavior in humans at doses not associated with tolerance and/or adverse effects. PMID:26784967

  3. Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers.

    PubMed

    Ashare, R L; Kimmey, B A; Rupprecht, L E; Bowers, M E; Hayes, M R; Schmidt, H D

    2016-01-19

    Tobacco smoking remains the leading cause of preventable death worldwide and current smoking cessation medications have limited efficacy. Thus, there is a clear need for translational research focused on identifying novel pharmacotherapies for nicotine addiction. Our previous studies demonstrated that acute administration of an acetylcholinesterase inhibitor (AChEI) attenuates nicotine taking and seeking in rats and suggest that AChEIs could be repurposed for smoking cessation. Here, we expand upon these findings with experiments designed to determine the effects of repeated AChEI administration on voluntary nicotine taking in rats as well as smoking behavior in human smokers. Rats were trained to self-administer intravenous infusions of nicotine (0.03 mg kg(-1) per 0.59 ml) on a fixed-ratio-5 schedule of reinforcement. Once rats maintained stable nicotine taking, galantamine or donepezil was administered before 10 consecutive daily nicotine self-administration sessions. Repeated administration of 5.0 mg kg(-1) galantamine and 3.0 mg kg(-1) donepezil attenuated nicotine self-administration in rats. These effects were reinforcer-specific and not due to adverse malaise-like effects of drug treatment as repeated galantamine and donepezil administration had no effects on sucrose self-administration, ad libitum food intake and pica. The effects of repeated galantamine (versus placebo) on cigarette smoking were also tested in human treatment-seeking smokers. Two weeks of daily galantamine treatment (8.0 mg (week 1) and 16.0 mg (week 2)) significantly reduced smoking rate as well as smoking satisfaction and reward compared with placebo. This translational study indicates that repeated AChEI administration reduces nicotine reinforcement in rats and smoking behavior in humans at doses not associated with tolerance and/or adverse effects.

  4. Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers.

    PubMed

    Ashare, R L; Kimmey, B A; Rupprecht, L E; Bowers, M E; Hayes, M R; Schmidt, H D

    2016-01-01

    Tobacco smoking remains the leading cause of preventable death worldwide and current smoking cessation medications have limited efficacy. Thus, there is a clear need for translational research focused on identifying novel pharmacotherapies for nicotine addiction. Our previous studies demonstrated that acute administration of an acetylcholinesterase inhibitor (AChEI) attenuates nicotine taking and seeking in rats and suggest that AChEIs could be repurposed for smoking cessation. Here, we expand upon these findings with experiments designed to determine the effects of repeated AChEI administration on voluntary nicotine taking in rats as well as smoking behavior in human smokers. Rats were trained to self-administer intravenous infusions of nicotine (0.03 mg kg(-1) per 0.59 ml) on a fixed-ratio-5 schedule of reinforcement. Once rats maintained stable nicotine taking, galantamine or donepezil was administered before 10 consecutive daily nicotine self-administration sessions. Repeated administration of 5.0 mg kg(-1) galantamine and 3.0 mg kg(-1) donepezil attenuated nicotine self-administration in rats. These effects were reinforcer-specific and not due to adverse malaise-like effects of drug treatment as repeated galantamine and donepezil administration had no effects on sucrose self-administration, ad libitum food intake and pica. The effects of repeated galantamine (versus placebo) on cigarette smoking were also tested in human treatment-seeking smokers. Two weeks of daily galantamine treatment (8.0 mg (week 1) and 16.0 mg (week 2)) significantly reduced smoking rate as well as smoking satisfaction and reward compared with placebo. This translational study indicates that repeated AChEI administration reduces nicotine reinforcement in rats and smoking behavior in humans at doses not associated with tolerance and/or adverse effects. PMID:26784967

  5. Determination of co-administrated opioids and benzodiazepines in urine using column-switching solid-phase extraction and liquid chromatography-tandem mass spectrometry.

    PubMed

    Xiong, Lingjuan; Wang, Rong; Liang, Chen; Teng, Xiaomei; Jiang, Fengli; Zeng, Libo; Ye, Haiying; Ni, Chunfang; Yuan, Xiaoliang; Rao, Yulan; Zhang, Yurong

    2015-05-22

    Co-administration of opioids with benzodiazepines is very common around the world. A semi-automated method was developed for the determination of four opioids and two benzodiazepines as well as their metabolites (including glucuronide metabolites) in human urine, based on on-line column-switching-solid-phase extraction (CS-SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The CS-SPE was performed by loading 200μL of urine sample to an Oasis HLB cartridge. Detection was achieved using a LC-MS/MS system equipped with an electrospray ionization source (ESI). For unequivocal identification and confirmation, two selected reaction monitoring transitions were registered for each compound, and no co-elution of interferences was observed at the expected retention time. Significant ion suppressions were observed for most analytes during chromatographic runs, but isotope-labeled internal standards (ISs) were used and found to be useful to compensate for the determination error caused by the matrix effect. The assay's linearity ranged from 1-20ng/mL to 800-1000ng/mL for 23 compounds, except for lorazepam (LOR), whose linearity was in the range of 1-100ng/mL. This method showed to be precise and accurate. The relative standard deviation (RSD) % values of within-run precision, between-run precision and total precision were not greater than 10.4% (n=3), 12.9% (n=5) and 15.1% (n=15), respectively. Accuracy values were in the range of 87.5-110%. Limits of detection (LODs) ranged from 0.2ng/mL to 5ng/mL, and limits of quantification (LOQs) ranged from 1ng/mL to 20ng/mL. The method was applied to the assay of 12 samples from forensic cases, which exemplified the co-administration of benzodiazepines (BZDs) by some heroin abusers. This method was of high sensitivity, selectivity and reliability, minimum sample manipulation, semi-automation, and fairly high throughput (analysis time per sample was 20min). The method developed will be useful for the detection of co-administrated

  6. Pharmacokinetics of marbofloxacin in lactating cows after repeated intramuscular administrations and pharmacodynamics against mastitis isolated strains.

    PubMed

    Schneider, M; Vallé, M; Woehrlé, F; Boisramé, B

    2004-01-01

    The plasma and milk pharmacokinetics of marbofloxacin, a fluoroquinolone antibacterial compound, were evaluated in dairy cows, as well as its pharmacodynamic characteristics against mastitis-isolated pathogens. Marbofloxacin was given intramuscularly as a 10% aqueous solution to dairy cows either at a single dose or at repeated doses of 2 mg/kg once daily for 3 d. Blood and milk samples were collected for the determination of the concentration of marbofloxacin and of its putative metabolites: N-desmethyl-marbofloxacin and N-oxide-marbofloxacin. Bacterial field isolates were from milk samples collected from dairy cows suspected of having an intramammary infection. After identification, the minimal inhibitory concentration (MIC) was determined against the isolated strains. The maximal marbofloxacin concentration (Cmax) observed in milk after the first administration was 1.024 microg/mL, and the area under the curve during the first dosing interval was 6.513 microg/h per milliliter. After the third administration, these parameters were slightly increased (about 20% at most). Both metabolites were detected in the milk, but their concentrations were below the limit of quantification. The MIC against 90% of the population (MIC90) of Escherichia coli was 0.016 microg/mL, and it was 0.229 microg/mL against Staphylococcus aureus. The following surrogate clinical outcome markers were obtained against E. coli strains: a Cmax/MIC ratio of 67 and an area under the curve/MIC ratio of 407 h. Hence, a possible efficacy of marbofloxacin in the treatment of E. coli-induced mastitis could be expected as the endpoints of 10 and 250 h, respectively, are reached.

  7. Hyperintense Dentate Nuclei on T1-Weighted MRI: Relation to Repeat Gadolinium Administration

    PubMed Central

    Adin, M.E.; Kleinberg, L.; Vaidya, D.; Zan, E.; Mirbagheri, S.; Yousem, D.M.

    2016-01-01

    BACKGROUND AND PURPOSE A hyperintense appearance of the dentate nucleus on T1-weighted MR images has been related to various clinical conditions, but the etiology remains indeterminate. We aimed to investigate the possible associations between a hyperintense appearance of the dentate nucleus on T1-weighted MR images in patients exposed to radiation and factors including, but not limited to, the cumulative number of contrast-enhanced MR images, amount of gadolinium administration, dosage of ionizing radiation, and patient demographics. MATERIALS AND METHODS The medical records of 706 consecutive patients who were treated with brain irradiation at The Johns Hopkins Medical Institutions between 1995 and 2010 were blindly reviewed by 2 readers. RESULTS One hundred eighty-four subjects were included for dentate nuclei analysis. Among the 184 subjects who cumulatively underwent 2677 MR imaging studies following intravenous gadolinium administration, 103 patients had hyperintense dentate nuclei on precontrast T1-weighted MR images. The average number of gadolinium-enhanced MR imaging studies performed in the group with normal dentate nuclei was significantly lower than that of the group with hyperintense dentate nuclei. The average follow-up time was 62.5 months. No significant difference was observed between hyperintense and normal dentate nuclei groups in terms of exposed radiation dose, serum creatinine and calcium/phosphate levels, patient demographics, history of chemotherapy, and strength of the scanner. No dentate nuclei abnormalities were found on the corresponding CT scans of patients with hyperintense dentate nuclei (n = 44). No dentate nuclei abnormalities were found in 53 healthy volunteers. CONCLUSIONS Repeat performance of gadolinium-enhanced studies likely contributes to a long-standing hyperintense appearance of dentate nuclei on precontrast T1-weighted-MR images. PMID:26294649

  8. Evaluation of safety profile of black shilajit after 91 days repeated administration in rats

    PubMed Central

    Velmurugan, C; Vivek, B; Wilson, E; Bharathi, T; Sundaram, T

    2012-01-01

    Objective To evaluate the safety of shilajit by 91 days repeated administration in different dose levels in rats. Methods In this study the albino rats were divided into four groups. Group I received vehicle and group II, III and IV received 500, 2 500 and 5 000 mg/kg of shilajit, respectively. Finally animals were sacrificed and subjected to histopathology and iron was estimated by flame atomic absorption spectroscopy and graphite furnace. Results The result showed that there were no significant changes in iron level of treated groups when compared with control except liver (5 000 mg/kg) and histological slides of all organs revealed normal except negligible changes in liver and intestine with the highest dose of shilajit. The weight of all organs was normal when compared with control. Conclusions The result suggests that black shilajit, an Ayurvedic formulation, is safe for long term use as a dietary supplement for a number of disorders like iron deficiency anaemia. PMID:23569899

  9. Effect of repeated administration of cadmium, captopril and its combination on plasma renin activity in rats.

    PubMed

    Nath, P V; Vivek, T

    1997-11-01

    The effects of normal saline (1 ml kg-1, i.p. for 5 days), cadmium acetate (1 mg kg-1, i.p. for 5 days), captopril (20 mg kg-1, p.o. for 5 days), or captopril (20 mg kg-1, p.o. for 5 days) plus cadmium acetate (1 mg kg-1, i.p. for 5 days) on blood pressure (BP), heart rate (HR), plasma renin activity (PRA) and respiratory rate (RR) were examined in male Sprague-Dawley (S-D) rats. Repeated administration of cadimum acetate produced a hypertensive response (P < 0.01) without significant changes in PRA, HR or RR. The captopril group was associated with hypotension (P < 0.01) but again PRA, HR and RR were not significantly altered. In the group receiving captopril p.o. and cadmium i.p., BP rose significantly compared with captopril alone but PRA, HR, RR were not altered. Cadmium-induced hypertension cannot be obviously accounted for on its basis of augmented plasma or tissue renin angiotensin involvement.

  10. Opioid Use in Fibromyalgia: A Cautionary Tale.

    PubMed

    Goldenberg, Don L; Clauw, Daniel J; Palmer, Roy E; Clair, Andrew G

    2016-05-01

    Multiple pharmacotherapies are available for the treatment of fibromyalgia (FM), including opioid analgesics. We postulate that the mechanism of action of traditional opioids predicts their lack of efficacy in FM. Literature searches of the MEDLINE and Cochrane Library databases were conducted using the search term opioid AND fibromyalgia to identify relevant articles, with no date limitations set. Citation lists in returned articles and personal archives of references were also examined for additional relevant items, and articles were selected based on the expert opinions of the authors. We found no evidence from clinical trials that opioids are effective for the treatment of FM. Observational studies have found that patients with FM receiving opioids have poorer outcomes than patients receiving nonopioids, and FM guidelines recommend against the use of opioid analgesics. Despite this, and despite the availability of alternative Food and Drug Administration-approved pharmacotherapies and the efficacy of nonpharmacologic therapies, opioids are commonly used in the treatment of FM. Factors associated with opioid use include female sex; geographic variation; psychological factors; a history of opioid use, misuse, or abuse; and patient or physician preference. The long-term use of opioid analgesics is of particular concern in the United States given the ongoing public health emergency relating to excess prescription opioid consumption. The continued use of opioids to treat FM despite a proven lack of efficacy, lack of support from treatment guidelines, and the availability of approved pharmacotherapy options provides a cautionary tale for their use in other chronic pain conditions.

  11. Opioid intoxication

    MedlinePlus

    ... develop. This is from the talc, cornstarch, or cellulose that is used to dilute or bind the ... McGraw-Hill; 2004:chap 167. Lank PM, Kusin S. Ethanol and opioid intoxication and withdrawal. In: Adams JG, ...

  12. Reduced activity of monoamine oxidase in the rat brain following repeated nandrolone decanoate administration.

    PubMed

    Birgner, Carolina; Kindlundh-Högberg, Anna M S; Oreland, Lars; Alsiö, Johan; Lindblom, Jonas; Schiöth, Helgi B; Bergström, Lena

    2008-07-11

    Anabolic androgenic steroids (AAS) are known as doping agents within sports and body-building, but are currently also abused by other groups in society in order to promote increased courage and aggression. We previously showed that 14 days of daily intramuscular injections of the AAS nandrolone decanoate (15 mg/kg) reduced the extracellular levels of the dopaminergic metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens shell using microdialysis. The aim of the present study was to investigate whether the same dose regimen of nandrolone decanoate may affect the activities of the dopamine-metabolizing enzymes monoamine oxidases A and B (MAO-A and MAO-B). A radiometric assay was used to determine the activities of MAO-A and MAO-B in rat brain tissues after 14 days of daily i.m. nandrolone decanoate injections at the doses 3 and 15 mg/kg. Gene transcript contents of MAO-A, MAO-B and cathecol-O-methyltransferase (COMT) were measured with quantitative real-time reverse transcription PCR. 3 mg/kg of nandrolone decanoate significantly reduced the activity of both MAO-A and -B in the caudate putamen. 15 mg/kg of nandrolone decanoate significantly reduced the activity of MAO-A in the amygdala and increased the gene transcript level of MAO-B in the substantia nigra. In conclusion, imbalanced MAO activities may contribute to explain the impulsive and aggressive behaviour often described in AAS abusers. The reduced MAO activities observed are in line with our previously presented findings of decreased extracellular levels of DOPAC and HVA in the rat brain, indicating decreased monoaminergic activity following repeated AAS administration. PMID:18539264

  13. Effect of repeated administration of dexfenfluramine on feeding and brain Fos in mice.

    PubMed

    Rowland, Neil E; Robertson, Kimberly; Green, D Joy

    2003-02-01

    The present study examines whether repeated administration of dexfenfluramine (DFEN) to mice is associated with progressive attenuation of its anorectic action and induction of Fos-immunoreactivity (Fos-ir) in some brain regions, both known effects in rats. ICR:Cd-1 mice were adapted to receiving for 30 min daily a sweetened milk gelatin dessert in addition to ad libitum access to chow. Mice were then injected with either DFEN (5-10 mg/kg) or saline vehicle every other day. These doses of DFEN acutely suppressed intake by approximately 50% and this action was sustained for at least eight injections. The anorectic effect of DFEN was no different between drug-naïve and DFEN-pretreated mice under conditions that produce complete tolerance in rats. In addition, unlike in rats, the acute anorectic effect of m-chlorophenylpiperazine (mCPP) was unaffected by prior DFEN treatment. Mice were perfused after the intake test on the final experimental day and their brain processed for Fos-ir. DFEN induced Fos-ir in brain regions analogous to those reported in rats and, also, as in rats, DFEN pretreatments reduced substantially the Fos-ir induced by acute DFEN in regions including central nucleus of amygdala, bed nucleus of stria terminalis, and the paraventricular hypothalamus (magno- and parvocellular divisions; PVN). Thus, while DFEN pretreatments reduce the effects of DFEN in many brain regions in both rats and mice, mice are unlike rats insofar as there is no tolerance to the anorectic action, at least in the nondeprivation protocol used here.

  14. Intrasubject variation in children of ifosfamide pharmacokinetics and metabolism during repeated administration.

    PubMed

    Boddy, A V; Yule, S M; Wyllie, R; Price, L; Pearson, A D; Idle, J R

    1996-01-01

    The aim of this study was to investigate intrasubject variability in ifosfamide (IFO) pharmacokinetics and metabolism which may influence clinical effect, since the pharmacology of this drug is dependent on metabolism. A group of 11 patients (ages 1-16 years) were studied on at least two occasions. IFO, 9 gm-2 was administered as a continuous infusion over 72 h. Plasma and urine samples were collected and concentrations of IFO and its metabolites were determined. Comparisons were made between courses in the same subject, allowing for differences in age and prior IFO treatment. There was a wide variation in drug (twofold) and metabolite (up to tenfold) AUCs between courses in the same patient. Although some patients did show an increase in clearance between courses (up to threefold), there was no significant consistent change in overall pharmacokinetics among the different courses studied in the same patient. There was a significant decrease (up to 63%) in the AUC of the inactive metabolite 3-dechloroethylifosfamide (3-DCI) in later courses compared with the first course studied (P = 0.032, paired t-test). This was matched by an increase in the AUC of the total dechloroethylated metabolites with course (P = 0.015, paired t-test). None of the other metabolites measured showed any consistent change in plasma or urine levels between courses. Overall, the AUC of parent drug correlated with age (r2 = 0.86, P = 0.011), and postinfusion half-life correlated with plasma bilirubin (r2 = 0.89, P = 0.007). This study demonstrated large and seemingly unpredictable intrasubject variability in IFO pharmacokinetics and metabolism during repeated administrations. Investigations relating the clinical effects of IFO to pharmacokinetics and metabolism must take this variation into account.

  15. Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration.

    PubMed

    Kenward, Hannah; Pelligand, Ludovic; Elliott, Jonathan

    2014-08-01

    Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies.

  16. The evolution of vertebrate opioid receptors

    PubMed Central

    Stevens, Craig W.

    2011-01-01

    The proteins that mediate the analgesic and other effects of opioid drugs and endogenous opioid peptides are known as opioid receptors. Opioid receptors consist of a family of four closely-related proteins belonging to the large superfamily of G-protein coupled receptors. The three types of opioid receptors shown unequivocally to mediate analgesia in animal models are the mu (MOR), delta (DOR), and kappa (KOR) opioid receptor proteins. The role of the fourth member of the opioid receptor family, the nociceptin or orphanin FQ receptor (ORL), is not as clear as hyperalgesia, analgesia, and no effect was reported after administration of ORL agonists. There are now cDNA sequences for all four types of opioid receptors that are expressed in the brain of six species from three different classes of vertebrates. This review presents a comparative analysis of vertebrate opioid receptors using bioinformatics and data from recent human genome studies. Results indicate that opioid receptors arose by gene duplication, that there is a vector of opioid receptor divergence, and that MOR shows evidence of rapid evolution. PMID:19273128

  17. Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts.

    PubMed

    Comer, Sandra D; Metz, Verena E; Cooper, Ziva D; Kowalczyk, William J; Jones, Jermaine D; Sullivan, Maria A; Manubay, Jeanne M; Vosburg, Suzanne K; Smith, Mary E; Peyser, Deena; Saccone, Phillip A

    2013-09-01

    This double-blind, placebo-controlled study investigated the effects of oral morphine (0, 45, 135 mg/70 kg) and oral oxycodone (0, 15, 45 mg/70 kg) on buprenorphine-maintained opioid addicts. As a 3: 1 morphine : oxycodone oral dose ratio yielded equivalent subjective and physiological effects in nondependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures - that is, a drug versus money and a drug versus drug procedure - were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater than those of high-dose morphine. The study demonstrated that a 3: 1 oral dose ratio of morphine : oxycodone was not equipotent in buprenorphine-dependent individuals. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest. PMID:23839029

  18. Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts

    PubMed Central

    Comer, Sandra D; Metz, Verena E; Cooper, Ziva D; Kowalczyk, William J; Jones, Jermaine D; Sullivan, Maria A; Manubay, Jeanne M; Vosburg, Suzanne K; Smith, Mary E; Peyser, Deena; Saccone, Phillip A

    2014-01-01

    This double-blind, placebo-controlled study investigated effects of oral morphine (0, 45, 135 mg/70kg) and oral oxycodone (0, 15, 45 mg/70kg) in buprenorphine-maintained opioid addicts. Since a 3:1 morphine:oxycodone dose ratio had yielded equivalent subjective and physiological effects in non-dependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures, i.e. a drug vs. money and a drug vs. drug procedure, were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater compared to high-dose morphine. The study demonstrated that a 3:1 dose ratio of morphine:oxycodone was not equipotent in buprenorphine-dependent subjects. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest. PMID:23839029

  19. Evaluation of prescription opioids using operant-based pain measures in rats.

    PubMed

    Morgan, Drake; Carter, Christy S; DuPree, Jameson P; Yezierski, Robert P; Vierck, Charles J

    2008-10-01

    Opioids are the most effective compounds available for the relief of pain, yet there are a number of side effects that are of great concern to clinicians. For example, opioids are powerful reinforcers, and the treatment of pain using opioids could lead to the development of addiction. In addition, there is an increasing body of literature demonstrating that the repeated administration of opioids could lead to a phenomenon called opioid-induced hyperalgesia (i.e., increased sensitivity to painful stimulation). Studies examining these potential adverse effects are necessary in the development of novel analgesics. Furthermore, most studies of pain sensitivity and pain relief use reflex-based procedures to identify analgesics; however, it is argued here that operant-based procedures provide measures that are more analogous to the human condition (i.e., the mechanisms of pain are similar to those in humans) and should be useful in the assessment of novel analgesics. A series of studies examining the effects of opioids and the influence of variables such as age are discussed to demonstrate the utility of this approach.

  20. Possible involvement of endogenous opioid system located downstream of α7 nicotinic acetylcholine receptor in mice with physical dependence on nicotine.

    PubMed

    Ueno, Keiko; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro; Wakida, Naoki; Yamamoto, Chizuko; Maeda, Takehiko; Ozaki, Masanobu; Kishioka, Shiroh

    2014-01-01

    We previously reported that nicotine (NIC)-induced analgesia was elicited in part by activation of the endogenous opioid system. Moreover, it is well known that NIC has physical-dependence liability, but its mechanism is unclear. Therefore, we examined whether physical dependence on NIC was mediated by activation of the endogenous opioid system in ICR mice. We evaluated increased serum corticosterone (SCS) as an indicator of NIC withdrawal, as it is a quantitative indicator of naloxone (opioid receptor antagonist, NLX)-precipitated morphine withdrawal in mice. In this study, NLX precipitated an SCS increase in mice receiving repeated NIC, by a dose-dependent mechanism, and correlated with the dose and number of days of repeated NIC administration. When an opioid receptor antagonist (naltrexone) was concomitantly administered with repeated NIC, the NLX-precipitated SCS increase was not elicited. Concomitant administration of the α7 nicotinic acetylcholine receptor (nAChR) antagonist (methyllycaconitine) with repeated NIC, but not the α4β2 nAChR antagonist (dihydro-β-erythroidine), did not elicit an SCS increase by NLX. Thus, a physical dependence on NIC was in part mediated by the activation of the endogenous opioid system, located downstream of α7 nAChR.

  1. Neuraxial Opioid-Induced Itch and Its Pharmacological Antagonism

    PubMed Central

    2015-01-01

    Given its profound analgesic nature, neuraxial opioids are frequently used for pain management. Unfortunately, the high incident rate of itch/pruritus after spinal administration of opioid analgesics reported in postoperative and obstetric patients greatly diminishes patient satisfaction and thus the value of the analgesics. Many endeavors to solve the mystery behind neuraxial opioid-induced itch had not been successful, as the pharmacological antagonism other than the blockade of mu opioid receptors remains elusive. Nevertheless, as the characteristics of all opioid receptor subtypes have become more understood, more studies have shed light on the potential effective treatments. This review discusses the mechanisms underlying neuraxial opioid-induced itch and compares pharmacological evidence in nonhuman primates with clinical findings across diverse drugs. Both nonhuman primate and human studies corroborate that mixed mu/kappa opioid partial agonists seem to be the most effective drugs in ameliorating neuraxial opioid-induced itch while retaining neuraxial opioid-induced analgesia. PMID:25861787

  2. EFFECT OF EPISODIC WEEKLY NICOTINE ADMINISTRATION ON REPEATED ACQUISITION IN RATS.

    EPA Science Inventory

    Our prior research showed both tolerance and sensitization to nicotine?s effects on motor activity with weekly dosing. This experiment determined the generality of this finding to conditioned behavior. After extended training on a repeated acquisition/performance schedule all ra...

  3. Repeated administration of estradiol promotes mechanisms of sexual excitation and inhibition: Glutamate signaling in the ventromedial hypothalamus attenuates excitation.

    PubMed

    Jones, Sherri Lee; Farisello, Lucia; Mayer-Heft, Nathaniel; Pfaus, James G

    2015-09-15

    Repeated administration of 10 μg of estradiol benzoate (EB) every 4 days to the ovariectomized (OVX) rat induces a behavioral sensitization of sexual behaviors. Repeated copulation or the receipt of vaginocervical stimulation (VCS) attenuates the sensitization of appetitive sexual behaviors, suggesting that VCS acts in opposition to the mechanisms that induce the sensitization. It is known that VCS accelerates the onset of estrous termination (characterized by a decrease in appetitive sexual behaviors, and an increase in defensive behaviors prior to the decline in lordosis), and glutamate transmission in the ventromedial hypothalamus (VMH), particularly via AMPA receptor signaling, is an important regulator of this effect. Thus, the current studies examined whether mechanisms of estrous termination are involved in the attenuated sensitization to EB that occurs with repeated copulation. In the first study, OVX rats received infusions of AMPA to the VMH on tests 2-4, and sexual behavior was measured on tests 1 and 5. Appetitive sexual behaviors were lower in females that received AMPA infusions in place of copulation compared to saline, suggesting that AMPA receptor activation by VCS may be playing a role in the attenuation of sensitization. In the second study, females that were not given the opportunity to copulate on tests 2-4 fell out of behavioral estrus faster than those that did, suggesting that both excitatory and inhibitory mechanisms of sexual behavior become sensitized with repeated administration of EB. Together these findings extend our hypothesis that repeated episodes of heat sensitize the activation of sexual behaviors to increase the probability of eventual fertilization.

  4. The delayed lung responses to single and repeated intratracheal administration of pure cobalt and hard metal powder in the rat

    SciTech Connect

    Lasfargues, G.; Lardot, C.; Lauwerys, R.; Lison, D.

    1995-05-01

    Epidemiological and clinical studies suggest that inhalation of cobalt metal dust (Co) mixed with tungsten carbide particles (WC), but not of cobalt dust alone, may cause interstitial pulmonary lesions (hard metal disease). In previous studies in the rat, we have demonstrated the greater acute pulmonary toxicity of a WC-Co mixture was greater compared to Co or WC alone. The present study compares the delayed lung response after intratracheal administration of Co or WC-Co particles. The responses were also compared with those obtained after treatment with arsenic trioxide and crystalline silica used as reference materials producing an acute toxic insult and progressive fibrogenic response, respectively. Cellular and biochemical parameters were measured in bronchoalveolar lavage fluid following single and repeated intratracheal instillations. The results indicate the delayed lung response observed after WC-Co is different from that after cobalt metal alone. A single intratracheal dose of WC-Co (1, 5, or 10 mg/100 g body wt) induced an acute alveolitis which persisted for at least 1 month. Four months after a single instillation of WC-Co, no clear histological lung fibrosis could however be evidenced, indicating a reversibility of the lesions. The effects of cobalt (0.06, 0.3, or 0.6 mg/100 g body wt) were very modest, if any. Following repeated intratracheal instillations, increased lung hydroxyproline content and histopathological evidence of interstitial fibrosis were observed after WC-Co (4x1 mg/100 g body wt), but not after administration of each component separately, i.e., Co (4x0.06 mg/100 g body wt) or WC (4x1 mg/100 g body wt). The mechanism of the fibrotic reaction induced by WC-Co seems different from the progressive inflammatory reaction induced by crystalline silica. We suggest that it might result from a scarring reaction elicited by repeated acute insults as observed after repeated administration of arsenic trioxide. 34 refs., 10 figs., 3 tabs.

  5. Clinical pharmacology of non opioid analgesics in neonates.

    PubMed

    Allegaert, K; de Hoon, J; Van Overmeire, B; Devlieger, H

    2005-01-01

    An integrated approach of neonatal analgesia starts with the systematic evaluation of pain and should be followed by effective interventions, mainly based on the appropriate (i.e. safe and effective) administration of analgesics. In contrast to the more potent opioids, data on the pharmacokinetics and -dynamics of non-opioid analgesics in this specific population are still rare or even lacking. We therefore evaluated various aspects of developmental pharmacology of non-opioid analgesics (paracetamol, ibuprofen, acetylsalicyl acid) in neonates. We first performed a single dose propacetamol study in preterm and term neonates. Based on these preliminary findings, a repeated dose administration scheme was developed and tested and maturational aspects from preterm till teenage were documented. Although non-selective COX-inhibitors might be effective in the treatment of postoperative or inflammatory pain syndromes in neonates, potential efficacy should be balanced against the drugs' safety profile. Neonatal renal clearance strongly depends on glomerular filtration rate (GFR) and GFR itself strongly depends on the vaso-dilatative of prostaglandins on the afferent arterioli. We therefore evaluated the impact of the administration of ibuprofen or acetylsalicylic acid on renal clearance in preterm infants and hereby used amikacin clearance as a surrogate marker. We hereby documented the negative effect of ibuprofen on glomerular filtration rate in preterm infants up to 34 weeks and we were able to show that ibuprofen and acetylsalicylic acid had an equal impact on the glomerular filtration rate. PMID:16408826

  6. The anti-inflammatory effect of opioids.

    PubMed

    Gavalas, A; Victoratos, P; Yiangou, M; Hadjipetrou-Kourounakis, L; Rekka, E; Kourounakis, P

    1994-01-01

    The anti-inflammatory activity of two novel opioids PM and PO as well as of pethidine was studied. The mouse paw edema, induced by various phlogistic agents, was significantly inhibited after the administration of opioids, fact that was independent of their antioxidant properties. The anti-inflammatory action of the above opioids was not reversed by naloxone. These results suggest that a variety of complex regulatory activities may be performed by opioid agonists via naloxone-sensitive or naloxone insensitive receptors on inflammatory cells, directly or indirectly by the inhibition of cytokines and mediators involved in inflammation.

  7. Postoperative epidural opioid analgesia: what are the choices?

    PubMed

    de Leon-Casasola, O A; Lema, M J

    1996-10-01

    The administration of hydrophilic opioids via a continuous infusion results in selective spinal analgesia with a low incidence of side effects. Lipophilic opioids may also be associated with spinal effects. However, the doses required to produce postoperative analgesia also produce plasma concentrations within the MEAC. Thus, in clinical practice it may not be possible to limit epidural doses of lipophilic opioids to those associated with spinal analgesia. Regardless of the mechanism of action, epidural administration of lipophilic opioids may offer no clinical advantages over the IV route. Notwithstanding, epidural administration of small doses of lipophilic opioids in combination with local anesthetics may offer significant clinical advantages over systemic administration of opioids alone. Dose-ranging studies will be necessary to determine the ideal concentrations of opioids and local anesthetics, as well as the ratios of the two drugs to obtain optimal analgesia with minimal incidence of side effects.

  8. [Opioid tolerance and dependence--pharmacological aspects].

    PubMed

    Jaba, I M; Luncanu, I; Mungiu, O C

    2001-01-01

    Prolonged opioids administration leads inevitably to tolerance and dependence, a phenomenon we meet more often in healthy people than in ill patients. Tolerance means a hypersensibility of neuronal membranes as well as changes in the number and affinity of opioid receptors, which implies intake of larger doses to obtain the initial effect. Physical dependence, quite different of the psychological one, is the appearance of abstinence syndrome on sudden interruption of opioid administration or on administration of an antagonist. There is usually cross-tolerance in opioids, but it can also be incomplete, when the initial opioid can be replaced with another one that produces a milder abstinence syndrome. Classically, metadone is used in long time therapy, after detoxification with an antagonist is performed (naloxon, naltrexon). Modern pharmacological alternatives are levo-alpha-acetyl-methadol (LAAM) and agonists-antagonists (butorphanol, buprenorphine, pentazocine, nalbuphine). An antagonist can also be used if associated with an alpha--stimulant (clonidine), in order to remove noradrenergic manifestations of abstinence syndrome. Now other therapeutical principles are being studied: enkephalinaze inhibitors to reduce the abstinence syndrome, NMDA receptor antagonists, NO sintetasis inhibitors, that facilitates opioid analgesia and hinders tolerance development; colecystokinin-receptors agonists or antagonists to reduce tolerance on morphine. A recent study showed that the concomitant administration of an opioid agonist (sufentanil) and a calcium channels blocker (nimodipine) not only prevents from tolerance development but also triggers hypersensibility to analgesic effects of the opioid. PMID:12092171

  9. Increased 5-HT Levels Following Repeated Administration of Nigella sativa L. (Black Seed) Oil Produce Antidepressant Effects in Rats.

    PubMed

    Perveen, Tahira; Haider, Saida; Zuberi, Nudrat Anwar; Saleem, Sadia; Sadaf, Sana; Batool, Zehra

    2014-03-01

    The seeds of Nigella sativa L., commonly known as black seed or black cumin, and its extracts are used in folk medicine in the Middle East and in Asian countries for the promotion of good health and as a remedy for many ailments. These seeds have many acclaimed medicinal properties such as broncho-dilatory, immunopotentiating, analgesic, anti-inflammatory, and hypotensive. In the present study, the antidepressant activity following the repeated administration of Nigella sativa L. oil has been monitored using the forced swim test. Rats treated with Nigella sativa L. oil exhibited a significant increase in struggling time after oral administration of Nigella sativa L. oil (0.1 ml/kg/day) for four weeks. Nigella sativa L. oil increased brain 5-HT levels and decreased 5-HT turnover (5-HT/5-HIAA ratio). Levels of tryptophan increased significantly in the brain and plasma following the repeated administration of Nigella sativa L. oil. Nigella sativa L. oil showed a potential antidepressant-like effect.

  10. Development of tolerance after repeated administration of a selective muscarinic M1 antagonist biperiden in healthy human volunteers.

    PubMed

    Salin-Pascual, R J; Granados-Fuentes, D; Galicia-Polo, L; Nieves, E; Gillin, J C

    1993-02-01

    The muscarinic antagonist biperiden produces a dose-dependent inhibition of (REM) sleep on acute administration. The present study addressed the possibility of pharmacological tolerance after repeated biperiden administration. Six healthy volunteers were studied under sleep laboratory conditions in the following situations: one acclimatization, night, two baseline (that were averaged), 4 nights of biperiden administration, and 4 nights of placebo recovery administration. Six milligrams of biperiden and placebo were administered in identical capsules. Volunteers and technicians were blind to the order of the administration of the capsules. REM sleep time was reduced during the first and the second night, but was not significantly different in comparison with baseline by the third night. During placebo recovery nights, REM sleep time was not different from baseline. REM sleep latency was increased during the first and second nights of biperiden administration, but tolerance to this effect was observed by the third night. On placebo nights a dramatic shortening of REM latency was observed. The present findings support the hypothesis that anticholinergic drugs, even a selective M1 antagonist such as biperiden, induce tolerance soon after administration. A similar effect has been reported with scopolamine, a nonselective muscarinic antagonist, but the main difference is that biperiden withdrawal was not followed by an REM sleep rebound. The observed effect on REM sleep latency during placebo administration may be related to a supersensitivity to muscarinic M-1 receptors that trigger the first REM sleep period. Because short REM latency has been the main finding in the sleep of depressed patients, some implications of the present findings are discussed.

  11. Toxicokinetics of naringin, a putative antitussive, after 184-day repeated oral administration in rats.

    PubMed

    Liu, Menghua; Yang, Cuiping; Zou, Wei; Guan, Xiaoling; Zheng, Wenyan; Lai, Li; Fang, Siqi; Cai, Shuxing; Su, Weiwei

    2011-05-01

    The toxicokinetic characteristics of naringin were investigated in rats that had been orally administered naringin extract, a candidate for oral treatment of cough, prepared from Citrus grandis "Tomentosa", at 50, 250, or 1250 mg/kg/day in a repeated-dose study for 1, 32, 93, or 184 days. Increased values of the mean systemic exposure were approximately proportional to increases in dose levels during all collection intervals; no saturation was observed. No significant differences in mean systemic exposure were observed between male and female rats. Results provide a reference for interpretation of toxicology findings and relevance to clinical safety issues.

  12. Opioid and non-opioid mechanisms of footshock-induced analgesia: role of the spinal dorsolateral funiculus.

    PubMed

    Lewis, J W; Terman, G W; Watkins, L R; Mayer, D J; Liebeskind, J C

    1983-05-01

    Exposure to inescapable footshock causes either an opioid or non-opioid mediated analgesia in the rat depending on the temporal parameters of its administration. Lesions of the spinal dorsolateral funiculus significantly reduce both the opioid and non-opioid forms of this footshock-induced analgesia. Thus, these two neurochemically discrete pain-inhibitory systems appear to depend on the integrity of the same descending path, one known to be activated by morphine and by analgesic brain stimulation.

  13. The influence of repeated administration of poloxamer 407 on serum lipoproteins and protease activity in mouse liver and heart.

    PubMed

    Korolenko, Tatyana A; Tuzikov, Fedor V; Johnston, Thomas P; Tuzikova, Natalia A; Kisarova, Yana A; Zhanaeva, Svetlana Ya; Alexeenko, Tatyana V; Zhukova, Natalia A; Brak, Ivan V; Spiridonov, Victor K; Filjushina, Elena E; Cherkanova, Marina S; Monoszon, Anna A

    2012-11-01

    The effects of repeated administration of poloxamer 407 (P-407) on lipoprotein-cholesterol (LP-C) and lipoprotein-triglyceride (LP-TG) fractions and subfractions, as well as the effect on liver and heart proteases, were studied. Repeated administration of P-407 to male CBA mice resulted in a model of atherosclerosis with increased diastolic blood pressure; there was a drastic increase in total serum cholesterol and especially TG. A novel small-angle X-ray scattering method for the determination of the fractional and subfractional composition of LP-C and LP-TG was used. In chronically P-407-treated mice, P-407 significantly increased atherogenic low-density lipoprotein C (LDL-C) fractions, as well as intermediate-density lipoprotein C (IDL-C), and LDL₁₋₃-C subfractions, and very-low-density lipoprotein-C (VLDL-C) fractions, as well as VLDL₁₋₂-C and VLDL₃₋₅-C subfractions), to a lesser extent, the total anti-atherogenic high-density lipoprotein C (HDL-C) fraction, as well as HDL₂-C and HDL₃-C subfractions. Additionally, we demonstrated an increase in the serum chitotriosidase activity, without significant changes in serum matrix metalloprotease (MMP) activity. Morphological changes observed in P-407-treated mice included atherosclerosis in the heart and storage syndrome in the liver macrophages. P-407 significantly increased the activity of cysteine, aspartate proteases, and MMPs in the heart, and only the activity of cathepsin B and MMPs in the liver of mice. Thus, repeated administration of P-407 to mice induced atherosclerosis secondary to sustained dyslipidemia and formation of foamy macrophages in liver, and also modulated the activity of heart and liver proteases.

  14. Repeated cocaine administration results in supersensitivity of striatal D-2 dopamine autoreceptors to pergolide

    SciTech Connect

    Dwoskin, L.P.; Peris, J.; Yasuda, R.P.; Philpott, K.; Zahniser, N.R.

    1988-01-01

    Groups of rats administered cocaine-HCl (10 mg/kg, i.p.) or saline either acutely or once daily for 8 or 14 days were killed 24 hrs after the last dose. In striatal slices prelabelled with (/sup 3/H)DA, modulation of (/sup 3/H)-overflow by pergolide was used to measure D-2 autoreceptor activity. Compared to the contemporaneous control group pergolide produced a greater inhibition only in striatal slices from rats treated repeatedly with cocaine. In radioligand binding studies using striatal membranes from control rats, pergolide had a 500-fold greater affinity for the D-2, as opposed to the D-1, dopamine (DA) receptor subtype. These results indicate that repeated treatment with cocaine produces supersensitive striatal D-2 release-modulating autoreceptors consistent with a compensatory change to diminish the effect of elevated synaptic concentrations of DA produced by cocaine. In contrast, supersensitivity of D-2 receptors was not detected in (/sup 3/H)spiperone binding assays. 31 references, 2 figures, 1 table.

  15. 78 FR 31945 - Clinical Development Programs for Opioid Conversion; Public Workshop; Request for Comments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-28

    ... HUMAN SERVICES Food and Drug Administration Clinical Development Programs for Opioid Conversion; Public... equianalgesic opioid conversion tables in opioid product labels. Discussion will focus on the available data supporting the use of equianalgesic opioid conversion tables, problems associated with their use,...

  16. The delayed lung responses to single and repeated intratracheal administration of pure cobalt and hard metal powder in the rat.

    PubMed

    Lasfargues, G; Lardot, C; Delos, M; Lauwerys, R; Lison, D

    1995-05-01

    Epidemiological and clinical studies suggest that inhalation of cobalt metal dust (Co) mixed with tungsten carbide particles (WC), but not of cobalt dust alone, may cause interstitial pulmonary lesions (hard metal disease). In previous experimental studies in the rat, we have demonstrated the greater acute pulmonary toxicity of a WC-Co mixture compared to Co or WC alone. The present study was undertaken to compare in the same animal model the delayed lung response after intratracheal administration of Co or WC-Co particles (cobalt particle 6.3 wt%). The responses were also compared with those obtained after treatment with arsenic trioxide and crystalline silica used a reference materials producing an acute toxic insult and a progressive fibrogenic response, respectively. Cellular (total and differential counts) and biochemical parameters (LDH, N-acetyl-beta-D-glucosaminidase, total protein, albumin, fibronectin, and hyaluronic acid) were measured in bronchoalveolar lavage fluid following single and repeated intratracheal instillations. The results indicate that the delayed lung response observed after WC-Co is different from that after cobalt metal alone. A single intratracheal dose of WC-Co (1, 5, or 10 mg/100 g body wt) induced an acute alveolitis which persisted for at least 1 month. Four months after a single instillation of WC-Co, no clear histological lung fibrosis could however be evidenced, indicating a reversibility of the lesions. The effects of cobalt (0.06, 0.3, or 0.6 mg/100 g body wt) or tungsten carbide alone (1, 5, 10 mg/ 100 g body wt) were very modest, if any. Following repeated intratracheal instillations (four administrations at 1-month interval), increased lung hydroxyproline content and histopathological evidence of interstitial fibrosis were observed after WC-Co (4 x 1 mg/100 g body wt), but not after administration of each component separately, i.e., Co (4 x 0.06 mg/100 g body wt) or WC (4 x 1 mg/100 g body wt). The mechanism of the fibrotic

  17. The effects of repeated intravenous iohexol administration on renal function in healthy beagles – a preliminary report

    PubMed Central

    2012-01-01

    Background Contrast induced nephrotoxicity (CIN) is a well described syndrome in humans undergoing contrast medium examinations. To date CIN has received minimal attention in the veterinary literature despite increasing use of contrast medium examinations in computed tomographic studies. Methods This prospective study evaluated the effect of 1290 mg/kg iohexol given intravenously to 5 normal beagle dogs in a divided dose at an interval of 6–8 weeks. Renal function was evaluated by means of scintigraphically determined glomerular filtration rate (GFR) and a variety of laboratory assays. Results Only GFR showed a significant decrease (17%) after the second injection but not to a clinically or pathologically significant level. Conclusions No clinically significant effect of repeated contrast medium administration was determined in this limited study. However in dogs with reduced renal function the risk of CIN is likely to increase dramatically post contrast administration. PMID:22892108

  18. Inhibition of rat brain monoamine oxidase by repeated administration of pirlindol

    SciTech Connect

    Verevkina, I.V.; Asnina, V.V.; Gorkin, V.Z.; Mashovskii, M.D.

    1985-10-01

    Since pirlindol, like other antidepressants, is used for a long time and since its therapeutic effect usually appears 5-7 days or more after the beginning of treatment, the authors investigate its action on activity of MAO of types A and B in rat brain when administered repeatedly. MAO activity was determined in 50% homogenates of rat brain, made up in 10 mM phosphate buffer, pH 7.4, containing 2% detergent Triton X-100. It is shown that an important role in the antidepressant effect of pirlindol is played by its property of selectively blocking deamination of neurotrans mitters such as serotonin and noradrenalin in the human brain.

  19. Repeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertility

    NASA Astrophysics Data System (ADS)

    Bai, Yuhong; Zhang, Yi; Zhang, Jingping; Mu, Qingxin; Zhang, Weidong; Butch, Elizabeth R.; Snyder, Scott E.; Yan, Bing

    2010-09-01

    Soluble carbon nanotubes show promise as materials for in vivo delivery and imaging applications. Several reports have described the in vivo toxicity of carbon nanotubes, but their effects on male reproduction have not been examined. Here, we show that repeated intravenous injections of water-soluble multiwalled carbon nanotubes into male mice can cause reversible testis damage without affecting fertility. Nanotubes accumulated in the testes, generated oxidative stress and decreased the thickness of the seminiferous epithelium in the testis at day 15, but the damage was repaired at 60 and 90 days. The quantity, quality and integrity of the sperm and the levels of three major sex hormones were not significantly affected throughout the 90-day period. The fertility of treated male mice was unaffected; the pregnancy rate and delivery success of female mice that mated with the treated male mice did not differ from those that mated with untreated male mice.

  20. Comparative toxicity of silicon dioxide, silver and iron oxide nanoparticles after repeated oral administration to rats.

    PubMed

    Yun, Jun-Won; Kim, Seung-Hyun; You, Ji-Ran; Kim, Woo Ho; Jang, Ja-June; Min, Seung-Kee; Kim, Hee Chan; Chung, Doo Hyun; Jeong, Jayoung; Kang, Byeong-Cheol; Che, Jeong-Hwan

    2015-06-01

    Although silicon dioxide (SiO2), silver (Ag) and iron oxide (Fe2O3) nanoparticles are widely used in diverse applications from food to biomedicine, in vivo toxicities of these nanoparticles exposed via the oral route remain highly controversial. To examine the systemic toxicity of these nanoparticles, well-dispersed nanoparticles were orally administered to Sprague-Dawley rats daily over a 13-week period. Based on the results of an acute toxicity and a 14-day repeated toxicity study, 975.9, 1030.5 and 1000 mg kg(-1) were selected as the highest dose of the SiO2 , Ag and Fe2O3 nanoparticles, respectively, for the 13-week repeated oral toxicity study. The SiO2 and Fe2O3 nanoparticles did not induce dose-related changes in a number of parameters associated with the systemic toxicity up to 975.9 and 1000 mg kg(-1) , respectively, whereas the Ag nanoparticles resulted in increases in serum alkaline phosphatase and calcium as well as lymphocyte infiltration in liver and kidney, raising the possibility of liver and kidney toxicity induced by the Ag nanoparticles. Compared with the SiO2 and Fe2O3 nanoparticles showing no systemic distribution in all tissues tested, the Ag concentration in sampled blood and organs in the Ag nanoparticle-treated group significantly increased with a positive and/or dose-related trend, meaning that the systemic toxicity of the Ag nanoparticles, including liver and kidney toxicity, might be explained by extensive systemic distribution of Ag originating from the Ag nanoparticles. Our current results suggest that further study is required to identify that Ag detected outside the gastrointestinal tract were indeed a nanoparticle form or ionized form.

  1. 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.

  2. Repeated oral administration of capsaicin increases anxiety-like behaviours with prolonged stress-response in rats.

    PubMed

    Choi, Y-J; Kim, J Y; Yoo, S B; Lee, J-H; Jahng, J W

    2013-09-01

    This study was conducted to examine the psycho-emotional effects of repeated oral exposure to capsaicin, the principal active component of chili peppers. Each rat received 1 mL of 0.02 percent capsaicin into its oral cavity daily, and was subjected to behavioural tests following 10 daily administrations of capsaicin. Stereotypy counts and rostral grooming were significantly increased, and caudal grooming decreased, in capsaicin-treated rats during the ambulatory activity test. In elevated plus maze test, not only the time spent in open arms but also the percent arm entry into open arms was reduced in capsaicin-treated rats compared with control rats. In forced swim test, although swimming duration was decreased, struggling increased in the capsaicin group, immobility duration did not differ between the groups. Repeated oral capsaicin did not affect the basal levels of plasma corticosterone; however, the stress-induced elevation of plasma corticosterone was prolonged in capsaicin treated rats. Oral capsaicin exposure significantly increased c-Fos expression not only in the nucleus tractus of solitarius but also in the paraventricular nucleus. Results suggest that repeated oral exposure to capsaicin increases anxiety-like behaviours in rats, and dysfunction of the hypothalamic-pituitary-adrenal axis may play a role in its pathophysiology. PMID:23938388

  3. The hypothalamic-pituitary-luteal axis in women: effects of long-term orally active opioid antagonist (naltrexone) administration.

    PubMed

    Fulghesu, A M; Lanzone, A; Apa, R; Guido, M; Ciampelli, M; Cucinelli, F; Caruso, A; Mancuso, S

    1997-01-01

    Aim of our study is to assess the effect of a long-term oral opiate antagonist treatment during the luteal phase on the hypothalamic-pituitary-ovarian axis. Fourteen normovulatory women participated to the study. Immediately after the ovulation, the patients were randomly divided in two groups: in the first one women received naltrexone 50 mg/die orally (Antaxone Zambon Italy) from day 1 of the luteal phase for 7 days. In the second patients were treated with placebo for the same period and served as control group. On day 7, patients were hospitalized for a pulse pattern study followed by a GnRH test. LH, FSH, Estradiol, Progesterone were assayed. The naltrexone administration strongly increased the number as well as the amplitude of the gonadotropin pulses. The circulating P levels were also significantly higher in treated patients. The GnRH injection significantly increases the gonadotropin secretion in all patients. The stimulated LH and FSH secretion was significantly greater in treated patients when compared to controls. Such discharge of LH determined a significant increase of progesterone production in controls, but failed to stimulate the corpus luteum in treated patients. In conclusion the present paper strengthen an important role of the opioidergic system in the regulation of GnRH pulsatility in luteal phase. Moreover, our findings confirms the sensibility of the corpus luteum to LH and the possibility to stimulate the P secretion during the luteal phase.

  4. Prescription opioids. III. Disposition of oxycodone in oral fluid and blood following controlled single-dose administration.

    PubMed

    Cone, Edward J; DePriest, Anne Z; Heltsley, Rebecca; Black, David L; Mitchell, John M; LoDico, Charles; Flegel, Ron

    2015-04-01

    Oxycodone (OC) is recommended to be included as an analyte tested in the proposed Substance Abuse and Mental Health Services Administration (SAMHSA's) Mandatory Guidelines for Federal Workplace Drug Testing Programs using Oral Fluid (OF) Specimens. This study demonstrates the time course of OC and metabolites, noroxycodone (NOC), oxymorphone (OM) and noroxymorphone (NOM), in near-simultaneous paired OF and whole blood (BL) specimens by liquid chromatography-tandem mass spectrometry (LC-MS-MS) (limit of detection = 1 ng/mL OF, 5 ng/mL BL). A single dose of OC 20 mg controlled-release was administered to 12 healthy subjects followed by specimen collections for 52 h. Analyte prevalence was as follows: OF, OC > NOC > OM; and BL, OC > NOC > NOM. OC and NOC were frequently detected within 15-30 min in OF and 30 min to 2 h in BL. NOM and OM appeared between 1.5-5 h post-dose. The mean OF-to-BL (OF:BL) ratios and correlations were 5.4 for OC (r = 0.719) and 1.0 for NOC (r = 0.651). The period of detection for OF exceeded BL by ∼2-fold at similar cutoff concentrations. At a 1 ng/mL cutoff for OF, the mean detection time was 34 h for OC and NOC. These data provide new information that should facilitate interpretation of OC test results.

  5. Opioid System Modulates the Immune Function: A Review

    PubMed Central

    Liang, Xuan; Liu, Renyu; Chen, Chunhua; Ji, Fang; Li, Tianzuo

    2016-01-01

    Opioid receptors and their ligands produce powerful analgesia that is effective in perioperative period and chronic pain managements accompanied with various side effects including respiratory depression, constipation and addiction etc. Opioids can also interfere with the immune system, not only participating in the function of the immune cells, but also modulating innate and acquired immune responses. The traditional notion of opioids is immunosuppressive. Recent studies indicate that the role of opioid receptors on immune function is complicated, working through various different mechanisms. Different opioids or opioids administrations show various effects on the immune system: immunosuppressive, immunostimulatory, or dual effect. It is important to elucidate the relationship between opioids and immune function, since immune system plays critical role in various physiological and pathophysiological processes, including the inflammation, tumor growth and metastasis, drug abuse, and so on. This review article tends to have an overview of the recent work and perspectives on opioids and the immune function. PMID:26985446

  6. Implant Proves Effective At Combating Opioid Dependence

    MedlinePlus

    ... a film dissolved in the mouth. Buprenorphine provides effects that are similar to, but weaker than, opioids ... and Mental Health Services Administration (SAMHSA). But those effects level off at moderate doses, lowering the risk ...

  7. Repeated Neonatal Propofol Administration Induces Sex-Dependent Long-Term Impairments on Spatial and Recognition Memory in Rats

    PubMed Central

    Gonzales, Edson Luck T.; Yang, Sung Min; Choi, Chang Soon; Mabunga, Darine Froy N.; Kim, Hee Jin; Cheong, Jae Hoon; Ryu, Jong Hoon; Koo, Bon-Nyeo; Shin, Chan Young

    2015-01-01

    Propofol is an anesthetic agent that gained wide use because of its fast induction of anesthesia and rapid recovery post-anesthesia. However, previous studies have reported immediate neurodegeneration and long-term impairment in spatial learning and memory from repeated neonatal propofol administration in animals. Yet, none of those studies has explored the sex-specific long-term physical changes and behavioral alterations such as social (sociability and social preference), emotional (anxiety), and other cognitive functions (spatial working, recognition, and avoidance memory) after neonatal propofol treatment. Seven-day-old Wistar-Kyoto (WKY) rats underwent repeated daily intraperitoneal injections of propofol or normal saline for 7 days. Starting fourth week of age and onwards, rats were subjected to behavior tests including open-field, elevated-plus-maze, Y-maze, 3-chamber social interaction, novel-object-recognition, passive-avoidance, and rotarod. Rats were sacrificed at 9 weeks and hippocampal protein expressions were analyzed by Western blot. Results revealed long-term body weight gain alterations in the growing rats and sex-specific impairments in spatial (female) and recognition (male) learning and memory paradigms. A markedly decreased expression of hippocampal NMDA receptor GluN1 subunit in female- and increased expression of AMPA GluR1 subunit protein expression in male rats were also found. Other aspects of behaviors such as locomotor activity and coordination, anxiety, sociability, social preference and avoidance learning and memory were not generally affected. These results suggest that neonatal repeated propofol administration disrupts normal growth and some aspects of neurodevelopment in rats in a sex-specific manner. PMID:25995824

  8. Hepatotoxicity assessment of Mn-doped ZnS quantum dots after repeated administration in mice

    PubMed Central

    Yang, Yanjie; Lv, Shuang-Yu; Yu, Bianfei; Xu, Shuang; Shen, Jianmin; Zhao, Tong; Zhang, Haixia

    2015-01-01

    Doped ZnS quantum dots (QDs) have a longer dopant emission lifetime and potentially lower cytotoxicity compared to other doped QDs. The liver is the key organ for clearance and detoxification of xenobiotics by phagocytosis and metabolism. The present study was designed to synthesize and evaluate the hepatotoxicity of Mn-doped ZnS QDs and their polyethylene glycol-coated counterparts (1 mg/kg and 5 mg/kg) in mice. The results demonstrated that daily injection of Mn-doped ZnS QDs and polyethylene glycol-coated QDs via tail vein for 7 days did not influence body weight, relative liver weight, serum aminotransferases (alanine aminotransferase and aspartate aminotransferase), the levels of antioxidant enzymes (catalase, glutathione peroxidase, and superoxide dismutase), or malondialdehyde in the liver. Analysis of hepatocyte ultrastructure showed that Mn-doped ZnS QDs and polyethylene glycol-coated QDs mainly accumulated in mitochondria at 24 hours after repeated intravenous injection. No damage to cell nuclei or mitochondria was observed with either of the QDs. Our results indicate that Mn-doped ZnS QDs did not cause obvious damage to the liver. This study will assist in the development of Mn-doped ZnS QDs-based bioimaging and biomedical applications in the future. PMID:26396512

  9. Hepatotoxicity assessment of Mn-doped ZnS quantum dots after repeated administration in mice.

    PubMed

    Yang, Yanjie; Lv, Shuang-Yu; Yu, Bianfei; Xu, Shuang; Shen, Jianmin; Zhao, Tong; Zhang, Haixia

    2015-01-01

    Doped ZnS quantum dots (QDs) have a longer dopant emission lifetime and potentially lower cytotoxicity compared to other doped QDs. The liver is the key organ for clearance and detoxification of xenobiotics by phagocytosis and metabolism. The present study was designed to synthesize and evaluate the hepatotoxicity of Mn-doped ZnS QDs and their polyethylene glycol-coated counterparts (1 mg/kg and 5 mg/kg) in mice. The results demonstrated that daily injection of Mn-doped ZnS QDs and polyethylene glycol-coated QDs via tail vein for 7 days did not influence body weight, relative liver weight, serum aminotransferases (alanine aminotransferase and aspartate aminotransferase), the levels of antioxidant enzymes (catalase, glutathione peroxidase, and superoxide dismutase), or malondialdehyde in the liver. Analysis of hepatocyte ultrastructure showed that Mn-doped ZnS QDs and polyethylene glycol-coated QDs mainly accumulated in mitochondria at 24 hours after repeated intravenous injection. No damage to cell nuclei or mitochondria was observed with either of the QDs. Our results indicate that Mn-doped ZnS QDs did not cause obvious damage to the liver. This study will assist in the development of Mn-doped ZnS QDs-based bioimaging and biomedical applications in the future. PMID:26396512

  10. Mechanism of nephrotoxicity induced by repeated administration of cadmium chloride in rats

    SciTech Connect

    Sudo, Jun-ichi; Hayashi, Taiji; Kimura, Shin-ichi

    1996-07-01

    To explore the mechanism of Cd nephrotoxicity, CdCl{sub 2} was subcutaneously injected to rats, at 3 mg Cd/kg body weight once a day, for 8 d. In the liver, Cd bound to metallothioneins (MTs-Cd) rose from d 1 after the initiation of CdCl{sub 2} administration, and reached a plateau after the administration ceased. In the plasma, MTs-Cd rose from d 4, peaked on d 8, and gradually fell thereafter. In the kidney`s leucine aminopeptidase (LAP) and N-acetyl {beta}-D-glucosaminidase (NAG) fell during d 6-20, and Cd bound to cellular membranes (Mem-Cd) rose from d 1 and reached a plateau during d 6-20. The Mem-Cd levels were significantly correlated with the reduction in the LAP and NAG activity; the values of MTs-Cd plus Mem-Cd were almost equivalent to those of total Cd. These findings showed that the hepatic synthesis of MTs-Cd occurred followed by its release into plasma; the extent of renal injury was aggravated as the plasma level of MTs-Cd rose; and a greater part of the renal Cd distributed intracellularly as the MTs-binding form, while the residual Cd distributed as the cellular membrane-binding form. Also, it was suggested that Cd that occurred as the cullular membrane-binding form in the kidneys was involved in manifestation of renal injury. 29 refs., 9 figs., 1 tab.

  11. Disruption of spindle checkpoint function ahead of facilitation of cell proliferation by repeated administration of hepatocarcinogens in rats.

    PubMed

    Kimura, Masayuki; Mizukami, Sayaka; Watanabe, Yousuke; Hasegawa-Baba, Yasuko; Onda, Nobuhiko; Yoshida, Toshinori; Shibutani, Makoto

    2015-12-01

    We aimed to clarify the hepatocarcinogen-specific disruption of cell cycle checkpoint functions and its time course after repeated administration of hepatocarcinogens. Thus, rats were repeatedly administered with hepatocarcinogens (methapyrilene, carbadox and thioacetamide), a marginal hepatocarcinogen (leucomalachite green), hepatocarcinogenic promoters (oxfendazole and β-naphthoflavone) or non-carcinogenic hepatotoxicants (promethazine and acetaminophen) for 7, 28 or 90 days, and the temporal changes in cell proliferation, expression of G1/S and spindle checkpoint-related molecules, and apoptosis were examined using immunohistochemistry and/or real-time RT-PCR analysis. Hepatocarcinogens facilitating cell proliferation at day 28 of administration also facilitated cell proliferation and apoptosis at day 90. Hepatocarcinogen- or hepatocarcinogenic promoter-specific cellular responses were not detected by immunohistochemical single molecule analysis even after 90 days. Expression of Cdkn1a, Mad2l1, Chek1 and Rbl2 mRNA also lacked specificity to hepatocarcinogens or hepatocarcinogenic promoters. In contrast, all hepatocarcinogens and the marginally hepatocarcinogenic leucomalachite green induced Mdm2 upregulation or increase in the number of phosphorylated MDM2(+) cells from day 28, irrespective of the lack of cell proliferation facilitation by some compounds. However, different Tp53 expression levels suggest different mechanisms of induction or activation of MDM2 among hepatocarcinogens. On the other hand, hepatocarcinogenic methapyrilene and carbadox downregulated the number of both ubiquitin D(+) cells and proliferating cells remaining in M phase at day 28 and/or day 90, irrespective of the lack of cell proliferation facilitation in the latter. These results suggest that hepatocarcinogens disrupt spindle checkpoint function after 28 or 90 days of administration, which may be induced ahead of cell proliferation facilitation. PMID:26558467

  12. Disruption of spindle checkpoint function ahead of facilitation of cell proliferation by repeated administration of hepatocarcinogens in rats.

    PubMed

    Kimura, Masayuki; Mizukami, Sayaka; Watanabe, Yousuke; Hasegawa-Baba, Yasuko; Onda, Nobuhiko; Yoshida, Toshinori; Shibutani, Makoto

    2015-12-01

    We aimed to clarify the hepatocarcinogen-specific disruption of cell cycle checkpoint functions and its time course after repeated administration of hepatocarcinogens. Thus, rats were repeatedly administered with hepatocarcinogens (methapyrilene, carbadox and thioacetamide), a marginal hepatocarcinogen (leucomalachite green), hepatocarcinogenic promoters (oxfendazole and β-naphthoflavone) or non-carcinogenic hepatotoxicants (promethazine and acetaminophen) for 7, 28 or 90 days, and the temporal changes in cell proliferation, expression of G1/S and spindle checkpoint-related molecules, and apoptosis were examined using immunohistochemistry and/or real-time RT-PCR analysis. Hepatocarcinogens facilitating cell proliferation at day 28 of administration also facilitated cell proliferation and apoptosis at day 90. Hepatocarcinogen- or hepatocarcinogenic promoter-specific cellular responses were not detected by immunohistochemical single molecule analysis even after 90 days. Expression of Cdkn1a, Mad2l1, Chek1 and Rbl2 mRNA also lacked specificity to hepatocarcinogens or hepatocarcinogenic promoters. In contrast, all hepatocarcinogens and the marginally hepatocarcinogenic leucomalachite green induced Mdm2 upregulation or increase in the number of phosphorylated MDM2(+) cells from day 28, irrespective of the lack of cell proliferation facilitation by some compounds. However, different Tp53 expression levels suggest different mechanisms of induction or activation of MDM2 among hepatocarcinogens. On the other hand, hepatocarcinogenic methapyrilene and carbadox downregulated the number of both ubiquitin D(+) cells and proliferating cells remaining in M phase at day 28 and/or day 90, irrespective of the lack of cell proliferation facilitation in the latter. These results suggest that hepatocarcinogens disrupt spindle checkpoint function after 28 or 90 days of administration, which may be induced ahead of cell proliferation facilitation.

  13. Prescription Opioids during Pregnancy

    MedlinePlus

    ... brand names ConZip®, Ryzolt®, Ultram®) The street drug heroin also is an opioid. What problems can opioids ... to buy them illegally. People often start using heroin after becoming addicted to prescription opioids. Sometimes opioids ...

  14. Behavioral and neurochemical effects of repeated MDMA administration during late adolescence in the rat.

    PubMed

    Cox, Brittney M; Shah, Mrudang M; Cichon, Teri; Tancer, Manuel E; Galloway, Matthew P; Thomas, David M; Perrine, Shane A

    2014-01-01

    Adolescents and young adults disproportionately abuse 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy'); however, since most MDMA research has concentrated on adults, the effects of MDMA on the developing brain remain obscure. Therefore, we evaluated place conditioning to MDMA (or saline) during late adolescence and assessed anxiety-like behavior and monoamine levels during abstinence. Rats were conditioned to associate 5 or 10mg/kg MDMA or saline with contextual cues over 4 twice-daily sessions. Five days after conditioning, anxiety-like behavior was examined with the open field test and brain tissue was collected to assess serotonin (5-hydroxytryptamine, 5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the dorsal raphe, amygdala, and hippocampus by high-pressure liquid chromatography (HPLC). In a separate group of rats, anxiety-like and avoidant behaviors were measured using the light-dark box test under similar experimental conditions. MDMA conditioning caused a place aversion at 10, but not at 5, mg/kg, as well as increased anxiety-like behavior in the open field and avoidant behavior in light-dark box test at the same dose. Additionally, 10mg/kg MDMA decreased 5-HT in the dorsal raphe, increased 5-HT and 5-HIAA in the amygdala, and did not alter levels in the hippocampus. Overall, we show that repeated high (10mg/kg), but not low (5mg/kg), dose MDMA during late adolescence in rats increases anxiety-like and avoidant behaviors, accompanied by region-specific alterations in 5-HT levels during abstinence. These results suggest that MDMA causes a region-specific dysregulation of the serotonin system during adolescence that may contribute to maladaptive behavior.

  15. Repeated administration of angiotensin II reduces its dipsogenic effect without affecting saline intake.

    PubMed

    Vento, Peter J; Daniels, Derek

    2010-06-01

    Angiotensin II (Ang II) acts at central type 1 (AT(1)) receptors to increase intake of water and saline. In vitro studies demonstrated rapid desensitization of the AT(1) receptor after Ang II exposure, and behavioural studies in rats suggest that exposure to Ang II decreases the dipsogenic potency of subsequent Ang II. Nevertheless, the effect of repeated Ang II injections on saline intake remains untested, and a reliable protocol for examining this purported behavioural desensitization has not emerged from the literature. To address these issues, we established a reliable approach to study Ang II-induced dipsetic desensitization and used this approach to test the requirement of central AT(1) receptors and the specificity of the effect for water intake. Rats given a treatment regimen of three injections of Ang II (300 ng, intracerebroventricular), each separated by 20 min, drank less water than control rats after a subsequent test injection of Ang II. The effect was relatively short lasting, dependent on the dose and timing of Ang II, and was almost completely blocked by the AT(1) receptor antagonist losartan. In further testing, when rats were given access to both water and 1.5% saline, animals that received an Ang II treatment regimen drank less water than control animals, but saline intake was unaffected. These data support previous suggestions that Ang II-induced water and saline intakes are separable. Given the role of G protein uncoupling in desensitization of the AT(1) receptor, these data are consistent with the emerging hypothesis that AT(1) receptor G protein-dependent intracellular signalling pathways are more relevant for water, but not saline, intake.

  16. Urinary excretion of enzymes following repeated parenteral administration of cadmium to rats

    SciTech Connect

    Bonner, F.W.; King, L.J.; Parke, D.V.

    1980-06-01

    The effect of daily parenteral administration of cadmium (0.75, 1.5, and 3.0 mg/kg) on the urinary excretion of enzymes has been studied in the young male rat. Aspartate aminotransferase, alkaline phosphatase, ..gamma..-glutamyl transpeptidase, and leucine aminopeptidase all showed an initial significant increase around the second day of dosage, the intensity of which was dose related. A second phase of enzymuria occurred later, the onset of which was dose related. High-dose-group animals (3.0 mg/kg) exhibited this increase around Day 15, while the median (1.5 mg/kg) and low- (0.75 mg/kg)dose-group animals developed enzymuria around Days 21 and 38, respectively. This second phase of elevated enzyme levels in the urine was persistent, and is believed to represent the development of renal damage.

  17. The Changing Use of Intravenous Opioids in an Emergency Department

    PubMed Central

    Sutter, Mark E.; Wintemute, Garen J.; Clarke, Samuel O.; Roche, Bailey M.; Chenoweth, James A.; Gutierrez, Rory; Albertson, Timothy E.

    2015-01-01

    Introduction Government agencies are increasingly emphasizing opioid safety in hospitals. In 2012, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) started a sentinel event program, the “Safe Use of Opioids in Hospitals.” We sought to determine if opioid use patterns in our emergency department (ED) changed from 2011, before the program began, to 2013, after start of the program. Methods This was a retrospective study of all adult ED patients who received an intravenous opioid and had a serum creatinine measured. We recorded opioids used, dose prescribed, and serum creatinine. As an index of the safety of opioids, uses of naloxone after administration of an opioid was recorded. Results Morphine is still the most commonly used opioid by doses given, but its percentage of opioids used decreased from 68.9% in 2011 to 52.8% in 2013. During the same period, use of hydromorphone increased from 27.5% to 42.9%, while the use of fentanyl changed little (3.6% to 4.3%). Naloxone administration was rare after an opioid had been given. Opioids were not dosed in an equipotent manner. Conclusion The use of hydromorphone in our ED increased by 56% (absolute increase of 15.4%), while the use of morphine decreased by 30.5% (absolute decrease 16.1%) of total opioid use from 2011 to 2013. The JCAHO program likely was at least indirectly responsible for this change in relative dosing of the opioids. Based on frequency of naloxone administered after administration of an opioid, the use of opioids was safe. PMID:26759658

  18. Single-dose evaluation of safety, tolerability and pharmacokinetics of newly formulated hydromorphone immediate-release and hydrophilic matrix extended-release tablets in healthy Japanese subjects without co-administration of an opioid antagonist.

    PubMed

    Toyama, Kaoru; Uchida, Naoki; Ishizuka, Hitoshi; Sambe, Takehiko; Kobayashi, Shinichi

    2015-09-01

    This single dose, open-label study investigated the safety, tolerability and pharmacokinetics of single oral doses of newly formulated immediate-release (IR) and hydrophilic matrix extended-release (ER) hydromorphone tablets in healthy Japanese subjects without co-administration of an opioid antagonist under fasting and fed conditions. Plasma and urinary concentrations of hydromorphone and metabolites were measured by liquid-chromatography tandem mass-spectroscopy. Following administration of the ER tablet, plasma concentrations of hydromorphone slowly increased with a median tmax of 5.0 h and the Cmax decreased to 37% of the IR tablet, while the AUC0-inf was comparable with that of the IR tablet when administered at the same dose. The degree of fluctuation in the plasma concentration for the ER tablet was much lower than that of the IR tablet and certain levels of plasma concentrations were maintained after 24 h of ER dosing. The AUC0-inf and Cmax increased with food for both IR and ER tablets. The AUC0-inf of hydromorphone-3-glucoside was one-tenth of that of hydromorphone-3-glucuronide. A single oral administration of the hydromorphone tablets would be well-tolerated in healthy Japanese subjects despite a lack of co-administration of an opioid antagonist and the newly developed ER hydromorphone tablets may have the appropriate PK characteristics for once-daily dosing.

  19. Effects of repeated-low level sodium chlorate administration on ruminal and fecal coliforms in sheep.

    PubMed

    Arzola, Claudio; Copado, Ramon; Epps, Sharon V R P; Rodriguez-Almeida, Felipe; Ruiz-Barrera, Oscar; Rodriguez-Muela, Carlos; Corral-Luna, Agustin; Castillo-Castillo, Yamicela; Diaz-Plascencia, Daniel

    2014-01-01

    Abstract The objective of this study was to evaluate the efficacy of oral sodium chlorate administration on reducing total coliform populations in ewes. A 30% sodium chlorate product or a sodium chloride placebo was administered to twelve lactating Dorper X Blackbelly or Pelibuey crossbred ewes averaging 65 kg body weight. The ewes were adapted to diet and management. Ewes were randomly assigned (4/treatment) to one of three treatments which were administered twice daily by oral gavage for five consecutive days: a control (TC) consisting of 3 g sodium chloride/animal/d, a T3 treatment consisting of 1.8 g of sodium chlorate/animal/d, and a T9 treatment consisting of 5.4 g sodium chlorate/animal/d; the latter was intended to approximate a lowest known effective dose. Ruminal samples collected by stomach tube and freshly voided fecal samples were collected daily beginning 3 days before treatment initiation and for 6 days thereafter. Contents were cultured quantitatively to enumerate total coliforms. There were no significant differences in total coliform numbers (log10 cfu/g) in the feces between treatments (P = 0.832). There were differences (P < 0.02) in ruminal coliform counts (log10 cfu/mL) between treatments (4.1, 4.3 and 5.0 log10/mL contents in TC, T3 and T9 Treatments, respectively) which tended to increase from the beginning of treatment until the 5th day of treatment (P < 0.05). Overall, we did not obtain the expected results with oral administration of sodium chloride at the applied doses. By comparing the trends in coliform populations in the rumen contents in all treatments, there was an increase over the days. The opposite trend occurred in the feces, due mainly to differences among rumen contents and feces in ewes administered the T9 treatment (P = 0.06). These results suggest that the low chlorate doses used here were suboptimal for the control of coliforms in the gastrointestinal tract of ewes.

  20. Peripherally mediated antinociception of the mu-opioid receptor agonist 2-[(4,5alpha-epoxy-3-hydroxy-14beta-methoxy-17-methylmorphinan-6beta-yl)amino]acetic acid (HS-731) after subcutaneous and oral administration in rats with carrageenan-induced hindpaw inflammation.

    PubMed

    Bileviciute-Ljungar, Indre; Spetea, Mariana; Guo, Yan; Schütz, Johannes; Windisch, Petra; Schmidhammer, Helmut

    2006-04-01

    Opioids induce analgesia by activating opioid receptors not only within the central nervous system but also on peripheral sensory neurons. This study investigated peripherally mediated antinociception produced by the mu-opioid receptor agonist 2-[(4,5alpha-epoxy-3-hydroxy-14beta-methoxy-17-methylmorphinan-6beta-yl)amino]acetic acid (HS-731) after s.c. and oral administration in rats with carrageenan-induced hindpaw inflammation. Antinociceptive effects after s.c. administration were assessed 3 h after intraplantar carrageenan injection and compared with those of centrally acting mu-opioid agonists 14-methoxymetopon and morphine. Opioid agonists caused dose-dependent increases in inflamed paw withdrawal latencies to mechanical and thermal stimulation. The time course of action was different, in that HS-731 (20 microg/kg s.c.) produced significant long-lasting effects up to 4 h after administration, whereas 14-methoxymetopon (20 microg/kg) and morphine (2 mg/kg) reached their peak of action at 10 to 30 min, and their effect declined rapidly thereafter. Subcutaneous administration of the peripherally selective opioid antagonist naloxone methiodide inhibited antinociception elicited by HS-731 (20 microg/kg s.c.), whereas it was ineffective against 14-methoxymetopon (20 microg/kg s.c.). Moreover, the antinociception produced by 100 microg/kg s.c. HS-731 was dose-dependently reversed by s.c. naloxone methiodide. This indicates that HS-731 preferentially activates peripheral opioid receptors, whereas 14-methoxymetopon mediates analgesia via central mechanisms. Orally administered HS-731 significantly reduced hyperalgesia in the inflamed paw induced by carrageenan, which was reversible by s.c. administered naloxone methiodide. These results show that systemic (s.c. and oral) treatment with the mu-opioid agonist HS-731 produces potent and long-lasting antinociception through peripheral mechanisms in rats with carrageenan-induced hindpaw inflammation.

  1. The prolongation of the lifespan of rats by repeated oral administration of [60]fullerene.

    PubMed

    Baati, Tarek; Bourasset, Fanchon; Gharbi, Najla; Njim, Leila; Abderrabba, Manef; Kerkeni, Abdelhamid; Szwarc, Henri; Moussa, Fathi

    2012-06-01

    Countless studies showed that [60]fullerene (C(60)) and derivatives could have many potential biomedical applications. However, while several independent research groups showed that C(60) has no acute or sub-acute toxicity in various experimental models, more than 25 years after its discovery the in vivo fate and the chronic effects of this fullerene remain unknown. If the potential of C(60) and derivatives in the biomedical field have to be fulfilled these issues must be addressed. Here we show that oral administration of C(60) dissolved in olive oil (0.8 mg/ml) at reiterated doses (1.7 mg/kg of body weight) to rats not only does not entail chronic toxicity but it almost doubles their lifespan. The effects of C(60)-olive oil solutions in an experimental model of CCl(4) intoxication in rat strongly suggest that the effect on lifespan is mainly due to the attenuation of age-associated increases in oxidative stress. Pharmacokinetic studies show that dissolved C(60) is absorbed by the gastro-intestinal tract and eliminated in a few tens of hours. These results of importance in the fields of medicine and toxicology should open the way for the many possible -and waited for- biomedical applications of C(60) including cancer therapy, neurodegenerative disorders, and ageing.

  2. Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia

    PubMed Central

    Oladosu, Folabomi A.; Conrad, Matthew S.; O’Buckley, Sandra C.; Rashid, Naim U.; Slade, Gary D.; Nackley, Andrea G.

    2015-01-01

    Background A subset of the population receiving opioids for the treatment of acute and chronic clinical pain develops a paradoxical increase in pain sensitivity known as opioid-induced hyperalgesia. Given that opioid analgesics are one of few treatments available against clinical pain, it is critical to determine the key molecular mechanisms that drive opioid-induced hyperalgesia in order to reduce its prevalence. Recent evidence implicates a splice variant of the mu opioid receptor known as MOR-1K in the emergence of opioid-induced hyperalgesia. Results from human genetic association and cell signaling studies demonstrate that MOR-1K contributes to decreased opioid analgesic responses and produces increased cellular activity via Gs signaling. Here, we conducted the first study to directly test the role of MOR-1K in opioid-induced hyperalgesia. Methods and Results In order to examine the role of MOR-1K in opioid-induced hyperalgesia, we first assessed pain responses to mechanical and thermal stimuli prior to, during, and following chronic morphine administration. Results show that genetically diverse mouse strains (C57BL/6J, 129S6, and CXB7/ByJ) exhibited different morphine response profiles with corresponding changes in MOR-1K gene expression patterns. The 129S6 mice exhibited an analgesic response correlating to a measured decrease in MOR-1K gene expression levels, while CXB7/ByJ mice exhibited a hyperalgesic response correlating to a measured increase in MOR-1K gene expression levels. Furthermore, knockdown of MOR-1K in CXB7/ByJ mice via chronic intrathecal siRNA administration not only prevented the development of opioid-induced hyperalgesia, but also unmasked morphine analgesia. Conclusions These findings suggest that MOR-1K is likely a necessary contributor to the development of opioid-induced hyperalgesia. With further research, MOR-1K could be exploited as a target for antagonists that reduce or prevent opioid-induced hyperalgesia. PMID:26270813

  3. Effects of repeated administration of rifampicin and isoniazid on vitamin D metabolism in mice.

    PubMed

    Sheng, Li; Xue, Ying; He, Xin; Zhu, Yungui; Li, Huande; Wu, Yanqin; Dang, Ruili; Tang, Mimi; Jiang, Pei

    2015-12-01

    Vitamin D deficiency is prevalent in tuberculosis (TB) patients and the anti-TB drugs, especially rifampicin (RIF) and isoniazid (INH), are associated with altered endocrine actions of vitamin D. Although it is well-known that these two drugs can affect a variety of cytochrome P450 (CYP450) activity, their influence on the CYP450 enzymes involved in vitamin D metabolism remains largely unknown. To fill this critical gap, serum vitamin D status and the expression of hepatic CYP2R1 and CYP27A1 and renal CYP27B1 and CYP24A1 were assessed in mice following 3-week exposure to 100 mg/kg/day RIF or (and) 50 mg/kg/day INH. Unexpectedly, we found either RIF or co-treatment the two drugs increased the concentrations of 25-hydroxyvitamin D3 (25(OH)D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), without affecting 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) status. In parallel, enhanced hepatic expressions of 25-hydroxylase enzymes, CYP2R1 and (or) CYP27A1, were found in RIF and RIF+INH groups. However, co-administration of RIF and INH inhibited the expression of CYP27B1, while inducing CYP24A1 expression. Collectively, our data firstly showed that RIF and co-treatment of RIF and INH can both enhance 25-hydroxylation and 24-hydroxylation of vitamin D, providing novel evidence for the involvement of anti-TB drugs in the metabolism of vitamin D.

  4. Prescription Opioid Epidemic and Infant Outcomes

    PubMed Central

    Dudley, Judith; Martin, Peter R.; Harrell, Frank E.; Warren, Michael D.; Hartmann, Katherine E.; Ely, E. Wesley; Grijalva, Carlos G.; Cooper, William O.

    2015-01-01

    BACKGROUND AND OBJECTIVES: Although opioid pain relievers are commonly prescribed in pregnancy, their association with neonatal outcomes is poorly described. Our objectives were to identify neonatal complications associated with antenatal opioid pain reliever exposure and to establish predictors of neonatal abstinence syndrome (NAS). METHODS: We used prescription and administrative data linked to vital statistics for mothers and infants enrolled in the Tennessee Medicaid program between 2009 and 2011. A random sample of NAS cases was validated by medical record review. The association of antenatal exposures with NAS was evaluated by using multivariable logistic regression, controlling for maternal and infant characteristics. RESULTS: Of 112 029 pregnant women, 31 354 (28%) filled ≥1 opioid prescription. Women prescribed opioid pain relievers were more likely than those not prescribed opioids (P < .001) to have depression (5.3% vs 2.7%), anxiety disorder (4.3% vs 1.6%) and to smoke tobacco (41.8% vs 25.8%). Infants with NAS and opioid-exposed infants were more likely than unexposed infants to be born at a low birth weight (21.2% vs 11.8% vs 9.9%; P < .001). In a multivariable model, higher cumulative opioid exposure for short-acting preparations (P < .001), opioid type (P < .001), number of daily cigarettes smoked (P < .001), and selective serotonin reuptake inhibitor use (odds ratio: 2.08 [95% confidence interval: 1.67–2.60]) were associated with greater risk of developing NAS. CONCLUSIONS: Prescription opioid use in pregnancy is common and strongly associated with neonatal complications. Antenatal cumulative prescription opioid exposure, opioid type, tobacco use, and selective serotonin reuptake inhibitor use increase the risk of NAS. PMID:25869370

  5. Effects of methiothepin on changes in brain serotonin release induced by repeated administration of high doses of anorectic serotoninergic drugs

    NASA Technical Reports Server (NTRS)

    Gardier, A. M.; Kaakkola, S.; Erfurth, A.; Wurtman, R. J.

    1992-01-01

    We previously observed, using in vivo microdialysis, that the potassium-evoked release of frontocortical serotonin (5-HT) is suppressed after rats receive high doses (30 mg/kg, i.p., daily for 3 days) of fluoxetine, a selective blocker of 5-HT reuptake. We now describe similar impairments in 5-HT release after repeated administration of two other 5-HT uptake blockers, zimelidine and sertraline (both at 20 mg/kg, i.p. for 3 days) as well as after dexfenfluramine (7.5 mg/kg, i.p. daily for 3 days), a drug which both releases 5-HT and blocks its reuptake. Doses of these indirect serotonin agonists were about 4-6 times the drug's ED50 in producing anorexia, a serotonin-related behavior. In addition, methiothepin (20 microM), a non-selective receptor antagonist, locally perfused through the dialysis probe 24 h after the last drug injection, enhanced K(+)-evoked release of 5-HT at serotoninergic nerve terminals markedly in control rats and slightly in rats treated with high doses of dexfenfluramine or fluoxetine. On the other hand, pretreatment with methiothepin (10 mg/kg, i.p.) one hour before each of the daily doses of fluoxetine or dexfenfluramine given for 3 days, totally prevented the decrease in basal and K(+)-evoked release of 5-HT. Finally, when methiothepin was injected systemically the day before the first of 3 daily injections of dexfenfluramine, it partially attenuated the long-term depletion of brain 5-HT and 5-HIAA levels induced by repeated administration of high doses of dexfenfluramine. These data suggest that drugs which bring about the prolonged blockade of 5-HT reuptake - such as dexfenfluramine and fluoxetine - can, by causing prolonged increases in intrasynaptic 5-HT levels as measured by in vivo microdialysis, produce receptor-mediated long-term changes in the processes controlling serotonin levels and dynamics.

  6. Opioid Analgesics and Nicotine: More Than Blowing Smoke.

    PubMed

    Yoon, Jin H; Lane, Scott D; Weaver, Michael F

    2015-09-01

    Practitioners are highly likely to encounter patients with concurrent use of nicotine products and opioid analgesics. Smokers present with more severe and extended chronic pain outcomes and have a higher frequency of prescription opioid use. Current tobacco smoking is a strong predictor of risk for nonmedical use of prescription opioids. Opioid and nicotinic-cholinergic neurotransmitter systems interact in important ways to modulate opioid and nicotine effects: dopamine release induced by nicotine is dependent on facilitation by the opioid system, and the nicotinic-acetylcholine system modulates self-administration of several classes of abused drugs-including opioids. Nicotine can serve as a prime for the use of other drugs, which in the case of the opioid system may be bidirectional. Opioids and compounds in tobacco, including nicotine, are metabolized by the cytochrome P450 enzyme system, but the metabolism of opioids and tobacco products can be complicated. Accordingly, drug interactions are possible but not always clear. Because of these issues, asking about nicotine use in patients taking opioids for pain is recommended. When assessing patient tobacco use, practitioners should also obtain information on products other than cigarettes, such as cigars, pipes, smokeless tobacco, and electronic nicotine delivery systems (ENDS, or e-cigarettes). There are multiple forms of behavioral therapy and pharmacotherapy available to assist patients with smoking cessation, and opioid agonist maintenance and pain clinics represent underutilized opportunities for nicotine intervention programs.

  7. Opioid Analgesics and Nicotine: More Than Blowing Smoke.

    PubMed

    Yoon, Jin H; Lane, Scott D; Weaver, Michael F

    2015-09-01

    Practitioners are highly likely to encounter patients with concurrent use of nicotine products and opioid analgesics. Smokers present with more severe and extended chronic pain outcomes and have a higher frequency of prescription opioid use. Current tobacco smoking is a strong predictor of risk for nonmedical use of prescription opioids. Opioid and nicotinic-cholinergic neurotransmitter systems interact in important ways to modulate opioid and nicotine effects: dopamine release induced by nicotine is dependent on facilitation by the opioid system, and the nicotinic-acetylcholine system modulates self-administration of several classes of abused drugs-including opioids. Nicotine can serve as a prime for the use of other drugs, which in the case of the opioid system may be bidirectional. Opioids and compounds in tobacco, including nicotine, are metabolized by the cytochrome P450 enzyme system, but the metabolism of opioids and tobacco products can be complicated. Accordingly, drug interactions are possible but not always clear. Because of these issues, asking about nicotine use in patients taking opioids for pain is recommended. When assessing patient tobacco use, practitioners should also obtain information on products other than cigarettes, such as cigars, pipes, smokeless tobacco, and electronic nicotine delivery systems (ENDS, or e-cigarettes). There are multiple forms of behavioral therapy and pharmacotherapy available to assist patients with smoking cessation, and opioid agonist maintenance and pain clinics represent underutilized opportunities for nicotine intervention programs. PMID:26375198

  8. Hippocampal Aβ expression, but not phosphorylated tau, predicts cognitive deficits following repeated peripheral poly I:C administration.

    PubMed

    White, J D; Eimerbrink, M J; Hayes, H B; Hardy, A; Van Enkevort, E A; Peterman, J L; Chumley, M J; Boehm, G W

    2016-10-15

    Alzheimer's disease is marked by the accumulation of the amyloid-beta (Aβ) peptide, and increases in phosphorylation of the microtubule associated protein, tau. Changes in these proteins are considered responsible, in part, for the progressive neuronal degeneration and cognitive deficits seen in AD. We examined the effect of repeated consecutive peripheral poly I:C injections on cognitive deficits, central Aβ, and phosphorylated tau accumulation, following three treatment durations: 7, 14, and 21 days. Forty-eight hours after the final injection, animals were trained in a contextual fear-conditioning paradigm, and tested 24h later. Immediately after testing, the hippocampus was collected to quantify Aβ and phosphorylated tau accumulation. Results showed that, although poly I:C-induced Aβ was significantly elevated at all time points examined, poly I:C only disrupted cognition after 14 and 21 days of administration. Moreover, elevations in phosphorylated tau were not seen until the 14-day time point. Interestingly, phosphorylated tau expression then declined at the 21-day time point. Finally, we demonstrated that Aβ levels are a stronger predictor of cognitive dysfunction, explaining 37% of the variance, whereas phosphorylated tau levels only accounted for 0.2%. Taken together, these results support the hypothesis that inflammation-induced elevation in Aβ disrupts cognition, independently of phosphorylated tau, and suggest that long-term administration of poly I:C may provide a model to investigate the contribution of long-term inflammation toward the development of Alzheimer's-like pathology.

  9. Interactions among unit-price, fixed-ratio value, and dosing regimen in determining effects of repeated cocaine administration.

    PubMed

    Yoon, Jin Ho; Branch, Marc N

    2004-11-30

    Previous research has shown tolerance to cocaine that was dependent on fixed-ratio (FR) parameter size in the context of a multiple FR schedule of food reinforcement. Completion of the FR requirement in these studies resulted in the same magnitude of reinforcement, regardless of ratio size. The cost-to-benefits ratio (unit-price) was therefore not equated across the different FR components. The current study examined the effects of repeated administration of cocaine to pigeons when unit-price under FR schedules was either the same or different. Additionally, the role of a chronic variable-dosing versus chronic fixed-dosing procedure was examined when unit-price was equated across different ratio values. Pigeons were trained to key peck in daily sessions under a three-component multiple FR schedule of food presentation, according to which either 10, 30, or 100 pecks were required for each delivery of food. In Experiment 1, completion of the FR 10, FR 30, and FR 100 resulted in 1.5, 4.5, and 15.0 s access to food, respectively. That is, the response requirement was correlated with access to food time so that unit-price (pecks per second of access to food) was equated across components. After assessing acute effects of a range of doses of cocaine, drug administration occurred daily before each session, with the dose varying from day to day. Tolerance, the magnitude of which was unrelated to the peck requirement, developed under the repeated-dosing regimen. In order to assess whether having equal unit-price was responsible for producing similar levels of tolerance across components, daily drug administration continued in Experiment 2 using the variable-dose regimen, but the amount of food presented each time was fixed at 4.5 s access to food, yielding different unit-prices under the three pecking requirements. Subsequently, the conditions of Experiment 1 were reinstated, i.e., unit-price was equated. Making unit-price different or the same had little influence on

  10. Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice.

    PubMed

    Schiavon, Angélica Pupin; Bonato, Jéssica Mendes; Milani, Humberto; Guimarães, Francisco Silveira; Weffort de Oliveira, Rúbia Maria

    2016-01-01

    Therapeutic effects of antidepressants and atypical antipsychotics may arise partially from their ability to stimulate neurogenesis. Cannabidiol (CBD), a phytocannabinoid present in Cannabis sativa, presents anxiolytic- and antipsychotic-like effects in preclinical and clinical settings. Anxiolytic-like effects of repeated CBD were shown in chronically stressed animals and these effects were parallel with increased hippocampal neurogenesis. However, antidepressant-like effects of repeated CBD administration in non-stressed animals have been scarcely reported. Here we investigated the behavioral consequences of single or repeated CBD administration in non-stressed animals. We also determined the effects of CBD on cell proliferation and neurogenesis in the dentate gyrus (DG) and subventricular zone (SVZ). Single CBD 3mg/kg administration resulted in anxiolytic-like effect in mice submitted to the elevated plus maze (EPM). In the tail suspension test (TST), single or repeated CBD administration reduced immobility time, an effect that was comparable to those of imipramine (20 mg/kg). Moreover, repeated CBD administration at a lower dose (3 mg/kg) increased cell proliferation and neurogenesis, as seen by an increased number of Ki-67-, BrdU- and doublecortin (DCX)-positive cells in both in DG and SVZ. Despite its antidepressant-like effects in the TST, repeated CBD administration at a higher dose (30 mg/kg) decreased cell proliferation and neurogenesis in the hippocampal DG and SVZ. Our findings show a dissociation between behavioral and proliferative effects of repeated CBD and suggest that the antidepressant-like effects of CBD may occur independently of adult neurogenesis in non-stressed Swiss mice.

  11. Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice.

    PubMed

    Schiavon, Angélica Pupin; Bonato, Jéssica Mendes; Milani, Humberto; Guimarães, Francisco Silveira; Weffort de Oliveira, Rúbia Maria

    2016-01-01

    Therapeutic effects of antidepressants and atypical antipsychotics may arise partially from their ability to stimulate neurogenesis. Cannabidiol (CBD), a phytocannabinoid present in Cannabis sativa, presents anxiolytic- and antipsychotic-like effects in preclinical and clinical settings. Anxiolytic-like effects of repeated CBD were shown in chronically stressed animals and these effects were parallel with increased hippocampal neurogenesis. However, antidepressant-like effects of repeated CBD administration in non-stressed animals have been scarcely reported. Here we investigated the behavioral consequences of single or repeated CBD administration in non-stressed animals. We also determined the effects of CBD on cell proliferation and neurogenesis in the dentate gyrus (DG) and subventricular zone (SVZ). Single CBD 3mg/kg administration resulted in anxiolytic-like effect in mice submitted to the elevated plus maze (EPM). In the tail suspension test (TST), single or repeated CBD administration reduced immobility time, an effect that was comparable to those of imipramine (20 mg/kg). Moreover, repeated CBD administration at a lower dose (3 mg/kg) increased cell proliferation and neurogenesis, as seen by an increased number of Ki-67-, BrdU- and doublecortin (DCX)-positive cells in both in DG and SVZ. Despite its antidepressant-like effects in the TST, repeated CBD administration at a higher dose (30 mg/kg) decreased cell proliferation and neurogenesis in the hippocampal DG and SVZ. Our findings show a dissociation between behavioral and proliferative effects of repeated CBD and suggest that the antidepressant-like effects of CBD may occur independently of adult neurogenesis in non-stressed Swiss mice. PMID:26187374

  12. Opioid-induced hyperalgesia and burn pain.

    PubMed

    Holtman, Joseph R; Jellish, W Scott

    2012-01-01

    The treatment of pain produced during the management of burn injury has been an ongoing problem for physicians caring for these patients. The main therapeutic option for analgesia has been the repeated and prolonged use of opioids. The adverse effects of opioids are well known but the long term use of opioids which produces tolerance with accompanying dose escalation and dependence is most problematic. Another potentially important consequence of opioid exposure that sometimes masks as tolerance is that of opioid induced hyperalgesia. This syndrome is manifest as enhanced pain, sensitivity and loss of analgesic efficacy in patients treated with opioids who actually become sensitized to painful stimuli. This article focuses on the treatment of burn pain and how current analgesic therapies with opioids may cause hyperalgesia and affect the adequacy of treatment for burn pain. This article also provides possible modalities to help therapeutically manage these patients and considers future analgesic strategies which may help to improve pain management in this complicated patient population.

  13. Neonatal opioid withdrawal syndrome.

    PubMed

    Sutter, Mary Beth; Leeman, Lawrence; Hsi, Andrew

    2014-06-01

    Neonatal opioid withdrawal syndrome is common due to the current opioid addiction epidemic. Infants born to women covertly abusing prescription opioids may not be identified as at risk until withdrawal signs present. Buprenorphine is a newer treatment for maternal opioid addiction and appears to result in a milder withdrawal syndrome than methadone. Initial treatment is with nonpharmacological measures including decreasing stimuli, however pharmacological treatment is commonly required. Opioid monotherapy is preferred, with phenobarbital or clonidine uncommonly needed as adjunctive therapy. Rooming-in and breastfeeding may decease the severity of withdrawal. Limited evidence is available regarding long-term effects of perinatal opioid exposure.

  14. [Misuse of opioid analgesics. An internet analysis].

    PubMed

    Krüger, R; Meißner, W; Zimmer, A

    2014-10-01

    Apart from the prescribed administration and indications for pain relief, opioids are also used for unintended purposes. Information for misuse is circulated on the internet. In order to analyze the abuse of opioids and opiates,which are only available by prescription, defined search keywords were entered into the search engine of a German language internet forum on drugs in 2010 and 2013 and the results were evaluated. Items to be assessed and analyzed were the frequency of naming various substances and (in the first analysis only) aspects of their incorporation as well as user reports on various aspects of use (e.g. drug procurement, administration, effects and side effects). Tramadol was the most frequently quoted opioid followed by codeine, tilidine, morphine and oxycodone. Other opioids were named in only 10 % of the entries. Oral intake was the most frequently mentioned mode of administration followed by parenteral and nasal routes. These findings can support caregivers to identify unintended use of opioids and to increase awareness of the most frequently used opioids and modes of administration.

  15. Effects of co-administration of 2-arachidonylglycerol (2-AG) and a selective μ-opioid receptor agonist into the nucleus accumbens on high-fat feeding behaviors in the rat

    PubMed Central

    Parker, Kyle E.; McCall, Jordan G.; McGuirk, Sophia R.; Trivedi, Seema; Miller, Dennis K.; Will, Matthew J.

    2015-01-01

    Previous research has demonstrated that the nucleus accumbens is a site where opioids and cannabinoids interact to alter feeding behavior. However, the influence of the endocannabinoid 2-arachidonylglycerol (2-AG) on the well-characterized model of intra-accumbens opioid driven high-fat feeding behavior has not been explored. The present experiments examined high-fat feeding associated behaviors produced by the interaction of 2-AG and the µ-opioid receptor agonist DAla2,N,Me-Phe4,Gly-ol5-enkaphalin (DAMGO) administered into the nucleus accumbens. Sprague-Dawley rats were implanted with bilateral cannulae aimed at the nucleus accumbens and were co-administered both a sub-threshold dose of 2-AG (0 or 0.25µg/0.5µl/side) and DAMGO (0, 0.025µg or 0.25µg/0.5µl/side) in all dose combinations, and in a counterbalanced order. Animals were then immediately allowed a 2hr-unrestricted access period to a palatable high-fat diet. Consumption, number and duration of food hopper entries, and locomotor activity were all monitored. DAMGO treatment led to an increase in multiple behaviors, including consumption, duration of food hopper entry, and locomotor activity. However, combined intra-accumbens administration of DAMGO and a subthreshold dose of 2- AG led to a significant increase in number of food hopper entries and locomotor activity, compared to DAMGO by itself. The results confirm that intra-accumbens administration of subthreshold dose of the endogenous cannabinoid 2-AG increases the DAMGO-induced approach and locomotor behaviors associated with high-fat feeding. PMID:26100333

  16. Effects of co-administration of 2-arachidonylglycerol (2-AG) and a selective µ-opioid receptor agonist into the nucleus accumbens on high-fat feeding behaviors in the rat.

    PubMed

    Parker, Kyle E; McCall, Jordan G; McGuirk, Sophia R; Trivedi, Seema; Miller, Dennis K; Will, Matthew J

    2015-08-27

    Previous research has demonstrated that the nucleus accumbens is a site where opioids and cannabinoids interact to alter feeding behavior. However, the influence of the endocannabinoid 2-arachidonylglycerol (2-AG) on the well-characterized model of intra-accumbens opioid driven high-fat feeding behavior has not been explored. The present experiments examined high-fat feeding associated behaviors produced by the interaction of 2-AG and the μ-opioid receptor agonist DAla(2),N,Me-Phe(4),Gly-ol(5)-enkaphalin (DAMGO) administered into the nucleus accumbens. Sprague-Dawley rats were implanted with bilateral cannulae aimed at the nucleus accumbens and were co-administered both a sub-threshold dose of 2-AG (0 or 0.25 μg/0.5 μl/side) and DAMGO (0, 0.025 μg or 0.25 μg/0.5 μl/side) in all dose combinations, and in a counterbalanced order. Animals were then immediately allowed a 2h-unrestricted access period to a palatable high-fat diet. Consumption, number and duration of food hopper entries, and locomotor activity were all monitored. DAMGO treatment led to an increase in multiple behaviors, including consumption, duration of food hopper entry, and locomotor activity. However, combined intra-accumbens administration of DAMGO and a subthreshold dose of 2-AG led to a significant increase in number of food hopper entries and locomotor activity, compared to DAMGO by itself. The results confirm that intra-accumbens administration of subthreshold dose of the endogenous cannabinoid 2-AG increases the DAMGO-induced approach and locomotor behaviors associated with high-fat feeding. PMID:26100333

  17. Determinants of nurses' intention to administer opioids for pain relief.

    PubMed

    Edwards, H E; Nash, R E; Najman, J M; Yates, P M; Fentiman, B J; Dewar, A; Walsh, A M; McDowell, J K; Skerman, H M

    2001-09-01

    A statewide cross-sectional survey was conducted in Australia to identify the determinants of registered nurses' intention to administer opioids to patients with pain. Attitudes, subjective norms and perceived control, the key determinants of the Theory of Planned Behavior, were found to independently predict nurses' intention to administer opioids to these patients. Perceived control was the strongest predictor. Nurses reported positive overall attitudes towards opioids and their use in pain management. However, many negative attitudes were identified; for example, administering the least amount of opioid and encouraging patients to have non-opioids rather than opioids for pain relief. The findings related to specific attitudes and normative pressures provide insight into registered nurses' management of pain for hospitalized patients and the direction for educational interventions to improve registered nurses' administration of opioids for pain management.

  18. Dopamine D4 receptors linked to protein kinase G are required for changes in dopamine release followed by locomotor activity after repeated cocaine administration.

    PubMed

    Oh, Jeong Hwan; Lee, Dong Kun; Shim, Yoon-Bo; Ryu, In Soo; Seo, Su Yeon; Kim, Jieun; Yang, Ju Hwan; Cho, Hyun-Wook; Choe, Eun Sang

    2015-05-01

    We previously found that the dopamine D2-type receptors (D2 and D3 receptors), coupled to protein kinase G (PKG), upregulate locomotor activity after repeated cocaine administration. In this study, D4 receptors, another type of D2 receptor also coupled to PKG, were examined to determine their requirement in the regulation of locomotor activity after repeated cocaine administration. The results demonstrated that repeated injections of cocaine (20 mg/kg), given once a day for seven consecutive days, significantly increased extracellular dopamine concentrations. Intra-caudate infusion of the D4 receptor agonist, PD168077 (10 nmol), and the PKG inhibitor, KT5823 (2 nmol), significantly decreased the repeated cocaine-induced increase in dopamine levels and locomotor activity. However, intra-caudate infusion of KT5823, but not PD168077, decreased ∆FosB immunoreactivity elevated by repeated cocaine administration. These findings suggest that D4 receptors linked to PKG could be a key modulator for dopamine release required for changes in locomotor activity caused by repeated cocaine exposure. PMID:25702161

  19. Effects of chronic and repeated repeated coritcosterone administration in rearing chickens on physiology, the onset of lay and egg production in hens.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A corticosterone (CORT) model was used to study the effects of repeated stress during rearing phase on physiology and performance of hens’ in subsequent laying period. Two hundred and seventy Hy-line laying birds were reared in environmentally controlled battery cages. At 7, 11, and 15 wk of age bir...

  20. Ca2+/calmodulin-dependent protein kinase II alpha is required for the initiation and maintenance of opioid-induced hyperalgesia.

    PubMed

    Chen, Yan; Yang, Cheng; Wang, Zaijie Jim

    2010-01-01

    Repeated administration of opioids not only leads to tolerance and dependence, but also results in nociceptive enhancement called opioid-induced hyperalgesia (OIH). Nociceptive mediators involved in OIH generation remain poorly understood. In the present study, we tested the hypothesis that Ca(2+)/calmodulin-depent protein kinase II (CaMKIIalpha) is critical for OIH. Opioid-induced hyperalgesia was produced by repeated morphine administration or pellet implantation in mice. Correlating with the development of tactile allodynia and thermal hyperalgesia, spinal CaMKIIalpha activity was significantly increased in OIH. KN93, a CaMKII inhibitor, dose- and time-dependently reversed OIH and CaMKII activation without impairing locomotor coordination. To elucidate the specific CaMKII isoform involved, we targeted CaMKIIalpha by using small interfering RNA and demonstrated that knockdown of spinal CaMKIIalpha attenuated OIH. Furthermore, morphine failed to induce OIH in CaMKIIalpha(T286A) point mutant mice, although wild-type littermate mice developed robust OIH after repeated treatments with morphine. These data implicate, for the first time, an essential role of CaMKIIalpha as a cellular mechanism leading to and maintaining opioid-induced hyperalgesia.

  1. Repeated and chronic administration of Vardenafil or Sildenafil differentially affects emotional and socio-sexual behavior in mice.

    PubMed

    Dadomo, H; Parmigiani, S; Nicolini, Y; Freschini, S; Gioiosa, L; Patrelli, T S; Palanza, P; Volpi, R

    2013-09-15

    Selective phosphodiesterases (PDEs) inhibitors have been widely studied as therapeutic agents for treatment of various human diseases, including cardiotonics, vasodilators, smooth muscle relaxants, antidepressants, antithrombotics, antiasthmatics, and agents for improving learning and memory. Although Sildenafil(®) and Vardenafil(®) have similar chemical formulae, the same target and interact with many of the same residues at the active site of phosphodiesterse-5 (PDE-5), they exhibit both in vitro and in vivo some important functional differences that could differentially affect behavior. Therefore we assessed whether repeated and chronic administration of Vardenafil and Sildenafil at a dose based upon human treatment can differentially affect aggressive, social, emotional and sexual behavior. To this aim, the effects of Sildenafil (10mg/kg) or Vardenafil (2mg/kg) (t.i.w., for 5 weeks) were observed in CD1 subordinate male mice in a low aggression and social subordination context. The results show that Sildenafil increased competitive aggression, environmental and social exploration, and reduced anxiety like behaviors as compared to controls, whereas Vardenafil had a significant major effect on appetitive and consummatory aspect of sexual behavior. This demonstrates that Sildenafil and Vardenafil, although being structurally and functionally similar, are characterized by different neuro-behavioral actions and can have differential therapeutic potentials. PMID:23850358

  2. Upregulation of nucleoside triphosphate diphosphohydrolase-1 and ecto-5'-nucleotidase in rat hippocampus after repeated low-dose dexamethasone administration.

    PubMed

    Drakulić, Dunja; Stanojlović, Miloš; Nedeljković, Nadežda; Grković, Ivana; Veličković, Nataša; Guševac, Ivana; Mitrović, Nataša; Buzadžić, Ivana; Horvat, Anica

    2015-04-01

    Although dexamethasone (DEX), a synthetic glucocorticoid receptor (GR) analog with profound effects on energy metabolism, immune system, and hypothalamic-pituitary-adrenal axis, is widely used therapeutically, its impact on the brain is poorly understood. The aim of the present study was to explore the effect of repeated low-dose DEX administration on the activity and expression of the ectonucleotidase enzymes which hydrolyze and therefore control extracellular ATP and adenosine concentrations in the synaptic cleft. Ectonucleotidases tested were ectonucleoside triphosphate diphosphohydrolase 1-3 (NTPDase1-3) and ecto-5'-nucleotidase (eN), whereas the effects were evaluated in two brain areas that show different sensitivity to glucocorticoid action, hippocampus, and cerebral cortex. In the hippocampus, but not in cerebral cortex, modest level of neurodegenerative changes as well as increase in ATP, ADP, and AMP hydrolysis and upregulation of NTPDase1 and eN mRNA expression ensued under the influence of DEX. The observed pattern of ectonucleotidase activation, which creates tissue volume with enhanced capacity for adenosine formation, is the hallmark of the response after different insults to the brain.

  3. A comparative pharmacokinetic and pharmacodynamic study of FSK0808 versus reference filgrastim after repeated subcutaneous administration in healthy Japanese men.

    PubMed

    Matsuguma, Kyoko; Matsuki, Shunji; Sakamoto, Kei; Shiramoto, Masanari; Nakagawa, Misato; Kimura, Miyuki; Irie, Shin; Kaneko, Daiki; Ohnishi, Akihiro

    2015-03-01

    FSK0808, a biosimilar of filgrastim, is a recombinant human granulocyte colony-stimulating factor developed by Fuji Pharmaceuticals and Mochida Pharmaceutical Co., Ltd. We conducted a double-blind, randomized, crossover study in healthy Japanese men, comparing the number of CD34-positive cells (CD34(+) cells) after repeated subcutaneous administration of either FSK0808 or the reference filgrastim (Gran(®) ). As primary endpoints, we compared the maximum number of CD34(+) cells (CD34(+)  Cmax ) and the time to reach CD34(+) Cmax (CD34(+) tmax ). As secondary endpoints, we compared the area under the curve for the number of CD34(+) cells over time at the 410 hours time point (CD34(+) AUC0-410 ), the parameters used to calculate the pharmacodynamic index of the absolute neutrophil count, and the pharmacokinetic parameters. Regarding the CD34(+) Cmax and the CD34(+) AUC0-410 values, the 95% confidence interval (CI) of the differences between the mean values for each drug was within the range of log(0.8)-log(1.25). With respect to the differences in the median values between drugs, the ratio against the reference filgrastim median value in the 95% CI was within the range of ± 0.2 for the CD34(+) tmax value. From these results, we considered that these drugs display equivalent pharmacodynamic and pharmacokinetic properties. PMID:27128214

  4. Effects of amphetamine on the human brain opioid system--a positron emission tomography study.

    PubMed

    Guterstam, Joar; Jayaram-Lindström, Nitya; Cervenka, Simon; Frost, J James; Farde, Lars; Halldin, Christer; Franck, Johan

    2013-05-01

    Studies in rodents have shown that psychostimulant drugs such as cocaine and amphetamine cause endorphin release in the brain reward system. There is also evidence for the involvement of the opioid system in human psychostimulant dependence. The acute effects of an i.v. psychostimulant drug on the brain opioid system, however, have not yet been investigated in humans. We hypothesized that an i.v. dose of amphetamine as compared to placebo would cause an opioid release in the human brain reward system, measurable as a reduction of the binding potential of the μ-opioid receptor radioligand [(11)C]carfentanil. Ten healthy young men were examined using positron emission tomography (PET) and [(11)C]carfentanil in three sessions: at baseline; after placebo; after an i.v. amphetamine dose of 0.3 mg/kg bodyweight. The order of amphetamine and placebo was double-blinded and randomized. PET examinations were performed with a Siemens high resolution research tomograph. Data were analysed with the simplified reference tissue model, applying manually drawn regions of interest for every subject. Using repeated measures analysis of variance, we found no significant differences in [(11)C]carfentanil binding potential between amphetamine and placebo conditions in any of the investigated brain regions. In contrast to data from rodent studies and a recent study of oral amphetamine administration in humans, an i.v. dose of amphetamine does not cause any acute opioid release in healthy human subjects. The postulated role of the opioid system in mediating the effects of amphetamine needs to be further investigated in animal models of the disease as well as in patient populations.

  5. Tolerance develops to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride in nerve-injured rats.

    PubMed

    He, Shao-Qiu; Yang, Fei; Perez, Federico M; Xu, Qian; Shechter, Ronen; Cheong, Yong-Kwan; Carteret, Alene F; Dong, Xinzhong; Sweitzer, Sarah M; Raja, Srinivasa N; Guan, Yun

    2013-11-01

    Peripherally acting opioids are potentially attractive drugs for the clinical management of certain chronic pain states due to the lack of centrally mediated adverse effects. However, it remains unclear whether tolerance develops to peripheral opioid analgesic effects under neuropathic pain conditions. We subjected rats to L5 spinal nerve ligation (SNL) and examined the analgesic effects of repetitive systemic and local administration of loperamide hydrochloride, a peripherally acting opioid agonist. We found that the inhibition of mechanical hypersensitivity, an important manifestation of neuropathic pain, by systemic loperamide (1.5mg/kg subcutaneously) decreased after repetitive drug treatment (tolerance-inducing dose: 0.75 to 6.0mg/kg subcutaneously). Similarly, repeated intraplantar injection of loperamide (150 μg/50 μL intraplantarly) and D-Ala(2)-MePhe(4)-Glyol(5) enkephalin (300 μg/50 μL), a highly selective mu-opioid receptor (MOR) agonist, also resulted in decreased inhibition of mechanical hypersensitivity. Pretreatment with naltrexone hydrochloride (5mg/kg intraperitoneally) and MK-801 (0.2mg/kg intraperitoneally) attenuated systemic loperamide tolerance. Western blot analysis showed that repetitive systemic administration of morphine (3mg/kg subcutaneously), but not loperamide (3mg/kg subcutaneously) or saline, significantly increased MOR phosphorylation in the spinal cord of SNL rats. In cultured rat dorsal root ganglion neurons, loperamide dose-dependently inhibited KCl-induced increases in [Ca(2+)]i. However, this drug effect significantly decreased in cells pretreated with loperamide (3 μM, 72 hours). Intriguingly, in loperamide-tolerant cells, the delta-opioid receptor antagonist naltrindole restored loperamide's inhibition of KCl-elicited [Ca(2+)]i increase. Our findings indicate that animals with neuropathic pain may develop acute tolerance to the antiallodynic effects of peripherally acting opioids after repetitive systemic and local drug

  6. Corticotropin releasing factor-1 receptor antagonism alters the biochemical, but not behavioral effects of repeated interleukin-1β administration.

    PubMed

    Wilhelm, Clare J; Murphy-Crews, Aaron; Menasco, Daniel J; Huckans, Marilyn S; Loftis, Jennifer M

    2012-01-01

    Activation of the immune system via administration of cytokines is used for the treatment of chronic viral infections such as hepatitis C and for cancers resistant to radiotherapy. Cytokine-based treatments induce a range of "sickness" behaviors (e.g. depression, anxiety, pain, anorexia, and fatigue). Activation of the hypothalamic pituitary-adrenal axis via the induction of corticotropin releasing factor (CRF) may underlie these unwanted side effects. This study used repeated systemic injections of the pro-inflammatory cytokine interleukin-1β (IL-1β) to model the sickness behaviors and biochemical effects of immune system activation. We assessed the ability of CRF type I receptor (CRF(1)) antagonism to reduce biochemical and behavioral signs of sickness induced by IL-1β treatment. Forty Wistar rats were assigned to one of four groups: 1) saline+vehicle; 2) saline+DMP904 (CRF(1) antagonist); 3) IL-1β+vehicle; 4) IL-1β+DMP904. Rats received intraperitoneal injections of either DMP904 or vehicle and of IL-1β or saline for six days. Sickness behavior was evaluated using body weight assessments and forced swim testing (FST). Blood and brain samples were collected to measure cytokine, p38 mitogen-activated protein kinase (MAPK), and phospho-p38 MAPK levels using multiplex techniques. There were significant reductions in body weights and FST immobility times associated with IL-1β administration. Rats administered IL-1β had significantly higher serum levels of IL-10, but not interferon-γ. Within the hippocampus, IL-1β reduced levels of p38 MAPK, but had no impact on levels of phospho-p38 MAPK except in the presence of DMP904. When administered alone, DMP904 had no significant effect on p38 MAPK or phospho-p38 MAPK in the hippocampus, but when given with IL-1β led to increased phosphorylation of p38 MAPK. IL-1β and DMP904 reduced levels of p38 MAPK within the hypothalamus, while co-administration of IL-1β and DMP904 abolished the effects of either drug alone

  7. Amphiphysin I but not dynamin I nor synaptojanin mRNA expression increased after repeated methamphetamine administration in the rat cerebrum and cerebellum.

    PubMed

    Hamamura, Mitsuko; Okouchi, Jiro; Ozawa, Hidetoshi; Kimuro, Yoshihiko; Iwaki, Akiko; Fukumaki, Yasuyuki

    2013-07-01

    Dopamine increases/decreases synaptic vesicle recycling and in schizophrenia the proteins/mRNA is decreased. We isolated cDNA clone, similar to amphiphysin 1 (vesicle protein) mRNA from the neocortex of rats injected repeatedly with methamphetamine using polymerase chain reaction (PCR) differential display. This clone is highly homologous to the 3' region of the human amphiphysin gene. PCR extension study using a primer specific for the rat amphiphysin 1 gene and a primer located within the clone revealed that it is the 3' UTR region of the rat amphiphysin 1 gene. Furthermore, in situ hybridization revealed that amphiphysin 1 mRNA is expressed in the cerebrum, medial thalamus, hippocampus and cerebellum. In the cerebellum, amphiphysin mRNA expression was confined to upper granule cell layer. Repeated methamphetamine administration increased amphiphysin I mRNA expression in both anterior part of the cerebrum, and the cerebellum. However, the repeated administration did not alter mRNA expression of the other vesicle proteins, synaptotagmin I, synapsin I, synaptojanin and dynamin I, we conclude that the repeated administration selectively increased amphiphysin 1 mRNA expression. Thus, amphiphysin 1 does not work as synaptic recycling, but it is suggested, as a part of pathogenesis of brain tissue injury (under Ca²⁺ and Mg²⁺ devoid environment) in repeated methamphetamine-injected states, the gene regulate actin-asssembly, learning, cell stress signaling and cell polarity.

  8. Opioid agonist and antagonist treatment differentially regulates immunoreactive mu-opioid receptors and dynamin-2 in vivo.

    PubMed

    Yoburn, Byron C; Purohit, Vishal; Patel, Kaushal; Zhang, Qiuyu

    2004-09-13

    Opioid agonists and antagonists can regulate the density of mu-opioid receptors in whole animal and in cell culture. High intrinsic efficacy agonists (e.g., etorphine), but not lower intrinsic efficacy agonists (e.g., morphine), produce mu-opioid receptor down-regulation and can alter the abundance of mu-opioid receptor mRNA. Conversely, opioid antagonists substantially increase the density of mu-opioid receptors without changing its mRNA. Mu-opioid receptor up-regulation has been associated with decreases in the trafficking protein dynamin-2, whereas mu-opioid receptor down-regulation produces an increase in dynamin-2 abundance. To probe the differences between opioid agonist and antagonist-induced mu-opioid receptor regulation, the current study determined changes in mu-opioid receptor density using a combined radioligand binding ([3H] DAMGO) and quantitative Western blotting approach in mouse spinal cord. Furthermore, the differences between intermittent and continuous dosing protocols were evaluated. Continuous (7-8 days) s.c. infusions of naloxone (5 mg/kg/day) or naltrexone (15 mg s.c. implant pellet) increased mu-opioid receptor density in radioligand binding assays (approximately +80%) in mouse spinal cord and down-regulated dynamin-2 abundance (approximately -30%), but had no effect on the abundance of immunoreactive mu-opioid receptor. Continuous (7 days) s.c. infusion of etorphine (200 microg/kg/day) decreased immunoreactive mu-opioid receptor (approximately -35%) and [3H] DAMGO binding (approximately -30%), and concurrently increased dynamin-2 abundance (approximately +40%). Continuous (7 days) morphine infusion (40 mg/kg/day plus 25 mg s.c. implant pellet) had no effect on any outcome measure. Delivery of the same daily dose of etorphine or naloxone using intermittent (every 24 h for 7 days) s.c. administration had no effect on immunoreactive mu-opioid receptor, [3H] DAMGO binding or dynamin-2 abundance. These data indicate that mu-opioid receptor

  9. Intranasal administration of crushed ALO-02 (extended-release oxycodone with sequestered naltrexone): A randomized, controlled abuse-potential study in nondependent recreational opioid users.

    PubMed

    Setnik, Beatrice; Bramson, Candace; Bass, Almasa; Levy-Cooperman, Naama; Malhotra, Bimal; Matschke, Kyle; Sommerville, Kenneth W; Wolfram, Gernot; Geoffroy, Pierre

    2015-12-01

    ALO-02 is an abuse-deterrent formulation consisting of capsules filled with pellets of extended-release oxycodone surrounding sequestered naltrexone. This randomized, double-blind, placebo-/active-controlled, 4-way crossover study examined the abuse potential of crushed ALO-02 administered intranasally to healthy, nondependent, recreational opioid users. Following drug discrimination and naloxone challenge, eligible participants (n = 32) entered a 4-way crossover treatment phase: crushed single dose of 1 of 2 placebos, ALO-02 30 mg/3.6 mg (oxycodone/naltrexone) or oxycodone immediate-release (IR) 30 mg. Primary end points were Drug Liking and High, measured on visual analog scales (VAS) summarized as maximum effect (Emax ) and effect occurring over 2 hours postdose (AUE0-2  h ). Crushed ALO-02 resulted in significantly lower scores versus oxycodone IR on Drug Liking (Emax , 60.5 vs 92.8; AUE0-2  h , 105.4 vs 160.0, respectively) and High (Emax , 25.2 vs 86.9; AUE0-2  h , 27.1 vs 136.4, respectively; n = 28; P < .0001). Adverse events occurred most frequently with oxycodone IR, followed by ALO-02, then placebo, and were considered mild and consistent with opioid therapy. Crushed ALO-02 administered intranasally to nondependent recreational opioid users resulted in significantly lower scores on Drug Liking/High VAS and other positive subjective measures versus crushed oxycodone IR, suggesting less abuse potential. Demonstration of actual abuse deterrence in the real world requires further research.

  10. Effect of the oral thrombin inhibitor dabigatran on allergic lung inflammation induced by repeated house dust mite administration in mice.

    PubMed

    de Boer, Johannes D; Berkhout, Lea C; de Stoppelaar, Sacha F; Yang, Jack; Ottenhoff, Roelof; Meijers, Joost C M; Roelofs, Joris J T H; van't Veer, Cornelis; van der Poll, Tom

    2015-10-15

    Asthma is a chronic disease of the airways; asthma patients are hampered by recurrent symptoms of dyspnoea and wheezing caused by bronchial obstruction. Most asthma patients suffer from chronic allergic lung inflammation triggered by allergens such as house dust mite (HDM). Coagulation activation in the pulmonary compartment is currently recognized as a feature of allergic lung inflammation, and data suggest that coagulation proteases further drive inflammatory mechanisms. Here, we tested whether treatment with the oral thrombin inhibitor dabigatran attenuates allergic lung inflammation in a recently developed HDM-based murine asthma model. Mice were fed dabigatran (10 mg/g) or placebo chow during a 3-wk HDM airway exposure model. Dabigatran treatment caused systemic thrombin inhibitory activity corresponding with dabigatran levels reported in human trials. Surprisingly, dabigatran did not lead to inhibition of HDM-evoked coagulation activation in the lung as measured by levels of thrombin-antithrombin complexes and D-dimer. Repeated HDM administration caused an influx of eosinophils and neutrophils into the lungs, mucus production in the airways, and a T helper 2 response, as reflected by a rise in bronchoalveolar IL-4 and IL-5 levels and a systemic rise in IgE and HDM-IgG1. Dabigatran modestly improved HDM-induced lung pathology (P < 0.05) and decreased IL-4 levels (P < 0.01), without influencing other HDM-induced responses. Considering the limited effects of dabigatran in spite of adequate plasma levels, these results argue against clinical evaluation of dabigatran in patients with asthma.

  11. [Breast Cancer Patient with Bone Metastases Who Was Able to Return Home without Using Opioids after Administration of Strontium-89 Chloride].

    PubMed

    Yamaguchi, Yumi; Uejima, Chihiro; Tada, Yoichiro; Takaya, Seigo; Yamashiro, Yutaka; Shibata, Shunsuke; Ishiguro, Minoru; Nishidoi, Hideaki; Kobayashi, Masami

    2016-09-01

    A 46-year-old woman underwent mastectomy for right inflammatory breast cancer.Three years later, she was diagnosed with multiple bone metastases and was treated with systemic chemotherapy and zoledronic acid.Six years after the mastectomy, she complained of severe sacral pain, and 40 Gy external radiotherapy was applied to the sacral metastases.Oxycodone was also administered, but dose escalation was difficult because of severe nausea and fatigue.A bone scan showed increased uptake of Tc99m in an area consistent with the painful regions, and an injection of 89SrCl2 was administered.Five weeks after the injection, her severe pain was relieved and she was able to discontinue the use of opioids completely.She successfully lived at home for 100 days without using opioids.In this case, radionuclide therapy with 89SrCl2 led to remarkable pain relief with an improvement in the quality of life of the patient. PMID:27628553

  12. 78 FR 28865 - Request for Comment on the Federal Guidelines for Opioid Treatment

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-16

    ..., (``Final Rule'' 66 FR 4075-4102, January 17, 2001) include standards for opioid treatment. OTPs are... Federal Guidelines for Opioid Treatment AGENCY: Substance Abuse and Mental Health Services Administration... draft of the Federal Guidelines for Opioid Treatment. These guidelines elaborate upon the Federal...

  13. Suspected opioid-induced hyperalgesia in an infant.

    PubMed

    Hallett, B R; Chalkiadis, G A

    2012-01-01

    One explanation for diminished opioid analgesic efficacy is opioid-induced hyperalgesia (OIH). We report a case of OIH in an infant with gastroschisis, requiring multiple surgical interventions and prolonged sedation for ventilation. This is the first report of OIH in an infant. On day 41 of life after nine separate surgical interventions, the patient's pain scores increased and remained elevated, despite increasing opioid administration. The patient also developed hyperalgesia, allodynia, and photophobia and became extremely irritable upon handling. Other possible causes were excluded, including interruption to opioid delivery, sepsis, acid-base and electrolyte disturbance, and ongoing surgical pathology. An opioid rotation to hydromorphone was initiated and ketamine was commenced. Sedation for ventilation was achieved with dexmedetomidine and midazolam infusions. Over a period of 24 h after opioid de-escalation, pain scores reduced rapidly and the patient became significantly less irritable with handling. All infusions were gradually weaned and eventually ceased.

  14. [Opioid-induced hyperalgesia. Pathophysiology and clinical relevance].

    PubMed

    Koppert, W

    2004-05-01

    Opioids are the drugs of choice for the treatment of moderate to severe acute and chronic pain. However, clinical evidence suggests that opioids can elicit increased sensitivity to noxious stimuli suggesting that administration of opioids can activate both pain inhibitory and pain facilitatory systems. Acute receptor desensitization via uncoupling of the receptor from G-proteins, up-regulation of the cAMP pathway, activation of the N-methyl-D-aspartate (NMDA) receptor system, as well as descending facilitation, have been proposed as potential mechanisms underlying opioid-induced hyperalgesia. Numerous reports exist demonstrating that opioid-induced hyperalgesia is observed both in animal and human experimental models. Brief exposures to micro-receptor agonists induce long-lasting hyperalgesic effects for days, which might by reflected by clinical observations that large doses of intraoperative micro-receptor agonists increased postoperative pain and morphine consumption. Furthermore, the prolonged use of opioids in patients often requires increasing doses and may be accompanied by the development of abnormal pain. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs like NMDA-antagonists, alpha(2)-agonists, or non-steroidal anti-inflammatory drugs (NSAIDs), opioid rotation or combinations of opioids with different receptor selectivity.

  15. Opioids, Pain, the Brain, and Hyperkatifeia: A Framework for the Rational Use of Opioids for Pain

    PubMed Central

    Shurman, Joseph; Koob, George F.; Gutstein, Howard B.

    2010-01-01

    Objective Opioids have relieved more human suffering than any other medication, but their use is still fraught with significant concerns of misuse, abuse, and addiction. This theoretical article explores the hypothesis that opioid misuse in the context of pain management produces a hypersensitivity to emotional distress, termed hyperkatifeia. Results In the misuse of opioids, neural substrates that mediate positive emotional states (brain reward systems) are compromised, and substrates mediating negative emotional states (brain stress systems) are enhanced. A reflection and early marker of such a nonhomeostatic state may be the development of opioid-induced hyperkatifeia, defined as the increased intensity of the constellation of negative emotional/motivational symptoms and signs observed during withdrawal from drugs of abuse (derived from the Greek “katifeia” for dejection or negative emotional state) and is most likely to occur in subjects in whom the opioid produces a break with homeostasis and less likely to occur when the opioid is restoring homeostasis, such as in effective pain treatment. When the opioid appropriately relieves pain, opponent processes are not engaged. However, if the opioid is administered in excess of need because of overdose, pharmacokinetic variables, or treating an individual without pain, then the body will react to that perturbation by engaging opponent processes in the domains of both pain (hyperalgesia) and negative emotional states (hyperkatifeia). Conclusions Repeated engagement of opponent processes without time for the brain’s emotional systems to reestablish homeostasis will further drive changes in emotional processes that may produce opioid abuse or addiction, particularly in individuals with genetic or environmental vulnerability. PMID:20545871

  16. Medication-Assisted Treatment For Opioid Addiction in Opioid Treatment Programs. Treatment Improvement Protocol (TIP) Series 43

    ERIC Educational Resources Information Center

    Tinkler, Emily; Vallejos Bartlett, Catalina; Brooks, Margaret; Gilbert, Johnatnan Max; Henderson, Randi; Shuman, Deborah, J.

    2005-01-01

    TIP 43 provides best-practice guidelines for medication-assisted treatment of opioid addiction in opioid treatment programs (OTPs). The primary intended audience for this volume is substance abuse treatment providers and administrators who work in OTPs. Recommendations in the TIP are based on both an analysis of current research and determinations…

  17. Repeated intravenous administrations of teneurin-C terminal associated peptide (TCAP)-1 attenuates reinstatement of cocaine seeking by corticotropin-releasing factor (CRF) in rats.

    PubMed

    Erb, Suzanne; McPhee, Matthew; Brown, Zenya J; Kupferschmidt, David A; Song, Lifang; Lovejoy, David A

    2014-08-01

    The teneurin c-terminal associated peptides (TCAP) have been implicated in the regulation of the stress response, possibly via a corticotropin-releasing factor (CRF)-related mechanism. We have previously shown that repeated intracerebroventricular (ICV) injections of TCAP-1 attenuate the reinstatement of cocaine seeking by CRF in rats. Here, we determined whether intravenous (IV) administrations of TCAP-1 would likewise attenuate CRF-induced reinstatement, and whether this effect would vary depending on the rat's history of cocaine self administration. Rats were trained to self-administer cocaine for 10 days, during once daily sessions that were either 3h ("short access"; ShA) or 6h ("long access"; LgA). Rats were then given five daily injections of TCAP-1 (0, 300, or 3,000 pmol, IV) in their home cage. Subsequently, they were returned to the self-administration chambers where extinction of cocaine seeking and testing for CRF-induced reinstatement of cocaine seeking was carried out. Repeated IV administrations of TCAP-1 were efficacious in attenuating CRF-induced reinstatement of cocaine seeking, but at different doses in ShA and LgA rats. Taken together, the findings extend previous work showing a consistent effect of repeated ICV TCAP-1 on CRF-induced reinstatement of cocaine seeking, and point to a potential therapeutic benefit of TCAP-1 in attenuating cocaine seeking behaviors.

  18. Opioids and endocrine dysfunction

    PubMed Central

    Hester, Joan

    2012-01-01

    The endocrine effects of opioids used for the management of persistent pain are poorly understood by clinicians and patients, and hormone levels are rarely measured. It is recognized that opioids exert this effect via the hypothalamic-pituitary-gonadal axis. Additional effects on adrenal hormones, weight, blood pressure and bone density may also occur. Symptoms and signs of sex hormone deficiency occur in both men and women but are under-reported and are often clinically unrecognized. The potential effects of long term opioid therapy on the endocrine system should be explained to patients before opioid therapy is commenced. Monitoring of sex hormones is recommended; if there are deficiencies opioids should be tapered and withdrawn, if this is clinically acceptable. If opioid therapy has to continue, hormone replacement therapy should be initiated and monitored by an endocrinologist. PMID:26516462

  19. Opioids and endocrine dysfunction.

    PubMed

    Seyfried, Oliver; Hester, Joan

    2012-02-01

    The endocrine effects of opioids used for the management of persistent pain are poorly understood by clinicians and patients, and hormone levels are rarely measured. It is recognized that opioids exert this effect via the hypothalamic-pituitary-gonadal axis. Additional effects on adrenal hormones, weight, blood pressure and bone density may also occur. Symptoms and signs of sex hormone deficiency occur in both men and women but are under-reported and are often clinically unrecognized. The potential effects of long term opioid therapy on the endocrine system should be explained to patients before opioid therapy is commenced. Monitoring of sex hormones is recommended; if there are deficiencies opioids should be tapered and withdrawn, if this is clinically acceptable. If opioid therapy has to continue, hormone replacement therapy should be initiated and monitored by an endocrinologist.

  20. The Impact of Repeated Rounds of Mass Drug Administration with Diethylcarbamazine Plus Albendazole on Bancroftian Filariasis in Papua New Guinea

    PubMed Central

    Weil, Gary J.; Kastens, Will; Susapu, Melinda; Laney, Sandra J.; Williams, Steven A.; King, Christopher L.; Kazura, James W.; Bockarie, Moses J.

    2008-01-01

    Background This study employed various monitoring methods to assess the impact of repeated rounds of mass drug administration (MDA) on bancroftian filariasis in Papua New Guinea, which has the largest filariasis problem in the Pacific region. Methodology/Principal Findings Residents of rural villages near Madang were studied prior to and one year after each of three rounds of MDA with diethylcarbamazine plus albendazole administered per World Health Organization (WHO) guidelines. The mean MDA compliance rate was 72.9%. Three rounds of MDA decreased microfilaremia rates (Mf, 1 ml night blood by filter) from 18.6% pre-MDA to 1.3% after the third MDA (a 94% decrease). Mf clearance rates in infected persons were 71%, 90.7%, and 98.1% after 1, 2, and 3 rounds of MDA. Rates of filarial antigenemia assessed by card test (a marker for adult worm infection) decreased from 47.5% to 17.1% (a 64% decrease) after 3 rounds of MDA. The filarial antibody rate (IgG4 antibodies to Bm14, an indicator of filarial infection status and/or exposure to mosquito-borne infective larvae) decreased from 59.3% to 25.1% (a 54.6% decrease). Mf, antigen, and antibody rates decreased more rapidly in children <11 years of age (by 100%, 84.2%, and 76.8%, respectively) relative to older individuals, perhaps reflecting their lighter infections and shorter durations of exposure/infection prior to MDA. Incidence rates for microfilaremia, filarial antigenemia, and antifilarial antibodies also decreased significantly after MDA. Filarial DNA rates in Anopheles punctulatus mosquitoes that had recently taken a blood meal decreased from 15.1% to 1.0% (a 92.3% decrease). Conclusions/Significance MDA had dramatic effects on all filariasis parameters in the study area and also reduced incidence rates. Follow-up studies will be needed to determine whether residual infection rates in residents of these villages are sufficient to support sustained transmission by the An. punctulatus vector. Lymphatic filariasis

  1. The socially evaluated cold-pressor test (SECPT) for groups: effects of repeated administration of a combined physiological and psychological stressor.

    PubMed

    Minkley, Nina; Schröder, Thomas P; Wolf, Oliver T; Kirchner, Wolfgang H

    2014-07-01

    The combined administration of physiological (cold pressor) and psychological (social-evaluative threat) stressors, as in the socially evaluated cold pressor test (SECPT; Schwabe et al., 2008) activates the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. Thus far, the SECPT has been administered exclusively to individual participants, which requires substantial personal effort and time. Therefore, the aim of the present study was to investigate whether and to what extent cardiovascular parameters (SNS) and salivary cortisol concentrations (HPA axis) are affected over the course of repeated SECPT administration in a group design. The SECPT was conducted in groups of seven or more persons and repeated twice with a 24-h interval between each administration. During the stress test, the participants (n=61) were videotaped and observed continuously while they immersed their hands into ice-cold (1 °C, experimental group) or room-temperature (20 °C, control group) water. Blood pressure, heart rate, salivary cortisol concentration, and subjective stress perception were measured. All of these parameters increased significantly during each of the three stress exposures; in contrast, they remained constant in the control group. Moreover, the heart rate response towards the stressor decreased significantly over the course of the repeated stress exposures and salivary cortisol concentration of the experimental group was elevated before the third SECPT administration. Our results indicate that the group SECPT activates the SNS and the HPA, leading to increased blood pressure, heart rate, and cortisol concentration. Moreover, the repeated administration leads to habituation exclusively of heart rate. PMID:24845183

  2. Opioid-induced endocrinopathy.

    PubMed

    Colameco, Stephen; Coren, Joshua S

    2009-01-01

    Debilitating chronic nonmalignant pain is often managed using opioid medications. However, with increased use of this drug class comes concern about adverse effects on patients' endocrine function. In the present review, the authors discuss opioid-induced interference with the hypothalamic-pituitary-gonadal axis, effects on adrenal androgen production, and endocrine deficiency. In addition, the authors describe symptomology for opioid-induced endocrinopathy as well as diagnostic testing options. Treatment modalities for those afflicted with this condition are also described.

  3. Repeated methylphenidate administration during lactation reduces maternal behavior, induces maternal tolerance, and increases anxiety-like behavior in pups in adulthood.

    PubMed

    Ponchio, R A; Teodorov, E; Kirsten, T B; Coelho, C P; Oshiro, A; Florio, J C; Bernardi, M M

    2015-01-01

    Methylphenidate (MPD) is a dopamine uptake inhibitor and the most commonly prescribed drug for the treatment of attention-deficit/hyperactivity disorder in children. Several studies have shown that such stimulants as cocaine and amphetamine that are administered during gestation and lactation may disrupt maternal behavior. Also, MPD is used in lactation. Repeated MPD administration can induce either sensitization or tolerance. The aim of the present study was to investigate whether repeated MPD administration alters maternal behavior and promotes tolerance or sensitization in these females. The effects in adult offspring were also examined in models of anxiety. Methylphenidate (5mg/kg) was administered from lactation day 2 to 4, and maternal pup retrieval behavior was assessed. This treatment was continued until lactation day 7. At weaning, the dams received a challenge dose of MPD, and general activity was evaluated in the open field. Striatal monoamine and metabolite levels were also measured to determine whether this treatment promotes behavioral or biochemical plasticity. The long-term behavioral effects of MPD exposure were evaluated in pups in adulthood. The results showed an increase in the latency to retrieve the first, second, and third pups and a decrease in the number of dams that retrieved all pups. After a challenge dose of MPD, the dams exhibited a decrease in locomotion frequency, an increase in immobility duration in the open field, and a decrease in striatal serotonin levels. In pups, anxiety-like behavior increased in the light/dark box test. These results indicate that repeated MPD administration during early lactation impairs maternal behavior, likely by decreasing maternal motivation. Repeated MPD administration induced maternal tolerance at weaning after a challenge dose of MPD, suggesting the development of central nervous system plasticity. In pups, maternal exposure to MPD during early lactation induced long-term effects and increased

  4. Repeated methylphenidate administration during lactation reduces maternal behavior, induces maternal tolerance, and increases anxiety-like behavior in pups in adulthood.

    PubMed

    Ponchio, R A; Teodorov, E; Kirsten, T B; Coelho, C P; Oshiro, A; Florio, J C; Bernardi, M M

    2015-01-01

    Methylphenidate (MPD) is a dopamine uptake inhibitor and the most commonly prescribed drug for the treatment of attention-deficit/hyperactivity disorder in children. Several studies have shown that such stimulants as cocaine and amphetamine that are administered during gestation and lactation may disrupt maternal behavior. Also, MPD is used in lactation. Repeated MPD administration can induce either sensitization or tolerance. The aim of the present study was to investigate whether repeated MPD administration alters maternal behavior and promotes tolerance or sensitization in these females. The effects in adult offspring were also examined in models of anxiety. Methylphenidate (5mg/kg) was administered from lactation day 2 to 4, and maternal pup retrieval behavior was assessed. This treatment was continued until lactation day 7. At weaning, the dams received a challenge dose of MPD, and general activity was evaluated in the open field. Striatal monoamine and metabolite levels were also measured to determine whether this treatment promotes behavioral or biochemical plasticity. The long-term behavioral effects of MPD exposure were evaluated in pups in adulthood. The results showed an increase in the latency to retrieve the first, second, and third pups and a decrease in the number of dams that retrieved all pups. After a challenge dose of MPD, the dams exhibited a decrease in locomotion frequency, an increase in immobility duration in the open field, and a decrease in striatal serotonin levels. In pups, anxiety-like behavior increased in the light/dark box test. These results indicate that repeated MPD administration during early lactation impairs maternal behavior, likely by decreasing maternal motivation. Repeated MPD administration induced maternal tolerance at weaning after a challenge dose of MPD, suggesting the development of central nervous system plasticity. In pups, maternal exposure to MPD during early lactation induced long-term effects and increased

  5. Effects of Repeated 3,4-Methylenedioxymethamphetamine Administration on Neurotransmitter Efflux and Sensory-Evoked Discharge in the Ventral Posterior Medial ThalamusS⃞

    PubMed Central

    Starr, M. A.; Page, M. E.

    2012-01-01

    3,4-Methylenedioxymethamphetamine (MDMA) is known to enhance tactile sensory perception, an effect that contributes to its popularity as a recreational drug. The neurophysiological basis for the effects of MDMA on somatosensation are unknown. However, MDMA interactions with the serotonin transporter (SERT) and subsequent enhancement of serotonin neurotransmission are well known. The rat trigeminal somatosensory system receives serotonergic afferents from the dorsal raphe nucleus. Because these fibers express SERT, they should be vulnerable to MDMA-induced effects. We found that administration of a challenge injection of MDMA (3 mg/kg i.p.) after repeated MDMA treatment (3 mg/kg per day for 4 days) elicits both serotonin and norepinephrine efflux in the ventral posterior medial (VPM) thalamus of Long-Evans hooded rats, the main relay along the lemniscal portion of the rodent trigeminal somatosensory pathway. We evaluated the potential for repeated MDMA administration to modulate whisker-evoked discharge of individual neurons in this region. After surgically implanting stainless steel eight-wire multichannel electrode bundles, we recorded spike train activity of single cells while activating the whisker pathway using a piezoelectric mechanical stimulator. We found that repeated MDMA administration increased the spontaneous firing rate but reduced both the magnitude and duration of whisker-evoked discharge in individual VPM thalamic neurons. The time course of drug action on neuronal firing patterns was generally consistent with fluctuations in neurotransmitter efflux as shown from our microdialysis studies. On the basis of these results, we propose that single use and repeated administration of MDMA may “distort,” rather than enhance, tactile experiences in humans, in part, by disrupting normal spike firing patterns through somatosensory thalamic relay circuits. PMID:21984836

  6. Parenteral opioids for maternal pain management in labour

    PubMed Central

    Ullman, Roz; Smith, Lesley A; Burns, Ethel; Mori, Rintaro; Dowswell, Therese

    2014-01-01

    Background Parenteral opioids are used for pain relief in labour in many countries throughout the world. Objectives To assess the acceptability, effectiveness and safety of different types, doses and modes of administration of parenteral opioids given to women in labour. Search methods We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (30 April 2011) and reference lists of retrieved studies. Selection criteria We included randomised controlled trials examining the use of intramuscular or intravenous opioids (including patient controlled analgesia) for women in labour. We looked at studies comparing an opioid with another opioid, placebo, other non-pharmacological interventions (TENS) or inhaled analgesia. Data collection and analysis At least two review authors independently assessed study eligibility, collected data and assessed risk of bias. Main results We included 57 studies involving more than 7000 women that compared an opioid with placebo, another opioid administered intramuscularly or intravenously or compared with TENS to the back. The 57 studies reported on 29 different comparisons, and for many outcomes only one study contributed data. Overall, the evidence was of poor quality regarding the analgesic effect of opioids, satisfaction with analgesia, adverse effects and harm to women and babies. There were few statistically significant results. Many of the studies had small sample sizes, and low statistical power. Overall findings indicated that parenteral opioids provided some pain relief and moderate satisfaction with analgesia in labour, although up to two-thirds of women who received opioids reported moderate or severe pain and/or poor or moderate pain relief one or two hours after administration. Opioid drugs were associated with maternal nausea, vomiting and drowsiness, although different opioid drugs were associated with different adverse effects. There was no clear evidence of adverse effects of opioids on the newborn. We

  7. The opioid system contributes to the acquisition of reinforcement for dietary fat but is not required for its maintenance.

    PubMed

    Sakamoto, Kazuhiro; Matsumura, Shigenobu; Okafuji, Yoko; Eguchi, Ai; Yoneda, Takeshi; Mizushige, Takafumi; Tsuzuki, Satoshi; Inoue, Kazuo; Fushiki, Tohru

    2015-01-01

    The opioid system plays an important role in ingestive behavior, especially with regard to palatable high-fat or sweetened foods. In the present study, we investigated the role of the opioid system in the regulation of ingestive behavior in mice with regard to dietary fat intake, reinforcement, and particularly the processes involved in development of these behavior types. Subcutaneous administration of the non-selective opioid receptor antagonist naltrexone (0.5 or 2.0mg/kg body weight [BW]) reduced the spontaneous intake of fat emulsion (Intralipid). We investigated the effect of naltrexone on reinforcement by using an operant behavioral paradigm under a progressive ratio schedule in which the number of lever presses required to obtain a test sample increased progressively. Mice showed stronger reinforcement by Intralipid as a function of concentration. However, naltrexone (0.5 or 2.0mg/kg BW) did not affect reinforcement at any concentration of Intralipid in mice that had repeatedly ingested Intralipid before testing was carried out. Intralipid ingestion also induced conditioned place preference (CPP), which is another evaluation index of reinforcement. High-dose naltrexone (2.0mg/kg BW) administration during CPP conditioning suppressed the reinforcement induced by Intralipid ingestion, although the drug administration (0.5 or 2.0mg/kg BW) during CPP testing did not affect reinforced behavior. These results suggest that the amount of fat ingestion and reinforcement for fat ingestion are separately regulated by the opioid system. Furthermore, our results indicate that the opioid system plays an important role in acquiring reinforcement for fat but is not required for maintenance of learned reinforcement.

  8. Opioid-induced immunosuppression: is it centrally mediated or peripherally mediated?

    PubMed

    Wei, Gang; Moss, Jonathan; Yuan, Chun Su

    2003-06-01

    Opioid compounds are commonly used pain medications. However, their administration is associated with a number of side-effects. Among them, opioid-induced immunosuppression is a significant medical problem, which is evidenced by a strong association between the use of opioids and exacerbated infections, including AIDS. Research data have demonstrated the effects of opioids to be suppressive on phagocytic, natural killer (NK), B and T cells. However, these immunosuppressive effects may be mediated by mechanisms different from those for antinociceptive actions. This article reviews possible central and peripheral mechanisms of opioid-induced immunosuppression. To the extent that peripherally mediated immunosuppressive effects play a significant role in opioid-induced immunosuppression, novel peripheral opioid antagonists may have a therapeutic role in attenuating opioid-induced immunosuppression without affecting analgesia.

  9. A review of opioid prescription in a teaching hospital in Colombia

    PubMed Central

    Moyano, Jairo; Figueras, Albert

    2012-01-01

    Introduction: Review of opioid prescriptions in a hospital provides valuable information to health care professionals which may contribute to proper pain management; opioid utilization studies may help uncover factors that can be improved for better prescribing. To evaluate the use of opioid analgesics in a university hospital, a review of opioids prescribed in hospitalized patients was developed. Methods: Information was obtained from the pharmacy database and medical records. The study period was 1 month. Results: Medical records of 1156 patients admitted in July 2009 were analyzed. The most widely prescribed opioid was tramadol; the preferred administration route was intravenous; the main indication was severe pain; and major prescribers were from surgical departments. Discussion: Underutilization of potent opioids for acute and chronic pain seems to occur. Conclusion: Most prescribers prefer weak opioids, given intravenously to treat acute and chronic pain, while some patients may benefit from the prescription of more potent opioids. PMID:23049273

  10. The impact of opioid analgesics on the gastrointestinal tract function and the current management possibilities

    PubMed Central

    2012-01-01

    Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal symptoms such as constipation, anorexia, nausea, vomiting, gastro-oesophageal reflux, delayed digestion, abdominal pain, bloating, hard stool and incomplete evacuation that significantly deteriorate patients’ quality of life and compliance. Approximately one third of patients treated with opioids do not adhere to the opioid regimen or simply quit the treatment due to OIBD. Several strategies are undertaken to prevent or treat OIBD. Traditional oral laxatives are used but their effectiveness is limited and they display adverse effects. Other possibilities comprise opioid switch or changing the administration route. New therapies target opioid receptors in the gut that seem to be the main source of OIBD. One is a combination of an opioid and opioid antagonist (oxycodone/naloxone) in prolonged-release tablets, and another is a purely peripherally acting opioid receptor antagonist (methylnaltrexone) available in subcutaneous injections. The aim of this article is to review the pathomechanism and possible treatment strategies of OIBD. PMID:23788866

  11. ACCUMULATION AND TISSUE DISPOSITION OF PARTICLE ASSOCIATED ELEMENTS IN THE RAT AFTER REPEATED INTRATRACHAEL ADMINISTRATION OF SOURCE PARTICLES

    EPA Science Inventory

    The goal of this study was to determine the fate of source particle tracer elements following repeated intratracheal instillation (IT) to rats. PM samples comprised Mt. St. Helens ash (MSH) with no water-soluble metals, and oil flyash emission PM (EPM) with water-leachable solubl...

  12. [Development of physical dependence on nicotine and endogenous opioid system--participation of α7 nicotinic acetylcholine receptor].

    PubMed

    Kishioka, Shiroh; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro; Yamamoto, Chizuko

    2014-10-01

    Nicotine (NIC) regulates various cellular functions acting on the nicotinic acetylcholine receptor (nAChR). And nAChR consists of ligand-gated cation channels with pentameric structure and composed of α and β subunits. In the central nervous system, α 4 β 2 and α 7 nAChRs are the most abundantly expressed as nAChR subtypes. There are several lines of evidence indicating that systemic administration of NIC elicits the release of endogenous opioids, such as, endorphins, enkephalins and dynorphins, in the brain. NIC exerts numerous acute effects, for example, antinociceptive effects and the activating effects of the hypothalamic-pituitary-adrenal (HPA) axis. In these effects, NIC-induced antinociception, but not HPA axis activation, was inhibited by opioid receptor antagonist, naloxone (NLX), and was also suppressed in morphine tolerated mice, indicating the participation of the endogenous opioid system in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception was antagonized by both α 4 β 2 and α 7 nAChR antagonists, while NIC-induced HPA axis activation was antagonized by α 4 β 2 nAChR antagonist, but not by α 7 nAChR antagonist. These results suggest that the endogenous opioid system may not be located on the downstream of α 4 β 2 nAChR. On the other hand, NIC has substantial physical dependence liability. NLX elicits NIC withdrawal after repeated NIC administration evaluated by corticosterone increase as a withdrawal sign, and NLX-precipitated NIC withdrawal is inhibited by concomitant administration of other opioid receptor antagonist, naltrexone, indicating the participation of endogenous opioid system in the development of physical dependence on NIC. NLX-precipitated NIC withdrawal was also inhibited by concomitant administration of an α 7 nAChR antagonist, but not an α 4 β 2 nAChR antagonist. Taken together, these findings suggest that the endogenous opioid system may be located on the downstream of α 7

  13. [Development of physical dependence on nicotine and endogenous opioid system--participation of α7 nicotinic acetylcholine receptor].

    PubMed

    Kishioka, Shiroh; Kiguchi, Norikazu; Kobayashi, Yuka; Saika, Fumihiro; Yamamoto, Chizuko

    2014-10-01

    Nicotine (NIC) regulates various cellular functions acting on the nicotinic acetylcholine receptor (nAChR). And nAChR consists of ligand-gated cation channels with pentameric structure and composed of α and β subunits. In the central nervous system, α 4 β 2 and α 7 nAChRs are the most abundantly expressed as nAChR subtypes. There are several lines of evidence indicating that systemic administration of NIC elicits the release of endogenous opioids, such as, endorphins, enkephalins and dynorphins, in the brain. NIC exerts numerous acute effects, for example, antinociceptive effects and the activating effects of the hypothalamic-pituitary-adrenal (HPA) axis. In these effects, NIC-induced antinociception, but not HPA axis activation, was inhibited by opioid receptor antagonist, naloxone (NLX), and was also suppressed in morphine tolerated mice, indicating the participation of the endogenous opioid system in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception was antagonized by both α 4 β 2 and α 7 nAChR antagonists, while NIC-induced HPA axis activation was antagonized by α 4 β 2 nAChR antagonist, but not by α 7 nAChR antagonist. These results suggest that the endogenous opioid system may not be located on the downstream of α 4 β 2 nAChR. On the other hand, NIC has substantial physical dependence liability. NLX elicits NIC withdrawal after repeated NIC administration evaluated by corticosterone increase as a withdrawal sign, and NLX-precipitated NIC withdrawal is inhibited by concomitant administration of other opioid receptor antagonist, naltrexone, indicating the participation of endogenous opioid system in the development of physical dependence on NIC. NLX-precipitated NIC withdrawal was also inhibited by concomitant administration of an α 7 nAChR antagonist, but not an α 4 β 2 nAChR antagonist. Taken together, these findings suggest that the endogenous opioid system may be located on the downstream of α 7

  14. Failure of acute and chronic administration of delta 9-tetrahydrocannabinol to affect the repeated acquisition of serial position response in pigeons.

    PubMed

    McMillan, D E

    1988-01-01

    Pigeons were trained to acquire a new four-response position sequence each day by pecking three response keys in a predetermined order. The key color varied after each correct response prior to food delivery. Acute administration of delta 9-tetrahydrocannabinol (delta 9-THC) up to a dose that completely eliminated responding, had no effect on total acquisition errors, or on within session patterns of error elimination. Chronic administration of delta 9-THC (3-10 mg/kg/day), either before or after the session for 4-7 weeks, also did not affect these error measures, although rates of responding were markedly suppressed and at times no responding occurred. Discontinuation of delta 9-THC administration for periods of 4-6 weeks also was without effect on errors. These experiments suggest that neither acute nor chronic delta 9-THC produce specific effects on the repeated acquisition of serial position responses in pigeons.

  15. Pharmacokinetics of repeated sodium salicylate administration to laying hens: evidence for time dependent increase in drug elimination from plasma and eggs.

    PubMed

    Poźniak, Błażej; Grabowski, Tomasz; Motykiewicz-Pers, Karolina; Bobrek, Kamila; Rak, Lech; Bobusia, Katarzyna; Gaweł, Andrzej; Świtała, Marcin

    2015-01-01

    Salicylates were the first non-steroid anti-inflammatory drugs (NSAIDs) to be used in any species and are still widely used in humans and livestock. However, the data on their pharmacokinetics in animals is limited, especially after repeated administration. Evidence exist that in chickens (Gallus gallus) salicylate (SA) may induce its own elimination. The aim of this study was to investigate salicylate pharmacokinetics and egg residues during repeated administration of sodium salicylate (SS) to laying hens. Pharmacokinetics of SA was assessed during 14 d oral administration of SS at daily doses of 50 mg/kg and 200 mg/kg body weight to laying hens. On the 1st, 7th and 14th d a 24 h-long pharmacokinetic study was carried out, whereas eggs were collected daily. Salicylate concentrations in plasma and eggs were determined using high-performance liquid chromatography with ultraviolet detection and pharmacokinetic variables were calculated using a non-compartmental model. Mean residence time (MRT), minimal plasma concentration (Cmin, C16h) and elimination half-life (T1/2el) of SA showed gradual decrease in layers administered with a lower dose. Total body clearance (ClB) increased. Layers administered with the higher dose showed a decrease only in the T1/2el. In the low dose group, SA was found only in the egg white and was low throughout the experiment. Egg whites from the higher dose group showed initially high SA levels which significantly decreased during the experiment. Yolk SA levels were lower and showed longer periods of accumulation and elimination. Repeated administration of SS induces SA elimination, although this effect may differ depending on the dose and production type of a chicken. Decreased plasma drug concentration may have clinical implications during prolonged SS treatment. PMID:25893240

  16. Repeated administration of aripiprazole produces a sensitization effect in the suppression of avoidance responding and phencyclidine-induced hyperlocomotion and increases D2 receptor-mediated behavioral function.

    PubMed

    Gao, Jun; Qin, Rongyin; Li, Ming

    2015-04-01

    The present study investigated how repeated administration of aripiprazole (a novel antipsychotic drug) alters its behavioral effects in two behavioral tests of antipsychotic activity and whether this alteration is correlated with an increase in dopamine D2 receptor function. Male adult Sprague-Dawley rats were first repeatedly tested with aripiprazole (3, 10 and 30 mg/kg, subcutaneously (sc)) or vehicle in a conditioned avoidance response (CAR) test or a phencyclidine (PCP) (3.20 mg/kg, sc)-induced hyperlocomotion test daily for five consecutive days. After 2-3 days of drug-free retraining or resting, all rats were then challenged with aripiprazole (1.5 or 3.0 mg/kg, sc). Repeated administration of aripiprazole progressively increased its inhibition of avoidance responding and PCP-induced hyperlocomotion. More importantly, rats previously treated with aripiprazole showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle in the challenge tests. An increased sensitivity to quinpirole (a selective D2/3 agonist) in prior aripiprazole-treated rats was also found in the quinpirole-induced hyperlocomotion test, suggesting an enhanced D2/3-mediated function. These findings suggest that aripiprazole, despite its distinct receptor mechanisms of action, induces a sensitization effect similar to those induced by other antipsychotic drugs and this effect may be partially mediated by brain plasticity involving D2/3 receptor systems.

  17. Buprenorphine for opioid addiction

    PubMed Central

    Ling, Walter; Mooney, Larissa; Torrington, Matthew

    2014-01-01

    SUMMARY Buprenorphine is a partial opioid agonist of the µ-receptor, and is used as a daily dose sublingual tablet or filmstrip for managing opioid addiction. In the USA, the Drug Addiction Treatment Act of 2000 made buprenorphine the only opioid medication for opioid addiction that can be prescribed in an office-based setting. Owing to its high affinity for the µ-receptor, buprenorphine inhibits the reinforcing effect of exogenous opioids. The ceiling effect of buprenorphine's µ-agonist activity reduces the potential for drug overdose and confers low toxicity even at high doses. Buprenorphine pharmacotherapy has proven to be a treatment approach that supports recovery from addiction while reducing or curtailing the use of opioids. This article examines buprenorphine pharmacotherapy for opioid addiction, focusing on the situation in the USA, and is based on a review of pertinent literature, and the authors’ research and clinical experience. The references in this paper were chosen according to the authors’ judgment of quality and relevance, and with respect to their familiarity and involvement in related research. PMID:24654720

  18. The epidemic of prescription opioid abuse, the subsequent rising prevalence of heroin use, and the federal response.

    PubMed

    Kanouse, Andrew B; Compton, Peggy

    2015-06-01

    Opioids are a mainstay in the treatment of pain both chronically and acutely. In the past 20 years, the prescribing of opioids has increased exponentially. As the population for whom opioids are indicated has grown, with the number of opioid prescriptions written increased, so have indicators of opioid misuse, abuse, morbidity, and mortality. The purpose of this article is to review and explore the combination of factors of events that led to the current "epidemic" of prescription opioid abuse and overdose deaths, as well as the subsequent resurgence of heroin use among opioid addicts. Federal initiatives to mount war on prescription opioid abuse are reviewed, including responses from the White House, Drug Enforcement Agency (DEA), Food and Drug Administration (FDA), and interagency initiatives. Many initiatives are currently in place to combat the rising rates of morbidity and mortality associated with opioids, and those involved are hopeful in their efforts to curb the epidemic of this deadly phenomenon.

  19. Cellular distribution of AMPA receptor subunits and mGlu5 following acute and repeated administration of morphine or methamphetamine.

    PubMed

    Herrold, Amy A; Persons, Amanda L; Napier, T Celeste

    2013-08-01

    Ionotropic AMPA receptors (AMPAR) and metabotropic glutamate group I subtype 5 receptors (mGlu5) mediate neuronal and behavioral effects of abused drugs. mGlu5 stimulation increases expression of striatal-enriched tyrosine phosphatase isoform 61 (STEP61 ) which internalizes AMPARs. We determined the rat brain profile of these proteins using two different classes of abused drugs, opiates, and stimulants. STEP61 levels, and cellular distribution/expression of AMPAR subunits (GluA1, GluA2) and mGlu5, were evaluated via a protein cross-linking assay in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral pallidum (VP) harvested 1 day after acute, or fourteen days after repeated morphine (8 mg/kg) or methamphetamine (1 mg/kg) (treatments producing behavioral sensitization). Acute morphine decreased GluA1 and GluA2 surface expression in mPFC and GluA1 in NAc. Fourteen days after repeated morphine or methamphetamine, mGlu5 surface expression increased in VP. In mPFC, mGlu5 were unaltered; however, after methamphetamine, STEP61 levels decreased and GluA2 surface expression increased. Pre-treatment with a mGlu5-selective negative allosteric modulator, blocked methamphetamine-induced behavioral sensitization and changes in mPFC GluA2 and STEP61 . These data reveal (i) region-specific distinctions in glutamate receptor trafficking between acute and repeated treatments of morphine and methamphetamine, and (ii) that mGlu5 is necessary for methamphetamine-induced alterations in mPFC GluA2 and STEP61 .

  20. Effect of repeated administration of phencyclidine on spatial performance in an eight-arm radial maze with delay in rats and mice.

    PubMed

    Li, Zhu; Kim, Chan H; Ichikawa, Junji; Meltzer, Herbert Y

    2003-05-01

    Phencyclidine (PCP) is an N-methyl-D-aspartate (NMDA) glutamate receptor channel noncompetitive antagonist that produces some of the symptoms of schizophrenia, including delusions, hallucinations, and negative symptoms as well as cognitive impairment. Thus, administration of PCP to rodents and nonhuman primates has been suggested to provide a potential animal model for schizophrenia. There have been some reports that 7-14 days of PCP administration can bring about enduring impairments in working memory in rodents but not all studies have been consistent in this regard. The present study determined whether repeated PCP administration impaired spatial performance in rats or mice trained to make minimal errors in an eight-arm radial maze task with a delay. Male Sprague-Dawley rats and C57BL/6J mice received 14 daily injection of vehicle or PCP (10 mg/kg, s.c.) followed by a withdrawal period of 1 week. The number of arm reentry errors and the distance traveled to complete the task were not significantly different between PCP-treated and vehicle-treated rats on 2, 8, and 14 days of PCP administration or 8 days following withdrawal of PCP. Mice treated with PCP for up to 2 weeks also had no significant differences in the number of arm reentry errors, travel distances, the numbers of visits to different arms during the first eight choices, or latencies to take all eight pellets compared to the vehicle-treated group. Thus, the present study failed to demonstrate that repeated administration of PCP to rats or mice produces enduring memory impairment. Factors potentially contributing to the discrepancies between various studies are discussed.

  1. Prescription of Opioids for Opioid-Naive Medical Inpatients

    PubMed Central

    Lail, Sharan; Sequeira, Kelly; Lieu, Jenny; Dhalla, Irfan A

    2014-01-01

    Background: Harms associated with prescription opioids are a major and increasing public health concern. Prescribing of opioids for inpatients may contribute to the problem, especially if primary care practitioners continue opioid therapy that is initiated in hospital. Objectives: To describe the extent and nature of opioid prescribing for opioid-naive patients (i.e., no use of opioids within 2 weeks before admission) on an internal medicine unit. Methods: This single-centre study involved chart review for opioid-naive patients admitted to the internal medicine unit of a large academic health sciences centre in Toronto, Ontario. Over 12 weeks, patients were prospectively identified for the study, and charts were later reviewed to characterize opioid use during the hospital stay and upon discharge. The primary outcomes were the proportions of opioid-naive patients for whom opioids were prescribed in hospital and upon discharge. Data on serious adverse events related to opioid use (e.g., need for naloxone or occurrence of falls) were also collected through chart review. Results: From July 4 to September 22, 2011, a total of 721 patients were admitted to the study unit, of whom 381 (53%) were classified as opioid-naive. Opioids were prescribed for 82 (22%) of these opioid-naive patients while they were in hospital. Among the opioid-naive patients, there were a total of 247 opioid prescriptions, with hydromorphone (110 prescriptions) and morphine (92 prescriptions) being the drugs most commonly prescribed. For 23 (28%) of the patients with a prescription for opioids in hospital (6% of all opioid-naive patients), an opioid was also prescribed upon discharge. The indication for opioids was documented in 16 (70%) of the 23 discharge prescriptions. No adverse events or deaths related to opioid use were identified during the hospital stays. Conclusions: Among opioid-naive patients admitted to the internal medicine unit, opioids were prescribed for about 1 in 5 patients, and

  2. New opioid prescribing guidelines favor non-opioid alternatives.

    PubMed

    2016-05-01

    Determined to make a dent in the growing problem of opioid addiction, the CDC has unveiled new guidelines for opioid prescribing for chronic pain. The recommendations urge providers to be more judicious in their prescribing, opting for opioids only after carefully weighing substantial risks and benefits. Public health authorities note the rampant use and misuse of opioids have "blurred the lines" between prescription opioids and illicit opioids. The new guidelines are designed to help frontline providers balance the need to manage their patients' chronic pain with the duty to curb dangerous prescribing practices. The recommendations are built around three principles: favor non-opioid alternatives for most cases of chronic pain, use the lowest effective dose when prescribing opioids, and exercise caution/monitor patients who are treated with opioids. PMID:27266000

  3. Effect of repeated administration of antidepressant drugs on the serum and brain concentration of testosterone and its metabolites.

    PubMed

    Przegaliński, E; Warchoł-Kania, A; Budziszewska, B; Jaworska, L

    1987-01-01

    A repeated oral treatment (twice daily, for 21 consecutive days) with 10 mg/kg of antidepressants imipramine, amitriptyline, citalopram, mianserin affects the level of testosterone and its metabolites (5 alpha-dihydrotestosterone and estradiol-17 beta) in the serum and brain structures (cerebral cortex, hypothalamus). Citalopram and mianserin increased significantly the serum testosterone concentration, while imipramine and amitriptyline reduced the concentration of 5 alpha-dihydrotestosterone. In the cerebral cortex a reduction in 5 alpha-dihydrotestosterone after imipramine, and in the hypothalamus a decrease in testosterone level after amitriptyline were observed. None of the investigated drugs influenced estradiol-17 beta concentration in the serum or in the brain. PMID:3503989

  4. Effect of Chronic Pain on Fentanyl Self-Administration in Mice

    PubMed Central

    Wade, Carrie L.; Krumenacher, Perry; Kitto, Kelley F.; Peterson, Cristina D.; Wilcox, George L.; Fairbanks, Carolyn A.

    2013-01-01

    The development of opioid addiction in subjects with established chronic pain is an area that is poorly understood. It is critically important to clearly understand the neurobiology associated with propensity toward conversion to addiction under conditions of chronic pain. To pose the question whether the presence of chronic pain influences motivation to self-administer opioids for reward, we applied a combination of rodent models of chronic mechanical hyperalgesia and opioid self-administration. We studied fentanyl self-administration in mice under three conditions that induce chronic mechanical hyperalgesia: inflammation, peripheral nerve injury, and repeated chemotherapeutic injections. Responding for fentanyl was compared among these conditions and their respective standard controls (naïve condition, vehicle injection or sham surgery). Acquisition of fentanyl self-administration behavior was reduced or absent in all three conditions of chronic hyperalgesia relative to control mice with normal sensory thresholds. To control for potential impairment in ability to learn the lever-pressing behavior or perform the associated motor tasks, all three groups were evaluated for acquisition of food-maintained responding. In contrast to the opioid, chronic hyperalgesia did not interfere with the reinforcing effect of food. These studies indicate that the establishment of chronic hyperalgesia is associated with reduced or ablated motivation to seek opioid reward in mice. PMID:24260176

  5. Repeated administrations of adrenocorticotropic hormone during late gestation in pigs: maternal cortisol response and effects on fetal HPA axis and brain neurotransmitter systems.

    PubMed

    Otten, W; Kanitz, E; Tuchscherer, M; Brüssow, K-P; Nürnberg, G

    2008-02-01

    The present study examined the effects of repeated adrenocorticotropic hormone (ACTH) administrations to sows during late gestation on hypothalamic-pituitary-adrenocortical (HPA) axis and brain neurotransmitter systems in their fetuses. ACTH (100 IU per animal, Synacthen Depot, n=6) or saline (n=5) was administered intramuscularly to sows every 2nd day from gestational day (GD) 85 to GD 101. Blood samples were taken from sows repeatedly within 12h after ACTH application on GD 85 and GD 101. On GD 105, fetuses were recovered under general anaesthesia for the collection of blood and brain samples. Plasma cortisol concentrations in sows increased significantly within 2h after ACTH application and returned to control levels after 10h post-application, showing a similar response at the beginning and at the end of the 16-day stimulation period. On GD 101, a significant increase of plasma glucose and insulin concentrations was found in sows after administration of ACTH and after a following feeding time. Number and body weight of fetuses were not affected by the maternal ACTH treatment. Cortisol concentrations in the umbilical vein were significantly decreased in fetuses from ACTH sows and a similar trend was observed in the umbilical artery and in the vena cava cranialis. Glucocorticoid receptor (GR) binding in hippocampus and hypothalamus did not differ between treatments. However, in hippocampus, serotonergic activity was increased in fetuses from ACTH-treated mothers as shown by significantly elevated 5-hydroxytryptamine (5-HT) levels. In conclusion, repeated administrations of ACTH during late gestation resulted in a reproducible cortisol response of sows and reduced cortisol concentrations in the fetal umbilical vein after the treatment period. Although the number of sows used in this experiment was low and differences between treatments were limited these findings indicate that excessive glucocorticoid exposure during gestation alters serotonergic activity in

  6. Repeated administrations of human umbilical cord blood cells improve disease outcomes in a mouse model of Sanfilippo syndrome type III B.

    PubMed

    Willing, Alison E; Garbuzova-Davis, Svitlana N; Zayko, Olga; Derasari, Hiranya M; Rawls, Ashley E; James, Chris R; Mervis, Ron F; Sanberg, Cyndy D; Kuzmin-Nichols, Nicole; Sanberg, Paul R

    2014-01-01

    Sanfilippo syndrome type III B (MPS III B) is an inherited disorder characterized by a deficiency of α-N-acetylglucosaminidase (Naglu) enzyme leading to accumulation of heparan sulfate in lysosomes and severe neurological deficits. We have previously shown that a single administration of human umbilical cord mononuclear cells (hUCB MNCs) into Naglu knockout mice decreased behavioral abnormalities and tissue pathology. In this study, we tested whether repeated doses of hUCB MNCs would be more beneficial than a single dose of cells. Naglu mice at 3 months of age were randomly assigned to either a Media-only group or one of three hUCB MNC treatment groups--single low dose (3 × 10(6) cells), single high dose (1.8 × 10(7) cells), or multiple doses (3 × 10(6) cells monthly for 6 months) delivered intravenously; cyclosporine was injected intraperitoneally to immune suppress the mice for the duration of the study. An additional control group of wild-type mice was also used. We measured anxiety in an open field test and cognition in an active avoidance test prior to treatment and then at monthly intervals for 6 months. hUCB MNCs restored normal anxiety-like behavior in these mice (p < 0.001). The repeated cell administrations also restored hippocampal cytoarchitecture, protected the dendritic tree, decreased GM3 ganglioside accumulation, and decreased microglial activation, particularly in the hippocampus and cortex. These data suggest that the neuroprotective effect of hUCB MNCs can be enhanced by repeated cell administrations. PMID:25565636

  7. Women Who Abuse Prescription Opioids: Findings from the Addiction Severity Index-Multimedia Version® Connect Prescription Opioid Database

    PubMed Central

    Green, Traci C.; Grimes Serrano, Jill M.; Licari, Andrea; Budman, Simon H.; Butler, Stephen F.

    2009-01-01

    Background Evidence suggests gender differences in abuse of prescription opioids. This study aimed to describe characteristics of women who abuse prescription opioids in a treatment-seeking sample and to contrast gender differences among prescription opioid abusers. Methods Data collected November 2005 to April 2008 derived from the Addiction Severity Index Multimedia Version Connect (ASI-MV® Connect) database. Bivariate and multivariable logistic regression examined correlates of prescription opioid abuse stratified by gender. Results 29,906 assessments from 220 treatment centers were included, of which 12.8% (N=3,821) reported past month prescription opioid abuse. Women were more likely than men to report use of any prescription opioid (29.8% females vs. 21.1% males, p< 0.001) and abuse of any prescription opioid (15.4% females vs. 11.1% males, p < 0.001) in the past month. Route of administration and source of prescription opioids displayed gender-specific tendencies. Women-specific correlates of recent prescription opioid abuse were problem drinking, age <54, inhalant use, residence outside of West US Census region, and history of drug overdose. Men-specific correlates were age <34, currently living with their children, residence in the South and Midwest, hallucinogen use, and recent depression. Women prescription opioid abusers were less likely to report a pain problem although they were more likely to report medical problems than women who abused other drugs. Conclusions Gender-specific factors should be taken into account in efforts to screen and identify those at highest risk of prescription opioid abuse. Prevention and intervention efforts with a gender-specific approach are warranted. PMID:19409735

  8. The impact of opioid-induced hyperalgesia for postoperative pain.

    PubMed

    Koppert, Wolfgang; Schmelz, Martin

    2007-03-01

    Clinical evidence suggests that--besides their well known analgesic activity - opioids can increase rather than decrease sensitivity to noxious stimuli. Based on the observation that opioids can activate pain inhibitory and pain facilitatory systems, this pain hypersensitivity has been attributed to a relative predominance of pronociceptive mechanisms. Acute receptor desensitization via uncoupling of the receptor from G-proteins, upregulation of the cAMP pathway, activation of the N-methyl-D-aspartate (NMDA)-receptor system, as well as descending facilitation, have been proposed as potential mechanisms underlying opioid-induced hyperalgesia. Numerous reports exist demonstrating that opioid-induced hyperalgesia is observed both in animal and human experimental models. Brief exposures to micro-receptor agonists induce long-lasting hyperalgesic effects for days in rodents, and also in humans large-doses of intraoperative micro-receptor agonists were found to increase postoperative pain and morphine consumption. Furthermore, the prolonged use of opioids in patients is often associated with a requirement for increasing doses and the development of abnormal pain. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs like NMDA-antagonists, alpha2-agonists, or non-steroidal anti-inflammatory drugs (NSAIDs), opioid rotation or combinations of opioids with different receptor/selectivity.

  9. The Useage of Opioids and their Adverse Effects in Gastrointestinal Practice: A Review

    PubMed Central

    Khansari, MahmoudReza; Sohrabi, MasourReza; Zamani, Farhad

    2013-01-01

    Opium is one of the oldest herbal medicines currently used as an analgesic, sedative and antidiarrheal treatment. The effects of opium are principally mediated by the μ-, κ- and δ-opioid receptors. Opioid substances consist of all natural and synthetic alkaloids that are derived from opium. Most of their effects on gastrointestinal motility and secretion result from suppression of neural activity. Inhibition of gastric emptying, increase in sphincter tone, changes in motor patterns, and blockage of peristalsis result from opioid use. Common adverse effects of opioid administration include sedation, dizziness, nausea, vomiting, constipation, dependency and tolerance, and respiratory depression. The most common adverse effect of opioid use is constipation. Although stool softeners are frequently used to decrease opioid-induced bowel dysfunction, however they are not efficacious. Possibly, the use of specific opioid receptor antagonists is a more suitable approach. Opioid antagonists, both central and peripheral, could affect gastrointestinal function and visceromotor sensitivity, which suggests an important role for endogenous opioid peptides in the control of gastrointestinal physiology. Underlying diseases or medications known to influence the central nervous system (CNS) often accelerate the opioid’s adverse effects. However, changing the opioid and/or route of administration could also decrease their adverse effects. Appropriate patient selection, patient education and discussion regarding potential adverse effects may assist physicians in maximizing the effectiveness of opioids, while reducing the number and severity of adverse effects. PMID:24829664

  10. Opioids and hypogonadism.

    PubMed

    2012-04-01

    Detailed reports of hypogonadotropic hypogonadism in patients receiving morphine analgesia were published in 2010. Symptoms included flushing and sweating, amenorrhoea, impotence and decreased libido. Epidemiological studies have examined a possible link between hypogonadism and opioid use, in both patients and drug addicts. Statistically significant decreases in plasma hormone concentrations were found, with lower testosterone and LH levels in men, and lower oestradiol, progesterone, LH and FSH levels in women. Animal studies have provided consistent results. It is suspected that opioids affect the hypothalamic-pituitary axis, inhibiting LH secretion. Patients should be warned of this risk. If signs of hypogonadism occur in a patient taking an opioid, the benefits and harms of treatment should be reassessed. If possible, the dose should be reduced or the opioid withdrawn.

  11. 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.

  12. Brain regional acetylcholinesterase activity and muscarinic acetylcholine receptors in rats after repeated administration of cholinesterase inhibitors and its withdrawal

    SciTech Connect

    Kobayashi, Haruo . E-mail: hk1664@iwate-u.ac.jp; Suzuki, Tadahiko; Sakamoto, Maki; Hashimoto, Wataru; Kashiwada, Keiko; Sato, Itaru; Akahori, Fumiaki; Satoh, Tetsuo

    2007-03-15

    Activity of acetylcholinesterase (AChE) and specific binding of [{sup 3}H]quinuclidinyl benzilate (QNB), [{sup 3}H]pirenzepine (PZP) and [{sup 3}H]AF-DX 384 to muscarinic acetylcholine receptor (mAChR) preparations in the striatum, hippocampus and cortex of rats were determined 1, 6 and 11 days after the last treatment with an organophosphate DDVP, a carbamate propoxur or a muscarinic agonist oxotremorine as a reference for 7 and 14 days. AChE activity was markedly decreased in the three regions 1 day after the treatment with DDVP for 7 and 14 days with a gradual recovery 6 to 11 days, and much less decreased 1, 6 and 11 days after the treatment with propoxur for 7 days but not for 14 days in the hippocampus and cortex. The binding of [{sup 3}H]-QNB, PZP and AF-DX 384 in the three regions was generally decreased by the treatment with DDVP for 7 and 14 days. Such down-regulations were generally restored 6 or 11 days after the treatment for 7 but not for 14 days. The down-regulation or up-regulation as measured by [{sup 3}H]-QNB, PZP and AF-DX 384 was observed 1, 6 or 11 days after treatment with propoxur for 7 days and/or 14 days. Repeated treatment with oxotremorine produced similar effects except AChE activity to DDVP. These results suggest that repeated inhibition of AChE activity may usually cause down-regulation of mAChRs with some exception in the hippocampus when a reversible antiChE propoxur is injected.

  13. Endogenous and xenobiotic metabolite profiling of liver extracts from SCID and chimeric humanized mice following repeated oral administration of troglitazone.

    PubMed

    Barnes, Alan J; Baker, David R; Hobby, Kirsten; Ashton, Simon; Michopoulos, Filippos; Spagou, Konstantina; Loftus, Neil J; Wilson, Ian D

    2014-01-01

    1. Metabonomic analysis, via a combination of untargeted and targeted liquid chromatography-mass spectrometry (LC-MS) and untargeted (1)H NMR spectroscopy-based metabolite profiling, was performed on aqueous (AQ) and organic liver extracts from control (SCID) and chimeric humanized (PXB) mice dosed with troglitazone at 0, 300 and 600 mg/kg/day for seven days. 2. LC-MS analysis of AQ liver extracts showed a more "human-like" profile for troglitazone metabolites for PXB, compared with SCID, mice. 3. LC-MS detected differences in endogenous metabolites, particularly lipid species in dosed mice, including elevated triacylglycerols and 1-alkyl,2-acylglycerophosphates as well as lowered diacylglycerophosphocholines and 1-alkyl,2-acylglycerophosphocholines for PXB compared with SCID mouse liver extracts. Following drug administration changes in the relative proportions of the ions for various unsaturated fatty acids were observed for both types of mouse, some of which were specific to PXB or SCID mice. 4.  (1)H NMR spectroscopy revealed that AQ PXB mouse liver extracts had elevated amounts of inosine, fumarate, creatine, aspartate, trimethylamine N-oxide, glycerophosphocholine, phosphocholine, choline, glutamine, glutamate, acetate, alanine and lactate relative to SCID mice and decreased histidine, glycogen, α- and β-glucose, taurine, and glutathione. Increased uracil and tyrosine concentrations were detected for PXB mice on troglitazone administration. 5. Metabonomic profiling thus showed clear differences between humanized and SCID mice, including after administration of troglitazone.

  14. Repeated low-dose kainate administration in C57BL/6J mice produces temporal lobe epilepsy pathology but infrequent spontaneous seizures.

    PubMed

    Umpierre, Anthony D; Bennett, Isaiah V; Nebeker, Lismore D; Newell, Thomas G; Tian, Bruce B; Thomson, Kyle E; White, H Steve; White, John A; Wilcox, Karen S

    2016-05-01

    More efficient or translationally relevant approaches are needed to model acquired temporal lobe epilepsy (TLE) in genetically tractable mice. The high costs associated with breeding and maintaining transgenic, knock-in, or knock-out lines place a high value on the efficiency of induction and animal survivability. Herein, we describe our approaches to model acquired epilepsy in C57BL/6J mice using repeated, low-dose kainate (KA) administration paradigms. Four paradigms (i.p.) were tested for their ability to induce status epilepticus (SE), temporal lobe pathology, and the development of epilepsy. All four paradigms reliably induce behavioral and/or electrographic SE without mortality over a 7d period. Two of the four paradigms investigated produce features indicative of TLE pathology, including hippocampal cell death, widespread astrogliosis, and astrocyte expression of mGluR5, a feature commonly reported in TLE models. Three of the investigated paradigms were able to produce aberrant electrographic features, such as interictal spiking in cortex. However, only one paradigm, previously published by others, produces spontaneous recurrent seizures over an eight week period. Presentation of spontaneous seizures is rare (N=2/14), with epilepsy preferentially developing in animals having a high number of seizures during SE. Overall, repeated, low-dose KA administration improves the efficiency and pathological relevance of a systemic KA insult, but does not produce a robust epilepsy phenotype under the experimental paradigms described herein. PMID:26896834

  15. Region-specific effects of isoflurane anesthesia on Fos immunoreactivity in response to intravenous cocaine challenge in rats with a history of repeated cocaine administration

    PubMed Central

    Kufahl, Peter R.; Peartree, Natalie A.; Heintzelman, Krista L.; Chung, Maggie; Neisewander, Janet L.

    2016-01-01

    We have previously shown that acute intravenous (i.v.) administration of cocaine increases Fos immunoreactivity in rats under isoflurane anesthesia. Given that Fos expression is a marker of neural activation, the results suggested that isoflurane is appropriate for imaging cocaine effects under anesthesia. However, most imaging research in this area utilizes subjects with a history of repeated cocaine exposure and this drug history may interact with anesthetic use differently from acute cocaine exposure. Thus, this study further examined Fos expression under isoflurane in rats with a history of repeated i.v. cocaine administration. Rats received daily injections of either saline or cocaine (2 mg/kg, i.v.) across 7 consecutive days, followed by 5 days of no drug exposure. On the test day, rats were either nonanesthetized or anesthetized under isoflurane and were given an acute challenge of cocaine (2 mg/kg, i.v.). Additional saline-exposed controls received a saline challenge. Ninety min after the drug challenge, the rats were perfused under isoflurane anesthesia and their brains were processed for Fos protein immunohistochemistry. We found that challenge injections of cocaine following a regimen of repeated cocaine exposure resulted in Fos expression in the prefrontal cortex and striatum roughly equivalent to that found in rats who had received the cocaine challenge after a history of vehicle injections. Additionally, isoflurane anesthesia resulted in a heterogeneous attenuation of cocaine-induced Fos expression, with the most robust effect in the orbital cortex but no effect in the nucleus accumbens core (NAcC). These results indicate that cocaine-induced Fos is preserved in the NAcC under isoflurane, suggesting that isoflurane can be used in imaging studies involving cocaine effects in this region. PMID:25451087

  16. Postovulatory effect of repeated intravenous administration of ACTH on the contractile activity of the oviduct, ova transport and endocrine status of recently ovulated and unrestrained sows.

    PubMed

    Mwanza, A M; Madej, A; Kindahl, H; Lundeheim, N; Einarsson, S

    2000-11-01

    The effect of repeated intravenous administration of ACTH (Synacthen depot) on the contractile activity of the oviduct, ova transport and endocrine status was studied in 11 Swedish crossbred (Landrace x Yorkshire) multiparous sows. In the second estrus after weaning, the ACTH group (Group A, n=6) sows were administered 0.01 mg/kg body weight of ACTH every 6 h commencing 4 to 8 h after ovulation, whereas the control group (Group C, n=5) sows were administered saline solution. Immediately after standing estrus, a Millar pressure transducer was placed about 3 cm into the isthmus via a laparotomy. Blood samples for hormonal analyses and pressure recordings of the oviduct were collected from all sows until slaughter. After slaughter, the genital tract opposite to the side with the transducer was retrieved, and 3 equal isthmic segments and the first third of the uterine horn portion adjacent to the UTJ were flushed separately for ova recovery. Cortisol levels were significantly (P<0.05) elevated after ACTH administration. Progesterone and PGF2alpha metabolite levels were significantly (P<0.05) elevated only after the first ACTH administration. No significant differences (P>0.05) were seen in the mean pressure and frequencies of phasic pressure fluctuations either before or after every ACTH administration between Groups A and C. No significant difference (P>0.05) was seen in the proportion of ova recovered in the different segments between Groups A and C. It can be concluded from the present study that the administration of ACTH (0.01 mg/kg body weight) to sows at 4 to 8 h after ovulation, and after each subsequent ACTH administration, elevates cortisol levels, whereas progesterone and PGF2alpha metabolite levels are elevated only after the first treatment, and that this has no effect on the mean isthmic pressure, the frequency of phasic pressure fluctuations or ova transport. PMID:11192189

  17. Effect of repeated oral administration of Bifidobacterium longum BB536 on apomorphine-induced rearing behavior in mice.

    PubMed

    Orikasa, Shuzo; Nabeshima, Kazumi; Iwabuchi, Noriyuki; Xiao, Jin-Zhong

    2016-01-01

    Schizophrenia is a chronic psychiatric illness. Disruption of the dopaminergic system has been suggested to be the pathogenic cause of this disease. The effect of Bifidobacterium longum BB536 (BB536) on schizophrenic behavior was investigated in an animal model. Daily administration of BB536 (10(9) CFU/mouse, p.o. for 2 weeks) was found to reduce rearing behavior augmented by the dopamine receptor agonist apomorphine and to decrease the resting level of plasma corticosterone and the ratio of kynurenine to tryptophan. These results suggest the potential of BB536 for supplemental treatment of the symptoms of schizophrenia.

  18. Effect of repeated oral administration of Bifidobacterium longum BB536 on apomorphine-induced rearing behavior in mice

    PubMed Central

    ORIKASA, Shuzo; NABESHIMA, Kazumi; IWABUCHI, Noriyuki; XIAO, Jin-Zhong

    2016-01-01

    Schizophrenia is a chronic psychiatric illness. Disruption of the dopaminergic system has been suggested to be the pathogenic cause of this disease. The effect of Bifidobacterium longum BB536 (BB536) on schizophrenic behavior was investigated in an animal model. Daily administration of BB536 (109 CFU/mouse, p.o. for 2 weeks) was found to reduce rearing behavior augmented by the dopamine receptor agonist apomorphine and to decrease the resting level of plasma corticosterone and the ratio of kynurenine to tryptophan. These results suggest the potential of BB536 for supplemental treatment of the symptoms of schizophrenia. PMID:27508116

  19. Evolution of opioid risk management and review of the classwide REMS for extended-release/long-acting opioids.

    PubMed

    Stanos, Steven

    2012-11-01

    In 2007, the Food and Drug Administration Amendments Act (FDAAA) afforded the US Food and Drug Administration (FDA) the ability to enforce postmarketing risk management strategies for prescription medicines. Under this policy, certain medications with known or potential risks could be required to have a Risk Evaluation and Mitigation Strategy (REMS), a risk management program designed to ensure that a product's therapeutic benefit outweighs its risks. Prescription opioid analgesics, particularly extended-release (ER)/long-acting (LA) formulations, have undergone scrutiny in recent years due to the serious risks associated with their use, especially when they are prescribed improperly, misused, or abused. In July 2012, the FDA approved a classwide REMS for ER and LA opioids. This ER/LA opioid REMS program is designed to improve prescriber education and patient awareness about safe opioid use to minimize the risks of addiction, unintentional overdose, and death. Because clinicians often encounter patients with moderate-to-severe chronic, noncancer pain who are in need of around-the-clock opioid analgesia, knowledge of the conditions of this classwide REMS may become essential to continue prescribing ER/LA opioids. This article briefly describes the changes in US risk management policies that have shaped today's regulatory environment and provides an overview of the requirements for the classwide ER/LA opioid REMS.

  20. Opioid analgesics: does potency matter?

    PubMed

    Passik, Steven D; Webster, Lynn

    2014-01-01

    Prescription opioid analgesics with a wide range of potencies are currently used for the treatment of chronic pain. Yet understanding the clinical relevance and therapeutic consequences of opioid potency remains ill defined. Both patients and clinicians alike have misperceptions about opioid potency, expecting that less-potent opioids will be less effective or fearing that more-potent opioids are more dangerous or more likely to be abused. In this review, common myths about the potency of opioid analgesics will be discussed. Clinicians should understand that pharmacologic potency per se does not necessarily imply more effective analgesia or higher abuse liability. Published dose conversion tables may not accurately calculate the dose for effective and safe rotation from one opioid to another in patients receiving long-term opioid therapy because they are based on limited data that may not apply to chronic pain. Differences in pharmacologic potency are largely accounted for by the actual doses prescribed, according to individualized patient need. Factors for achieving effective analgesia and reducing the risks involved with opioid use include careful medication selection based on patient characteristics, appropriate dosing titration and opioid rotation practices, knowledge of product formulation characteristics (eg, extended release, immediate release, and tamper-resistant features), and an awareness of differences in opioid pharmacokinetics and metabolism. Clinicians should remain vigilant in monitoring patients on any opioid medication, regardless of classification along the opioid potency continuum.

  1. Rational use of opioids.

    PubMed

    Mastronardi, P; Cafiero, T

    2001-04-01

    The role of analgesia and sedation in intensive care units (ICU) is ancillary to other intensive care strategies, nevertheless they permit that every other diagnostic and therapeutic procedure is safely performed by keeping the patient pain-free, anxiety-free and cooperative. Commonly used opioids in ICU include morphine, fentanyl, sufentanil and remifentanil. The choice among opioid drugs relies on their pharmacokinetics and their pharmacodynamic effects. Cardiovascular stability observed with fentanyl and sufentanil indicates their use in hemodynamically compromised patients. Short-acting remifentanil offers several advantages in patients requiring prolonged infusions. The organ-independent metabolism of this newer molecule may be valuable in patients with multiple organ failure. The main indications for opioid analgesia and sedation in ICU include: 1) Anxiety, pain and agitation: in turn, they can increase cardiac workload, myocardial oxygen consumption and rate of dysarrhythmias; 2) immediate postoperative period after major surgery; 3) short-term invasive procedures. Potential advantages offered by opioids in the ICU setting also include: a) Cardiac protection: in animal models, it has been observed that delta-opiate receptor stimulation confers a preconditioning-like protective effects against myocardial ischemia; b) Neuroprotection: recent studies suggest that mu- and kappa-opiate receptors are involved in ischemic preconditioning against seizures in the brain. During opioid therapy in the ICU, drug tolerance and withdrawal symptoms should be anticipated and the dose adjusted accordingly.

  2. Correlates and Consequences of Opioid Misuse among High-Risk Young Adults

    PubMed Central

    Schrager, Sheree M.; Silva, Karol; Jackson Bloom, Jennifer; Iverson, Ellen; Lankenau, Stephen E.

    2014-01-01

    Background. Prescription opioids are the most frequently misused class of prescription drug among young adults aged 18–25, yet trajectories of opioid misuse and escalation are understudied. We sought to model opioid misuse patterns and relationships between opioid misuse, sociodemographic factors, and other substance uses. Methods. Participants were 575 young adults age 16–25 who had misused opioids in the last 90 days. Latent class analysis was performed with models based on years of misuse, recency of misuse, and alternate modes of administration within the past 12 months, 3 months, and 30 days. Results. Four latent classes emerged that were differentially associated with heroin, cocaine, and methamphetamine use, tranquilizer misuse, daily opioid misuse, and opioid withdrawal. Alternate modes of administering opioids were associated with increased risk for these outcomes. Sociodemographic factors, homelessness, prescription history, and history of parental drug use were significantly associated with riskier opioid misuse trajectories. Conclusion. Young adults who reported more debilitating experiences as children and adolescents misused opioids longer and engaged in higher risk alternate modes of administering opioids. Data on decisions both to use and to alter a drug's form can be combined to describe patterns of misuse over time and predict important risk behaviors. PMID:25506462

  3. Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects

    PubMed Central

    Wanigasekera, Vishvarani; Lee, Michael C.; Rogers, Richard; Kong, Yazhuo; Leknes, Siri; Andersson, Jesper; Tracey, Irene

    2012-01-01

    Variability in opioid analgesia has been attributed to many factors. For example, genetic variability of the μ-opioid receptor (MOR)-encoding gene introduces variability in MOR function and endogenous opioid neurotransmission. Emerging evidence suggests that personality trait related to the experience of reward is linked to endogenous opioid neurotransmission. We hypothesized that opioid-induced behavioral analgesia would be predicted by the trait reward responsiveness (RWR) and the response of the brain reward circuitry to noxious stimuli at baseline before opioid administration. In healthy volunteers using functional magnetic resonance imaging and the μ-opioid agonist remifentanil, we found that the magnitude of behavioral opioid analgesia is positively correlated with the trait RWR and predicted by the neuronal response to painful noxious stimuli before infusion in key structures of the reward circuitry, such as the orbitofrontal cortex, nucleus accumbens, and the ventral tegmental area. These findings highlight the role of the brain reward circuitry in the expression of behavioral opioid analgesia. We also show a positive correlation between behavioral opioid analgesia and opioid-induced suppression of neuronal responses to noxious stimuli in key structures of the descending pain modulatory system (amygdala, periaqueductal gray, and rostral–ventromedial medulla), as well as the hippocampus. Further, these activity changes were predicted by the preinfusion period neuronal response to noxious stimuli within the ventral tegmentum. These results support the notion of future imaging-based subject-stratification paradigms that can guide therapeutic decisions. PMID:23045652

  4. The effect of a novel pentadecapeptide BPC 157 on development of tolerance and physical dependence following repeated administration of diazepam.

    PubMed

    Jelovac, N; Sikiric, P; Rucman, R; Petek, M; Perovic, D; Marovic, A; Anic, T; Seiwerth, S; Mise, S; Pigac, B; Duplancie, B; Turkovic, B; Dodig, G; Prkacin, I; Stancic-Rokotov, D; Zoricic, I; Aralica, G; Sebecic, B; Ziger, T; Slobodnjak, Z

    1999-09-30

    A novel gastric pentadecapeptide BPC 157 with different beneficial activities and anticonvulsant effect interacting with GABAergic system could improve diazepam efficacy coadministered (10 microg/kg, 10 ng/kg i.p.) with diazepam (5.0 mg/kg i.p.) twice daily for 10 days, since diazepam chronic medication would otherwise predispose for diazepam- tolerance/withdrawal development (shorter latency to convulsion after convulsant). In diazepam chronically treated mice, it attenuated diazepam tolerance (provoked by later acute administration of diazepam together with convulsant) and postponed physical dependence/withdrawal effects (provoked by later administration of isoniazid). In tolerance assay, at 42 h after the end of conditioning regimen, shorter preconvulsive latencies than in healthy (non-diazepam conditioned) mice following isoniazid (800 mg/kg i.p.) (as hallmark of tolerance) were observed if diazepam (5.0 mg/kg i.p.) was again given acutely to mice previously conditioned with diazepam alone (use of picrotoxin 3.0 mg/kg i.p., as convulsant, with acute application of diazepam in previously diazepam conditioned mice did not lead to tolerance hallmark). This was completely avoided in diazepam+BPC 157 10 microg or diazepam+BPC 157 10 ng chronically treated animals. In physical dependence assay (isoniazid challenge assessed at 6, 14, 42 and 72 h after conditioning medication), when compared to diazepam non-conditioned healthy mice, in diazepam conditioned mice residual anticonvulsive activity was not present already at the earliest post-conditioning interval (i.e., not different latency to isoniazid-convulsions), whereas shorter preconvulsive latencies (as physical dependence/withdrawal hallmark) were noted in diazepam conditioned mice following isoniazid challenge at 42 h and at 72 h after end of conditioning treatment. In diazepam+BPC 157 10 microg- conditioned mice, a residual anticonvulsive activity (i.e., longer latency to isoniazid convulsion) was noted at 6 h

  5. A Leptin-Mediated Central Mechanism in Analgesia-Enhanced Opioid Reward in Rats

    PubMed Central

    Lim, Grewo; Kim, Hyangin; McCabe, Michael F.; Chou, Chiu-Wen; Wang, Shuxing; Chen, Lucy L.; Marota, John J.A.; Blood, Anne; Breiter, Hans C.

    2014-01-01

    Opioid analgesics are commonly used in chronic pain management despite a potential risk of rewarding. However, it remains unclear whether opioid analgesia would enhance the opioid rewarding effect thereby contributing to opioid rewarding. Utilizing a rat paradigm of conditioned place preference (CPP) combined with ankle monoarthritis as a condition of persistent nociception, we showed that analgesia induced by either morphine or the nonsteroid anti-inflammatory drug ibuprofen increased CPP scores in arthritic rats, suggesting that analgesia itself had a rewarding effect. However, arthritic rats exhibited a significantly higher CPP score in response to morphine than ibuprofen. Thus, the rewarding effect of morphine was enhanced in the presence of persistent nociception, producing a phenomenon of analgesia-enhanced opioid reward. At the cellular level, administration of morphine activated a cascade of leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens (NAc), while administration of ibuprofen decreased glial activation with no effect on leptin expression in the NAc. Furthermore, the morphine rewarding effect was blocked in leptin deficient ob/ob mice or by neutralizing leptin or interleukin-1β in the NAc without diminishing morphine analgesia. The data indicate that systemic opioid can activate a leptin-mediated central mechanism in the NAc that led to the enhanced opioid rewarding effect. These findings provide evidence for an interaction between opioid analgesia and opioid rewarding, which may have implications in clinical opioid dose escalation in chronic pain management. PMID:25031415

  6. Pharmacokinetics of difloxacin and its concentration in body fluids and endometrial tissues of mares after repeated intragastric administration

    PubMed Central

    2005-01-01

    Abstract Pharmacokinetics of difloxacin and its distribution within the body fluids and endometrium of 6 mares were studied after intragastric (IG) administration of 5 individual doses. Difloxacin concentrations were serially measured in serum, urine, peritoneal fluid, synovial fluid, cerebrospinal fluid, and endometrium over 120 h. Bacterial susceptibility to difloxacin was determined for 174 equine pathogens over a 7-month period. Maximum serum concentration (Cmax) was 2.25 ± 0.70 μg/mL at 3.12 ± 2.63 h and Cmax after the 5th dose was 2.41 ± 0.86 μg/mL at 97.86 ± 1.45 h. The mean elimination half-life (t1/2) was 8.75 ± 2.77 h and area under the serum concentration versus time curve (AUC) was 25.13 ± 8.79 μg h/mL. Highest mean synovial fluid concentration was 1.26 ± 0.49 μg/mL at 100 h. Highest mean peritoneal fluid concentration was 1.50 ± 0.56 μg/mL at 98 h. Highest mean endometrial concentration was 0.78 ± 0.48 μg/g at 97.5 h. Mean cerebrospinal fluid concentration was 0.87 ± 0.52 μg/mL at 99 h. Highest mean urine concentration was 92.05 ± 30.35 μg/mL at 104 h. All isolates of Salmonella spp. and Pasteurella spp. were susceptible. In general, gram-negative organisms were more susceptible than gram-positives. Difloxacin appears to be safe, adequately absorbed, and well distributed to body fluids and endometrial tissues of mares and may be useful in the treatment of susceptible bacterial infections in adult horses. PMID:16187554

  7. Methylnaltrexone in the treatment of opioid-induced constipation

    PubMed Central

    Meerveld, Beverley Greenwood-Van; Standifer, Kelly M

    2008-01-01

    Constipation is a significant problem related to opioid medications used to manage pain. This review attempts to outline the latest findings related to the therapeutic usefulness of a μ opioid receptor antagonist, methylnaltrexone in the treatment of opioid-induced constipation. The review highlights methylnaltrexone bromide (Relistor™; Progenics/Wyeth) a quaternary derivative of naltrexone, which was recently approved in the United States, Europe and Canada. The Food and Drug Administration in the United States approved a subcutaneous injection for the treatment of opioid bowel dysfunction in patients with advanced illness who are receiving palliative care and when laxative therapy has been insufficient. Methylnaltrexone is a peripherally restricted, μ opioid receptor antagonist that accelerates oral–cecal transit in patients with opioid-induced constipation without reversing the analgesic effects of morphine or inducing symptoms of opioid withdrawal. An analysis of the mechanism of action and the potential benefits of using methylnaltrexone is based on data from published basic research and recent clinical studies. PMID:21677823

  8. Cellular mechanisms underlying the interaction between cannabinoid and opioid system.

    PubMed

    Parolaro, D; Rubino, T; Viganò, D; Massi, P; Guidali, C; Realini, N

    2010-04-01

    Recently, the presence of functional interaction between the opioid and cannabinoid system has been shown in various pharmacological responses. Although there is an increasing interest for the feasible therapeutic application of a co-administration of cannabinoids and opioids in some disorders (i.e. to manage pain, to modulate immune system and emotions) and the combined use of the two drugs by drug abusers is becoming largely diffuse, only few papers focused on cellular and molecular mechanisms underlying this interaction. This review updates the biochemical and molecular underpinnings of opioid and cannabinoid interaction, both within the central nervous system and periphery. The most convincing theory for the explanation of this reciprocal interaction involves (i) the release of opioid peptides by cannabinoids or endocannabinoids by opioids, (ii) the existence of a direct receptor-receptor interaction when the receptors are co-expressed in the same cells, and (iii) the interaction of their intracellular pathways. Finally, the cannabinoid/opioid interaction might be different in the brain rewarding networks and in those accounting for other pharmacological effects (antinociception, modulation of emotionality and cognitive behavior), as well as between the central nervous system and periphery. Further insights about the cannabinoid/opioid interaction could pave the way for new and promising therapeutic approaches.

  9. Prescription Opioids in Adolescence and Future Opioid Misuse

    PubMed Central

    Johnston, Lloyd; O’Malley, Patrick M.; Keyes, Katherine M.; Heard, Kennon

    2015-01-01

    BACKGROUND AND OBJECTIVE: Legitimate opioid use is associated with an increased risk of long-term opioid use and possibly misuse in adults. The objective of this study was to estimate the risk of future opioid misuse among adolescents who have not yet graduated from high school. METHODS: Prospective, panel data come from the Monitoring the Future study. The analysis uses a nationally representative sample of 6220 individuals surveyed in school in 12th grade and then followed up through age 23. Analyses are stratified by predicted future opioid misuse as measured in 12th grade on the basis of known risk factors. The main outcome is nonmedical use of a prescription opioid at ages 19 to 23. Predictors include use of a legitimate prescription by 12th grade, as well as baseline history of drug use and baseline attitudes toward illegal drug use. RESULTS: Legitimate opioid use before high school graduation is independently associated with a 33% increase in the risk of future opioid misuse after high school. This association is concentrated among individuals who have little to no history of drug use and, as well, strong disapproval of illegal drug use at baseline. CONCLUSIONS: Use of prescribed opioids before the 12th grade is independently associated with future opioid misuse among patients with little drug experience and who disapprove of illegal drug use. Clinic-based education and prevention efforts have substantial potential to reduce future opioid misuse among these individuals, who begin opioid use with strong attitudes against illegal drug use. PMID:26504126

  10. Cellular Composition of the Spleen and Changes in Splenic Lysosomes in the Dynamics of Dyslipidemia in Mice Caused by Repeated Administration of Poloxamer 407.

    PubMed

    Goncharova, N V; Shurlygina, A V; Mel'nikova, E V; Karmatskikh, O L; Avrorov, P A; Loktev, K V; Korolenko, T A

    2015-11-01

    We studied the effect of dyslipidemia induced by poloxamer 407 (300 mg/kg twice a week for 30 days) on cellular composition of the spleen and splenocyte lysosomes in mice. Changes in blood lipid profile included elevated concentrations of total cholesterol, aterogenic LDL, and triglycerides most pronounced in 24 h after the last poloxamer 407 injection; gradual normalization of lipid profile was observed in 4 days (except triglycerides) and 10 days. The most pronounced changes in the spleen (increase in organ weight and number of cells, inhibition in apoptosis, and reduced accumulation of vital dye acridine orange in lysosomes) were detected on day 4; on day 10, the indices returned to normal. Cathepsin D activity in the spleen also increased at these terms. The relationship between changes in the cellular composition of the spleen and dynamics of serum lipid profile in mice in dyslipidemia caused by repeated administrations of relatively low doses of poloxamer 407 is discussed.

  11. Cellular Composition of the Spleen and Changes in Splenic Lysosomes in the Dynamics of Dyslipidemia in Mice Caused by Repeated Administration of Poloxamer 407.

    PubMed

    Goncharova, N V; Shurlygina, A V; Mel'nikova, E V; Karmatskikh, O L; Avrorov, P A; Loktev, K V; Korolenko, T A

    2015-11-01

    We studied the effect of dyslipidemia induced by poloxamer 407 (300 mg/kg twice a week for 30 days) on cellular composition of the spleen and splenocyte lysosomes in mice. Changes in blood lipid profile included elevated concentrations of total cholesterol, aterogenic LDL, and triglycerides most pronounced in 24 h after the last poloxamer 407 injection; gradual normalization of lipid profile was observed in 4 days (except triglycerides) and 10 days. The most pronounced changes in the spleen (increase in organ weight and number of cells, inhibition in apoptosis, and reduced accumulation of vital dye acridine orange in lysosomes) were detected on day 4; on day 10, the indices returned to normal. Cathepsin D activity in the spleen also increased at these terms. The relationship between changes in the cellular composition of the spleen and dynamics of serum lipid profile in mice in dyslipidemia caused by repeated administrations of relatively low doses of poloxamer 407 is discussed. PMID:26608379

  12. Repeated dose (28-day) administration of silver nanoparticles of varied size and coating does not significantly alter the indigenous murine gut microbiome.

    PubMed

    Wilding, Laura A; Bassis, Christine M; Walacavage, Kim; Hashway, Sara; Leroueil, Pascale R; Morishita, Masako; Maynard, Andrew D; Philbert, Martin A; Bergin, Ingrid L

    2016-01-01

    Silver nanoparticles (AgNPs) have been used as antimicrobials in a number of applications, including topical wound dressings and coatings for consumer products and biomedical devices. Ingestion is a relevant route of exposure for AgNPs, whether occurring unintentionally via Ag dissolution from consumer products, or intentionally from dietary supplements. AgNP have also been proposed as substitutes for antibiotics in animal feeds. While oral antibiotics are known to have significant effects on gut bacteria, the antimicrobial effects of ingested AgNPs on the indigenous microbiome or on gut pathogens are unknown. In addition, AgNP size and coating have been postulated as significantly influential towards their biochemical properties and the influence of these properties on antimicrobial efficacy is unknown. We evaluated murine gut microbial communities using culture-independent sequencing of 16S rRNA gene fragments following 28 days of repeated oral dosing of well-characterized AgNPs of two different sizes (20 and 110 nm) and coatings (PVP and Citrate). Irrespective of size or coating, oral administration of AgNPs at 10 mg/kg body weight/day did not alter the membership, structure or diversity of the murine gut microbiome. Thus, in contrast to effects of broad-spectrum antibiotics, repeat dosing of AgNP, at doses equivalent to 2000 times the oral reference dose and 100-400 times the effective in vitro anti-microbial concentration, does not affect the indigenous murine gut microbiome.

  13. Opioid Use Disorders.

    PubMed

    Sharma, Bikash; Bruner, Ann; Barnett, Gabrielle; Fishman, Marc

    2016-07-01

    Opioid use and addiction in adolescents and young adults is a health problem of epidemic proportions, with devastating consequences for youth and their families. Opioid overdose is a life-threatening emergency that should be treated with naloxone, and respiratory support if necessary. Overdose should always be an opportunity to initiate addiction treatment. Detoxification is often a necessary, but never sufficient, component of treatment for OUDs. Treatment for OUDs is effective but treatment capacity is alarmingly limited and under-developed. Emerging consensus supports the incorporation of relapse prevention medications such as buprenorphine and extended release naltrexone into comprehensive psychosocial treatment including counseling and family involvement. PMID:27338968

  14. Repeated Administration of a Mutant Cocaine Esterase: Effects on Plasma Cocaine Levels, Cocaine-Induced Cardiovascular Activity, and Immune Responses in Rhesus Monkeys

    PubMed Central

    Collins, Gregory T.; Brim, Remy L.; Noon, Kathleen R.; Narasimhan, Diwahar; Lukacs, Nicholas W.; Sunahara, Roger K.; Woods, James H.

    2012-01-01

    Previous studies have demonstrated the capacity of a long-acting mutant form of a naturally occurring bacterial double mutant cocaine esterase (DM CocE) to antagonize the reinforcing, discriminative, convulsant, and lethal effects of cocaine in rodents and reverse the increases in mean arterial pressure (MAP) and heart rate (HR) produced by cocaine in rhesus monkeys. This study was aimed at characterizing the immunologic responses to repeated dosing with DM CocE and determining whether the development of anti-CocE antibodies altered the capacity of DM CocE to reduce plasma cocaine levels and ameliorate the cardiovascular effects of cocaine in rhesus monkeys. Under control conditions, intravenous administration of cocaine (3 mg/kg) resulted in a rapid increase in the plasma concentration of cocaine (n = 2) and long-lasting increases in MAP and HR (n = 3). Administration of DM CocE (0.32 mg/kg i.v.) 10 min after cocaine resulted in a rapid hydrolysis of cocaine with plasma levels below detection limits within 5 to 8 min. Elevations in MAP and HR were significantly reduced within 25 and 50 min of DM CocE administration, respectively. Although slight (10-fold) increases in anti-CocE antibodies were observed after the fourth administration of DM CocE, these antibodies did not alter the capacity of DM CocE to reduce plasma cocaine levels or ameliorate cocaine's cardiovascular effects. Anti-CocE titers were transient and generally dissipated within 8 weeks. Together, these results suggest that highly efficient cocaine esterases, such as DM CocE, may provide a novel and effective therapeutic for the treatment of acute cocaine intoxication in humans. PMID:22518021

  15. Repeated administration of a mutant cocaine esterase: effects on plasma cocaine levels, cocaine-induced cardiovascular activity, and immune responses in rhesus monkeys.

    PubMed

    Collins, Gregory T; Brim, Remy L; Noon, Kathleen R; Narasimhan, Diwahar; Lukacs, Nicholas W; Sunahara, Roger K; Woods, James H; Ko, Mei-Chuan

    2012-07-01

    Previous studies have demonstrated the capacity of a long-acting mutant form of a naturally occurring bacterial double mutant cocaine esterase (DM CocE) to antagonize the reinforcing, discriminative, convulsant, and lethal effects of cocaine in rodents and reverse the increases in mean arterial pressure (MAP) and heart rate (HR) produced by cocaine in rhesus monkeys. This study was aimed at characterizing the immunologic responses to repeated dosing with DM CocE and determining whether the development of anti-CocE antibodies altered the capacity of DM CocE to reduce plasma cocaine levels and ameliorate the cardiovascular effects of cocaine in rhesus monkeys. Under control conditions, intravenous administration of cocaine (3 mg/kg) resulted in a rapid increase in the plasma concentration of cocaine (n = 2) and long-lasting increases in MAP and HR (n = 3). Administration of DM CocE (0.32 mg/kg i.v.) 10 min after cocaine resulted in a rapid hydrolysis of cocaine with plasma levels below detection limits within 5 to 8 min. Elevations in MAP and HR were significantly reduced within 25 and 50 min of DM CocE administration, respectively. Although slight (10-fold) increases in anti-CocE antibodies were observed after the fourth administration of DM CocE, these antibodies did not alter the capacity of DM CocE to reduce plasma cocaine levels or ameliorate cocaine's cardiovascular effects. Anti-CocE titers were transient and generally dissipated within 8 weeks. Together, these results suggest that highly efficient cocaine esterases, such as DM CocE, may provide a novel and effective therapeutic for the treatment of acute cocaine intoxication in humans. PMID:22518021

  16. The Central Reinforcing Properties of Ethanol Are Mediated by Endogenous Opioid Systems: Effects of Mu and Kappa Opioid Antagonists

    PubMed Central

    Nizhnikov, Michael E.; Varlinskaya, Elena I.; Spear, Norman E.

    2010-01-01

    Endogenous opioid systems are implicated in the reinforcing effects of ethanol and may play a substantial role in modulating the central reinforcing effects of ethanol early in ontogeny. This possibility was explored in the present study through the use of an olfactory conditioning paradigm with centrally administered ethanol serving as an unconditioned stimulus (US). In Experiment 1, newborn rat pups were treated with either a selective mu antagonist CTOP or kappa selective antagonist nor-BNI prior to olfactory conditioning. Experiment 2 tested the effectiveness of an alternative, shorter-duration kappa opioid antagonist GNTI in altering ethanol reinforcement. Experiment 3 investigated whether the effectiveness of pharmacological blockade of opioid receptors was due to the disruption of learning per se using an olfactory aversive conditioning paradigm with intraoral quinine serving as a US. Central administration of either mu or kappa opioid antagonists prior to conditioning disrupted the reinforcing effects of ethanol in newborn rats. The kappa opioid antagonist GNTI was as effective as nor-BNI. These effects of opioid antagonists on ethanol reinforcement are unlikely to be due to a disruption of all types of conditioning, since CTOP did not affect aversive reinforcement to intraoral infusions of quinine. The present results support the hypothesis that in newborn rats, the reinforcing properties of ethanol are mediated by the endogenous activity at mu and kappa opioid receptors. PMID:22267966

  17. Opioid Drugs in Patients With Liver Disease: A Systematic Review

    PubMed Central

    Soleimanpour, Hassan; Safari, Saeid; Shahsavari Nia, Kavous; Sanaie, Sarvin; Alavian, Seyed Moayed

    2016-01-01

    Context The liver, one of the most important organs of the body, is known to be responsible for several functions. The functional contribution of the liver to the metabolism of carbohydrates, protein, drugs and toxins, fats and cholesterol and many other biological processes are still unknown. Liver disorders are classified into two types: acute and chronic. Different drugs are used in liver diseases to treat and control pain. Most pain relief medications such as opioids are metabolized via the liver; therefore, the adverse reactions of drugs are probably higher for patients with liver disease. The current study aimed to evaluate the effects of opioid drugs on patients with liver disease; therefore, it is necessary to select suitable opioids for such patients. Evidence Acquisition This review was written by referring to research literature including 70 articles and four textbooks published from 1958 to 2015 on various reputable sites. Searches were carried out on the key phrases of narcotic pain relievers (opioids), acute and chronic hepatic failure, opioid adverse drug reactions, drug-induced liver injury (DILI) and other similar keywords. References included a variety of research papers (descriptive and analytical), intervention and review articles. Results In patients with liver disease, administration of opioid analgesics should be observed, accurately. As a general rule, lower doses of drugs should be administered at regular intervals based on the signs of drug accumulation. Secondly, the interactions of opioid drugs with different levels of substrates of the P450 cytochrome enzyme should be considered. Conclusions Pain management in patients with liver dysfunction is always challenging to physicians because of the adverse reactions of drugs, especially opioids. Opioids should be used cautiously since they can cause sedation, constipation and sudden encephalopathy effects. Since the clearance of these drugs in patients with hepatic insufficiency is decreased

  18. Pleasure-related analgesia activates opioid-insensitive circuits.

    PubMed

    Kut, Elvan; Candia, Victor; von Overbeck, Jan; Pok, Judit; Fink, Daniel; Folkers, Gerd

    2011-03-16

    Recent findings suggest that pain and pleasure share common neurochemical circuits, and studies in animals and humans show that opioid-mediated descending pathways can inhibit or facilitate pain. We explored the role of endogenous opioid neurotransmission in pleasure-related analgesia. μ-Opioidergic activity was blocked with 0.2 mg/kg naloxone to assess its effects on hedonic responses to pleasant emotional pictures (International Affective Picture System) and its modulating effects on heat pain tolerance. Naloxone did not alter subjective and autonomous reactions to pleasure induction or overall mood of participants. In addition, pleasure-related increases in pain tolerance persisted after reversal of endogenous μ-opioidergic neurotransmission. Subjective pain intensity and unpleasantness ratings increased after naloxone administration. These findings suggest that, in addition to opioid-sensitive circuits, mainly opioid-insensitive pain-modulating circuits are activated during pleasure-related analgesia. PMID:21411655

  19. Repeated ketamine administration alters N-methyl-D-aspartic acid receptor subunit gene expression: implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans.

    PubMed

    Xu, Ke; Lipsky, Robert H

    2015-02-01

    For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis.

  20. Repeated administration of propofol upregulated the expression of c-Fos and cleaved-caspase-3 proteins in the developing mouse brain

    PubMed Central

    Cui, Yin; Ling-Shan, Gou; Yi, Liu; Xing-Qi, Wang; Xue-Mei, Zhuang; Xiao-Xing, Yin

    2011-01-01

    Objectives and Aim: This study was designed to analyze the relationship between the expression of c-Fos protein and apoptosis in the hippocampus following propofol administration in infant mice. There are reports that certain drugs, including the general anesthetics applied in pediatrics and obstetrics, could block N-methyl-D-aspartate glutamate receptors and activate γ-aminobutyric acid type A receptors. Furthermore, some anesthetics could trigger neuroapoptosis and the expression of c-Fos in the developing rodent brain. Propofol is a general anesthetic increasingly used in pediatrics and obstetrics, and is reported to be able to interact with both γ-aminobutyric acid type A and N-methyl-D-aspartate glutamate receptors. No adequate evaluations have been available as to whether the dosage of propofol to maintain anaesthesia could trigger the expression of c-Fos and apoptosis. Materials and Methods: Intraperitoneal injections of propofol (50, 100 and 150 mg/kg) or vehicle were administered every 90 minutes (4 times) in infant mice (5–7 days old). 30 minutes after the final administration, the protein expressions of c-Fos and cleaved-caspase-3 in the hippocampus were determined by immunohistochemistry and Western blotting. Results: It was demonstrated that the expressions of cleaved-caspase-3 and c-Fos were upregulated in the hippocampal CA3 region in this study. Conclusions: The upregulated c-Fos expression induced by repeated injections of propofol might evoke neuroapoptosis. PMID:22144767

  1. Treating Pain with Opioids

    MedlinePlus

    ... it costs. Ask if they have a drug discount program that can help you pay less for your medicine. Buy your medicine from the pharmacy that gives you the cheapest price.  Sign up for patient assistance programs: Most companies that make medicines have programs that Opioids: Howhaerleptpheeoypulesetdh? ...

  2. Opioid Antagonist Impedes Exposure.

    ERIC Educational Resources Information Center

    Merluzzi, Thomas V.; And Others

    1991-01-01

    Thirty spider-phobic adults underwent exposure to 17 phobic-related, graded performance tests. Fifteen subjects were assigned to naltrexone, an opioid antagonist, and 15 were assigned to placebo. Naltrexone had a significant effect on exposure, with naltrexone subjects taking significantly longer to complete first 10 steps of exposure and with…

  3. Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia.

    PubMed

    Chen, Lucy; Sein, Michael; Vo, Trang; Amhmed, Shihab; Zhang, Yi; Hilaire, Kristin St; Houghton, Mary; Mao, Jianren

    2014-01-01

    Opioid analgesics are commonly used to manage moderate to severe pain. However, the long-term use of opioids could lead to opioid tolerance (OT) and opioid-induced hyperalgesia (OIH). Distinguishing OIH from OT would impact the practice of opioid therapy because opioid dose adjustment may differentially influence OT and OIH. Currently, there are no standard criteria of OT versus OIH causing considerable ambiguity in clinical interpretation and management of these conditions. The authors designed a practitioner-based survey consisting of 20 targeted questions. Answering these questions would require responders' actual clinical experiences with opioid therapy. The survey was conducted between 2011 and 2012 through direct mails or e-mails to 1,408 physicians who are currently practicing in the United States. The authors find that certain clinical characteristics (eg, increased pain despite opioid dose escalation) are often used by practitioners to make differential diagnosis of OT and OIH despite some overlap in their clinical presentation. A key difference in clinical outcome is that OT and OIH could be improved and exacerbated by opioid dose escalation, respectively. Our survey results revealed a significant knowledge gap in some responders regarding differential diagnosis and management of OT and OIH. The results also identified several issues, such as opioid dose adjustment and clinical comorbidities related to OT and OIH, which require future patient-based studies.

  4. Neurobiology of opioid dependence in creating addiction vulnerability

    PubMed Central

    Evans, Christopher J.; Cahill, Catherine M.

    2016-01-01

    Opioid drugs are potent modulators of many physiological and psychological processes. When given acutely, they can elicit the signature responses of euphoria and analgesia that societies have coveted for centuries. Repeated, or chronic, use of opioids induces adaptive or allostatic changes that modify neuronal circuitry and create an altered normality — the “drug-dependent” state. This state, at least that exhibited by those maintained continuously on long-acting opioid drugs such as methadone or buprenorphine, is generally indistinguishable from the drug-naïve state for most overt behaviors. The consequences of the allostatic changes (cellular, circuit, and system adaptations) that accompany the drug-dependent state are revealed during drug withdrawal. Drug cessation triggers a temporally orchestrated allostatic re-establishment of neuronal systems, which is manifested as opposing physiological and psychological effects to those exhibited by acute drug intoxication. Some withdrawal symptoms, such as physical symptoms (sweating, shaking, and diarrhea) resolve within days, whilst others, such as dysphoria, insomnia, and anxiety, can linger for months, and some adaptations, such as learned associations, may be established for life. We will briefly discuss the cellular mechanisms and neural circuitry that contribute to the opioid drug-dependent state, inferring an emerging role for neuroinflammation. We will argue that opioid addictive behaviors result from a learned relationship between opioids and relief from an existing or withdrawal-induced anxiogenic and/or dysphoric state. Furthermore, a future stressful life event can recall the memory that opioid drugs alleviate negative affect (despair, sadness, and anxiety) and thereby precipitate craving, resulting in relapse. A learned association of relief of aversive states would fuel drug craving in vulnerable people living in an increasingly stressful society. We suggest that this route to addiction is

  5. Neurobiology of opioid dependence in creating addiction vulnerability.

    PubMed

    Evans, Christopher J; Cahill, Catherine M

    2016-01-01

    Opioid drugs are potent modulators of many physiological and psychological processes. When given acutely, they can elicit the signature responses of euphoria and analgesia that societies have coveted for centuries. Repeated, or chronic, use of opioids induces adaptive or allostatic changes that modify neuronal circuitry and create an altered normality - the "drug-dependent" state. This state, at least that exhibited by those maintained continuously on long-acting opioid drugs such as methadone or buprenorphine, is generally indistinguishable from the drug-naïve state for most overt behaviors. The consequences of the allostatic changes (cellular, circuit, and system adaptations) that accompany the drug-dependent state are revealed during drug withdrawal. Drug cessation triggers a temporally orchestrated allostatic re-establishment of neuronal systems, which is manifested as opposing physiological and psychological effects to those exhibited by acute drug intoxication. Some withdrawal symptoms, such as physical symptoms (sweating, shaking, and diarrhea) resolve within days, whilst others, such as dysphoria, insomnia, and anxiety, can linger for months, and some adaptations, such as learned associations, may be established for life. We will briefly discuss the cellular mechanisms and neural circuitry that contribute to the opioid drug-dependent state, inferring an emerging role for neuroinflammation. We will argue that opioid addictive behaviors result from a learned relationship between opioids and relief from an existing or withdrawal-induced anxiogenic and/or dysphoric state. Furthermore, a future stressful life event can recall the memory that opioid drugs alleviate negative affect (despair, sadness, and anxiety) and thereby precipitate craving, resulting in relapse. A learned association of relief of aversive states would fuel drug craving in vulnerable people living in an increasingly stressful society. We suggest that this route to addiction is contributive to

  6. Oral Administration of Recombinant Lactococcus lactis Expressing HSP65 and Tandemly Repeated P277 Reduces the Incidence of Type I Diabetes in Non-Obese Diabetic Mice

    PubMed Central

    Ma, Yanjun; Liu, Jingjing; Hou, Jing; Dong, Yuankai; Lu, Yong; Jin, Liang; Cao, Rongyue; Li, Taiming; Wu, Jie

    2014-01-01

    Diabetes mellitus type 1 (DM1) is an autoimmune disease that gradually destroys insulin-producing beta-cells. We have previously reported that mucosal administration of fusion protein of HSP65 with tandem repeats of P277 (HSP65-6P277) can reduce the onset of DM1 in non-obese diabetic (NOD) mice. To deliver large amounts of the fusion protein and to enhance long-term immune tolerance effects, in the present study, we investigated the efficacy of using orally administrated L. lactis expressing HSP65-6P277 to reduce the incidence of DM1 in NOD mice. L. lactis strain NZ9000 was engineered to express HSP65-6P277 either constitutively or by nisin induction. After immunization via gavage with the recombinant L. lactis strains to groups of 4-week old female NOD mice for 36 weeks, we observed that oral administration of recombinant L. Lactis resulted in the prevention of hyperglycemia, improved glucose tolerance and reduced insulitis. Immunologic analysis showed that treatment with recombinant L. lactis induced HSP65- and P277- specific T cell immuno-tolerance, as well as antigen-specific proliferation of splenocytes. The results revealed that the DM1-preventing function was in part caused by a reduction in the pro-inflammatory cytokine IFN-γ and an increase in the anti-inflammatory cytokine IL-10. Orally administered recombinant L. lactis delivering HSP65-6P277 may be an effective therapeutic approach in preventing DM1. PMID:25157497

  7. Adrenal Activity during Repeated Long-Access Cocaine Self-Administration is Required for Later CRF-Induced and CRF-Dependent Stressor-Induced Reinstatement in Rats

    PubMed Central

    Graf, Evan N; Hoks, Michael A; Baumgardner, Jean; Sierra, Jose; Vranjkovic, Oliver; Bohr, Colin; Baker, David A; Mantsch, John R

    2011-01-01

    Understanding the neurobiological processes that contribute to the establishment and expression of stress-induced regulation of cocaine use in addicted individuals is important for the development of new and better treatment approaches. It has been previously shown that rats self-administering cocaine under long-access conditions (6 h daily) display heightened susceptibility to the reinstatement of extinguished cocaine seeking by a stressor, electric footshock, or i.c.v. administration of the stressor-responsive neuropeptide, corticotropin-releasing factor (CRF). This study tested the hypothesis that adrenal responsiveness during earlier long-access cocaine self-administration (SA) is necessary for the establishment of later CRF-dependent stress-induced reinstatement. Reinstatement by footshock, but not a cocaine challenge (10 mg/kg, i.p.) following long-access SA, was blocked by i.c.v. administration of the CRF receptor antagonist, α-helical CRF9−41 (10 μg). Elimination of SA-induced adrenal responses through surgical adrenalectomy and diurnal corticosterone replacement (ADX/C) before 14 days of SA under long-access conditions had minimal impact on cocaine SA, but blocked later footshock-induced reinstatement. By contrast, ADX/C after SA, but before extinction and reinstatement testing, failed to reduce footshock-induced reinstatement. Likewise, ADX/C before 14 days long-access SA prevented later reinstatement by i.c.v. CRF (0.5 or 1.0 μg). However, significant CRF-induced reinstatement was observed when rats underwent ADX/C following SA, but before extinction and reinstatement testing, although a modest but statistically nonsignificant reduction in sensitivity to CRF's reinstating effects was observed. Taken together, these findings suggest that adrenal-dependent neuroadaptations in CRF responsiveness underlie the increased susceptibility to stress-induced relapse that emerges with repeated cocaine use. PMID:21412222

  8. Pharmacokinetics of human activated protein C. 2nd communication: tissue distribution study of a lyophilized purified human activated protein C after single or repeated intravenous administration in male mice and placental transfer and milk passage study after intravenous administration in pregnant and lactating mice.

    PubMed

    Ishii, S; Mochizuki, T; Nagao, T; Kudo, S; Fujita, A; Taniguchi, K; Kondo, S; Kiyoki, M

    1995-05-01

    Tissue distribution studies of human activated protein C (CAS 42617-41-4, APC) were performed in mice after single or repeated administration, and placental transfer and milk passage study were investigated. At 15 min after a single intravenous administration of 125I-APC, radioactivity was mainly distributed to the blood and blood rich organ, such as liver, and then rapidly eliminated. The radioactivity distributed to tissues was almost negligible at 24 h after administration except for the thyroid. The qualitative study of the distribution of radioactivity to tissues by whole body autoradiography demonstrated the correspondence to the result of the quantitative assay of distribution of radioactivity after single administration of 125I-APC. The influence of repeated administration of APC on its pharmacokinetic disposition was studied by administering 125I-APC once a day to mice for 14 days. Though plasma radioactivity at 15 min in mice during repeated administration of 125I-APC was almost similar to that at 15 min after a single administration, the radioactivity at 24 h after administration was 2 times higher than that after a single administration. The profile of plasma radioactivity during and after repeated administration corresponded to the simulation curve which was described with the pharmacokinetic parameters obtained previously after the single administration. Distribution profile after repeated administration at 15 min after the 4th, 7th, 10th and 14th administration was almost similar to that at 15 min after a single administration except for the thyroid and spleen. In the thyroid, the radioactivity was 500 times higher than that after a single administration, and HPLC analysis demonstrated that the radioactivity was attributed to thyroglobulin. As to the spleen, the radioactivity was about 52% of that after a single administration. During the repeated administration, the spleen became larger than that after a single administration and the final weight

  9. The Economic Impact of Opioid Use in the Management of Chronic Nonmalignant Pain.

    PubMed

    Lipman, Arthur; Webster, Lynn

    2015-10-01

    Chronic nonmalignant pain (CNMP), defined as persistent pain that is not attributable to a potentially life-limiting condition and has a duration of at least 3 months, is widespread in the United States. Moderate-to-severe CNMP often is treated with opioid analgesics, and there is ongoing debate regarding appropriate allocation of opioids to treat CNMP because long-term treatment can result in problematic side effects, drug misuse, or abuse leading to detrimental medical, social, and economic consequences. Furthermore, therapeutic strategies arising from concerns about the misuse of opioids may impede the treatment of patients who require strong analgesics for adequate pain relief. While current CNMP management includes nonpharmacologic and pharmacologic approaches, including acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids, there is debate regarding the risk-benefit profile of opioids for chronic pain treatment. Mitigation of opioid misuse and abuse and proper administration of opioid analgesics must be balanced against providing appropriate analgesia. To accomplish this, managed care policies could implement guidelines that focus on evaluating risk characteristics for opioid misuse and abuse, use opioid dose-sparing strategies, and encourage the use of alternative analgesics or nonpharmacologic therapy when appropriate. The purpose of this review is to examine challenges and costs associated with CNMP management using opioids and to summarize alternative therapeutic approaches.

  10. No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia.

    PubMed Central

    Stein, C; Pflüger, M; Yassouridis, A; Hoelzl, J; Lehrberger, K; Welte, C; Hassan, A H

    1996-01-01

    Pain treatment with centrally acting opiates is limited by tolerance. Tolerance is a decreasing effect of a drug with prolonged administration of that drug or of a related (e.g., endogenous) compound acting at the same receptor. This is often associated with a downregulation of receptors. In peripheral inflamed tissue, both locally expressed opioid peptides and morphine can produce powerful analgesia mediated by similar populations of opioid receptors. We hypothesized that the chronic presence of endogenous opioids in inflamed joints might convey downregulation of peripheral opioid receptors and tolerance to the analgesic effects of intraarticular morphine. We assessed these effects after arthroscopic surgery in patients with and without histologically verified synovial cellular infiltration, and we examined synovial opioid peptides and opioid receptors by immunocytochemistry and autoradiography, respectively. We found that, despite an abundance of opioid-containing cells in pronounced synovitis, morphine is at least as effective as in patients without such cellular infiltrations, and there is no major downregulation of peripheral opioid receptors. Thus, opioids expressed in inflamed tissue do not produce tolerance to peripheral morphine analgesia. Tolerance may be less pronounced for peripherally than for centrally acting opioids, which provides a promising perspective for the treatment of chronic pain in arthritis and other inflammatory conditions. PMID:8698872

  11. The Economic Impact of Opioid Use in the Management of Chronic Nonmalignant Pain.

    PubMed

    Lipman, Arthur; Webster, Lynn

    2015-10-01

    Chronic nonmalignant pain (CNMP), defined as persistent pain that is not attributable to a potentially life-limiting condition and has a duration of at least 3 months, is widespread in the United States. Moderate-to-severe CNMP often is treated with opioid analgesics, and there is ongoing debate regarding appropriate allocation of opioids to treat CNMP because long-term treatment can result in problematic side effects, drug misuse, or abuse leading to detrimental medical, social, and economic consequences. Furthermore, therapeutic strategies arising from concerns about the misuse of opioids may impede the treatment of patients who require strong analgesics for adequate pain relief. While current CNMP management includes nonpharmacologic and pharmacologic approaches, including acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids, there is debate regarding the risk-benefit profile of opioids for chronic pain treatment. Mitigation of opioid misuse and abuse and proper administration of opioid analgesics must be balanced against providing appropriate analgesia. To accomplish this, managed care policies could implement guidelines that focus on evaluating risk characteristics for opioid misuse and abuse, use opioid dose-sparing strategies, and encourage the use of alternative analgesics or nonpharmacologic therapy when appropriate. The purpose of this review is to examine challenges and costs associated with CNMP management using opioids and to summarize alternative therapeutic approaches. PMID:26402389

  12. A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates.

    PubMed

    Ding, Huiping; Czoty, Paul W; Kiguchi, Norikazu; Cami-Kobeci, Gerta; Sukhtankar, Devki D; Nader, Michael A; Husbands, Stephen M; Ko, Mei-Chuan

    2016-09-13

    Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various well-honed behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ∼10- to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abuse-free opioid analgesics. PMID:27573832

  13. The relationship between the pharmacokinetics and pharmacodynamics of spinal opioids. Minireview based on a doctoral thesis.

    PubMed

    Sjöström, S

    1988-01-01

    Spinal opioids have been used clinically since the late seventies to treat acute, traumatic, obstetric and chronic pain. In this article the influence of the pharmacokinetics on the dynamics of intrathecal and epidural opioid administration are discussed with reference to current knowledge. PMID:2905092

  14. Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction

    PubMed Central

    Leppert, Wojciech

    2015-01-01

    Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal (GI) symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation, which significantly impair patients’ quality of life and may lead to undertreatment of pain. Traditional laxatives are often prescribed for OIBD symptoms, although they display limited efficacy and exert adverse effects. Other strategies include prokinetics and change of opioids or their administration route. However, these approaches do not address underlying causes of OIBD associated with opioid effects on mostly peripheral opioid receptors located in the GI tract. Targeted management of OIBD comprises purely peripherally acting opioid receptor antagonists and a combination of opioid receptor agonist and antagonist. Methylnaltrexone induces laxation in 50%–60% of patients with advanced diseases and OIBD who do not respond to traditional oral laxatives without inducing opioid withdrawal symptoms with similar response (45%–50%) after an oral administration of naloxegol. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN) in one tablet (a ratio of 2:1) provides analgesia with limited negative effect on the bowel function, as oxycodone displays high oral bioavailability and naloxone demonstrates local antagonist effect on opioid receptors in the GI tract and is totally inactivated in the liver. OXN in daily doses of up to 80 mg/40 mg provides equally effective analgesia with improved bowel function compared to oxycodone administered alone in patients with chronic non-malignant and cancer-related pain. OIBD is a common complication of long-term opioid therapy and may lead to quality of life deterioration and undertreatment of pain. Thus, a complex assessment and management that addresses underlying causes and patomechanisms of OIBD is recommended. Newer strategies comprise methylnaltrexone or OXN administration in the management of OIBD

  15. Lack of increased signal intensity in the dentate nucleus after repeated administration of a macrocyclic contrast agent in multiple sclerosis: An observational study.

    PubMed

    Eisele, Philipp; Alonso, Angelika; Szabo, Kristina; Ebert, Anne; Ong, Melissa; Schoenberg, Stefan O; Gass, Achim

    2016-09-01

    Recently, several studies reported increased signal intensity (SI) in the dentate nucleus (DN) after repeated application of gadolinium-based contrast agents (GBCAs), suggesting a deposition of gadolinium in this location. Patients with relapsing-remitting multiple sclerosis (RRMS) frequently show increased permeability of the blood-brain barrier as part of the inflammatory process in the brain parenchyma, which theoretically might increase the risk of gadolinium deposition. In this retrospective study, we investigated a possible increasing SI in the DN after repeated administrations of the macrocyclic contrast agent gadoterate meglumine.Forty-one RRMS patients (33 women, mean age 38 years) with at least 6 prior gadolinium-enhanced examinations (single dose gadoterate meglumine) were identified. A total of 279 unenhanced T1-weighted examinations were analyzed.SI ratio differences did not differ between the first and last MRI examination, neither for the DN-to-pons ratio (P = 0.594) nor for the DN-to-cerebellum ratio (P = 0.847). There was no correlation between the mean DN-to-pons, or between the mean DN-to-cerebellum SI ratio and the number of MRI examinations (P = 0.848 and 0.891), disease duration (P = 0.676 and 0.985), and expanded disability status scale (EDSS) (P = 0.639 and 0.945).We found no signal increases in the DN after a minimum of 6 injections of the macrocyclic GBCA gadoterate meglumine in RRMS patients. This warrants further investigations in regard to the true pathophysiologic basis of intracerebral gadolinium deposition. PMID:27684794

  16. Impaired recovery of brain muscarinic receptor sites following an adaptive down-regulation induced by repeated administration of diisopropyl fluorophosphate in aged rats

    SciTech Connect

    Pintor, A.; Fortuna, S.; De Angelis, S.; Michalek, H. )

    1990-01-01

    Potential age-related differences in the recovery rate of brain cholinesterase activity (ChE) and muscarinic acetylcholine receptor binding sites (mAChRs) following reduction induced by repeated treatment with diisopropyl fluorophosphate (DFP) were evaluated in Sprague-Dawley rats. Male 3- and 24-month old rats were s.c. injected with DFP on alternate days for 2 weeks and killed 48 hr and 7, 14, 21, 28 and 35 days after the last treatment. In the hippocampus and striatum, but not in the cerebral cortex, of control rats there as a significant age-related decline of ChE activity and maximal density of 3H-QNB binding sites (Bmax). The repeated administration of DFP during the first week caused a syndrome of cholinergic stimulation both in aged and young rats. The syndrome was more pronounced, in terms of intensity and duration in aged than in young animals resulting in 40 and 12% mortality, respectively; during the second week the syndrome attenuated in the two age-groups. The percentage inhibition of brain ChE at the end of DFP treatment did not differ between young and surviving aged rats. The down-regulation of mACRs was present in the three brain regions of both young and age rats (from 20 to 40%). Factorial analysis of variance showed significant differences for age, recovery rate, and significant interaction between age and recovery rate, both for ChE and mAChRs in young rats the three brain areas.

  17. The acceptability of repeat Internet-based hybrid diet assessment of previous 24-h dietary intake: administration of the Oxford WebQ in UK Biobank.

    PubMed

    Galante, Julieta; Adamska, Ligia; Young, Alan; Young, Heather; Littlejohns, Thomas J; Gallacher, John; Allen, Naomi

    2016-02-28

    Although dietary intake over a single 24-h period may be atypical of an individual's habitual pattern, multiple 24-h dietary assessments can be representative of habitual intake and help in assessing seasonal variation. Web-based questionnaires are convenient for the participant and result in automatic data capture for study investigators. This study reports on the acceptability of repeated web-based administration of the Oxford WebQ--a 24-h recall of frequency from a set food list suitable for self-completion from which energy and nutrient values can be automatically generated. As part of the UK Biobank study, four invitations to complete the Oxford WebQ were sent by email over a 16-month period. Overall, 176 012 (53% of those invited) participants completed the online version of the Oxford WebQ at least once and 66% completed it more than once, although only 16% completed it on all four occasions. The response rate for any one round of invitations varied between 34 and 26%. On most occasions, the Oxford WebQ was completed on the same day that they received the invitation, although this was less likely if sent on a weekend. Participants who completed the Oxford WebQ tended to be white, female, slightly older, less deprived and more educated, which is typical of health-conscious volunteer-based studies. These findings provide preliminary evidence to suggest that repeated 24-h dietary assessment via the Internet is acceptable to the public and a feasible strategy for large population-based studies. PMID:26652593

  18. Short-Term Effects of Repeated Olfactory Administration of Homeopathic Sulphur or Pulsatilla on Electroencephalographic Alpha Power in Healthy Young Adults

    PubMed Central

    Bell, Iris R.; Brooks, Audrey J.; Howerter, Amy; Jackson, Nicholas; Schwartz, Gary E.

    2011-01-01

    Introduction Homeopathic pathogenetic trials usually rely on symptom self report measures. Adding objective biomarkers could enhance detection of subtle initial remedy effects. The present feasibility study examined electroencephalographic (EEG) effects of repeated olfactory administration of two polycrest remedies. Methods College student volunteers (ages 18–30, both sexes) from an introductory psychology course were screened for good health and relatively elevated Sulphur OR Pulsatilla symptom scores on the Homeopathic Constitutional Type Questionnaire. Subjects underwent a series of 3 once-weekly double-blind sessions during which they repeatedly sniffed the remedy matched to their CTQ type and solvent controls. Each remedy was given in a 6c, 12c, and 30c potency, one potency per week, in randomly assigned order. Solvent controls included both plain distilled water and a water-ethanol (95%) solution. All sniff test solutions were further diluted just prior to laboratory sessions (0.5 ml test solution in 150 ml distilled water). Within a session, remedies and control solvents were administered via 2-second sniffs (8 sniffs of each of 4 different succussion levels for the potency in randomized order). Primary outcome variable was relative EEG power (alpha 1 8–10 hertz; alpha 2 10–12 hertz) averaged over 19 electrode sites, including all succussions for a given potency. Results Mixed-effect models revealed significant main effects for remedy type (Sulphur>Pulsatilla) in both alpha bands, controlling for gender, baseline resting EEG alpha, and solvent control responses. Additional analyses showed significant non-linear interactions between dilution and time (weekly session) in alpha 2 for both remedies and alpha 1 for Sulphur. Conclusion EEG alpha offers an objective biomarker of remedy effects for future studies and potential method for distinguishing time-dependent effects of specific remedies and remedy potencies from one another. PMID:21962194

  19. Neurobiological mechanisms involved in nicotine dependence and reward: participation of the endogenous opioid system

    PubMed Central

    Berrendero, Fernando; Robledo, Patricia; Trigo, José Manuel; Martín-García, Elena; Maldonado, Rafael

    2010-01-01

    Nicotine is the primary component of tobacco that maintains the smoking habit and develops addiction. The adaptive changes of nicotinic acetylcholine receptors produced by repeated exposure to nicotine play a crucial role in the establishment of dependence. However, other neurochemical systems also participate in the addictive effects of nicotine including glutamate, cannabinoids, GABA and opioids. This review will cover the involvement of these neurotransmitters in nicotine addictive properties, with a special emphasis on the endogenous opioid system. Thus, endogenous enkephalins and beta-endorphins acting on mu-opioid receptors are involved in nicotine rewarding effects, whereas opioid peptides derived from prodynorphin participate in nicotine aversive responses. An upregulation of mu-opioid receptors has been reported after chronic nicotine treatment that could counteract the development of nicotine tolerance, whereas the downregulation induced on kappa-opioid receptors seems to facilitate nicotine tolerance. Endogenous enkephalins acting on mu-opioid receptors also play a role in the development of physical dependence to nicotine. In agreement with these actions of the endogenous opioid system, the opioid antagonist naltrexone has shown to be effective for smoking cessation in certain subpopulations of smokers. PMID:20170672

  20. Opioids: The Prescription Drug & Heroin Overdose Epidemic

    MedlinePlus

    ... Resources Law Enforcement Resources Opioids: The Prescription Drug & Heroin Overdose Epidemic Opioids are natural or synthetic chemicals ... in your brain or body. Common opioids include heroin and prescription drugs such as oxycodone, hydrocodone, and ...

  1. Treating Chronic Pain with Opioids: Comparing Effectiveness and Cost

    MedlinePlus

    Treating Chronic Pain with Opioids: Comparing Effectiveness and Cost What are opioids? Opioids are very strong prescription ... using opioids. We compared the effectiveness, safety, and cost of different opioids. We chose these as Consumer ...

  2. Opioids in chronic noncancer pain.

    PubMed

    Manchikanti, Laxmaiah; Benyamin, Ramsin; Datta, Sukdeb; Vallejo, Ricardo; Smith, Howard

    2010-05-01

    Chronic noncancer pain is highly prevalent with associated negative effects on function and quality of life of the individuals involved. Opioids have been shown to decrease pain and improve function in some patients with chronic noncancer pain, but they are not always effective and are associated with multiple complications, including drug misuse, abuse and diversion. Furthermore, the effectiveness of opioids in decreasing pain and improving function has not been proven conclusively, resulting in continued uncertainty about long-term benefits of opioids for chronic noncancer pain. Ideally, in modern medicine, clinical decisions are made based on information derived from high quality evidence. Since no such evidence exists for chronic opioid therapy in chronic noncancer pain, this review describes various aspects of opioid therapy in chronic noncancer pain, including adherence monitoring, along with a ten-step process outlining the principles of effective and safe opioid use.

  3. Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

    PubMed Central

    Mall, Christine; Sckisel, Gail D.; Proia, David A.; Mirsoian, Annie; Grossenbacher, Steven K.; Pai, Chien-Chun Steven; Chen, Mingyi; Monjazeb, Arta M.; Kelly, Karen; Blazar, Bruce R.; Murphy, William J.

    2016-01-01

    ABSTRACT Monoclonal antibodies (mAbs) targeting coinhibitory molecules such as PD-1, PD-L1 and CTLA-4 are increasingly used as targets of therapeutic intervention against cancer. While these targets have led to a critical paradigm shift in treatments for cancer, these approaches are also plagued with limitations owing to cancer immune evasion mechanisms and adverse toxicities associated with continuous treatment. It has been difficult to reproduce and develop interventions to these limitations preclinically due to poor reagent efficacy and reagent xenogenecity not seen in human trials. In this study, we investigated adverse effects of repeated administration of PD-1 and PD-L1 mAbs in the murine 4T1 mammary carcinoma model. We observed rapid and fatal hypersensitivity reactions in tumor bearing mice within 30–60 min after 4–5 administrations of PD-L1 or PD-1 mAb but not CTLA-4 antibody treatment. These events occurred only in mice bearing the highly inflammatory 4T1 tumor and did not occur in mice bearing non-inflammatory tumors. We observed that mortality was associated with systemic accumulation of IgG1 antibodies, antibodies specific to the PD-1 mAb, and accumulation of Gr-1high neutrophils in lungs which have been implicated in the IgG mediated pathway of anaphylaxis. Anti-PD-1 associated toxicities were alleviated when PD-1 blockade was combined with the therapeutic HSP90 inhibitor, ganetespib, which impaired immune responses toward the xenogeneic PD-1 mAb. This study highlights a previously uncharacterized fatal hypersensitivity exacerbated by the PD-1/PD-L1 axis in the broadly used 4T1 tumor model as well as an interesting relationship between this particular class of checkpoint blockade and tumor-dependent immunomodulation. PMID:27057446

  4. The relation between dopamine oxidation currents in the nucleus accumbens and conditioned increases in motor activity in rats following repeated administration of d-amphetamine or cocaine.

    PubMed

    Di Ciano, P; Blaha, C D; Phillips, A G

    1998-03-01

    Chronoamperometric recording techniques were used to monitor extracellular dopamine efflux in the nucleus accumbens associated with unconditioned and conditioned increases in motor activity in rats, following the intravenous administration of either d-amphetamine (0.63 mg/kg) or cocaine (3 mg/kg), or the presentation of a conditioned stimulus paired repeatedly with one of these psychostimulants. Each drug was administered daily for 7 days, either in the home cage or an environment in which a compound stimulus (light offset, odour) was presented. Rats in control groups received saline instead of drug in the distinctive test environment. On day 7 of training, significant increases in unconditioned motor activity were observed in the 30 min session following infusions of either d-amphetamine or cocaine. Associated dopamine oxidation currents in the nucleus accumbens increased immediately following administration of either drug and remained significantly elevated above baseline during the entire 30 min recording period. On the test day, presentation of the conditioned stimulus with vehicle infusions, in the distinct environment, was accompanied by an increase in dopamine oxidation currents and a conditioned increase in motor activity, only in the groups in which these stimuli had been paired with d-amphetamine or cocaine. Neither the magnitude or duration of the conditioned motor activity matched the corresponding change in extracellular dopamine efflux in the nucleus accumbens. Accordingly, it is argued that the increase in dopamine concentration serves as a neurochemical correlate of the unconditioned and conditioned stimuli. The change in motor activity constitutes the unconditioned and conditioned responses that are subserved by the neural systems activated by the initial rise in extracellular dopamine. PMID:9753179

  5. Combating an Epidemic of Prescription Opioid Abuse.

    PubMed

    Pon, Doreen; Awuah, Kwaku; Curi, Danielle; Okyere, Ernest; Stern, Craig S

    2015-11-01

    The past decade has witnessed an alarming increase in the number of deaths due to prescription opioids that has paralleled the rise in the number of opioid prescriptions dispensed. Prescription drug monitoring programs, abuse-deterrent formulations and proper disposal of opioids have been promoted to help combat the opioid epidemic. We discuss changes that dentists, the third most frequent prescribers of opioids, can implement to help reduce the risk of prescription opioid abuse in their communities. PMID:26798885

  6. Combating an Epidemic of Prescription Opioid Abuse.

    PubMed

    Pon, Doreen; Awuah, Kwaku; Curi, Danielle; Okyere, Ernest; Stern, Craig S

    2015-11-01

    The past decade has witnessed an alarming increase in the number of deaths due to prescription opioids that has paralleled the rise in the number of opioid prescriptions dispensed. Prescription drug monitoring programs, abuse-deterrent formulations and proper disposal of opioids have been promoted to help combat the opioid epidemic. We discuss changes that dentists, the third most frequent prescribers of opioids, can implement to help reduce the risk of prescription opioid abuse in their communities.

  7. Early repeated administration of progesterone improves the recovery of neuropathic pain and modulates spinal 18kDa-translocator protein (TSPO) expression.

    PubMed

    Liu, Xiaoming; Li, Weiyan; Dai, Lihua; Zhang, Tingting; Xia, Weiliang; Liu, Hongjun; Ma, Ke; Xu, Jianguo; Jin, Yi

    2014-09-01

    Although progesterone was reported to be a neuroprotective agent against injuries to the nervous system, including the peripheral neuropathy, the mechanisms of its dose or timing-related effects remain unclear. Translocator protein (TSPO) is predominantly located in the mitochondrial outer membrane and has been recently implicated in modulation of several brain injuries and nociception. This experiment was conducted using a rat model of L5 spinal nerve ligation (SNL) to observe the effects of progesterone against allodynia development in an 84-day period and to explore the spinal TSPO expression after treatment. Our results demonstrated that a 10-day progesterone treatment started right after injury at a dose of 15 mg/kg/d or more could significantly increase the mechanical thresholds within the 84-day observation period. Moreover, increased TSPO expression was observed in the ipsilateral spinal dorsal horn after SNL surgery and reached its peak on Day 14. A treatment regimen of pharmacological progesterone augmented this spinal TSPO activation and expression before Day 28 and after Day 56. Both the anti-nociception and TSPO activation augment effect of progesterone were completely abolished by 5α-reductase inhibitor finasteride but not progesterone receptor antagonist mifepristone. These results indicate that early repeated administration of progesterone could improve the recovery of neuropathic pain and modulate spinal TSPO activation which were dependent on its 5α-reductase metabolites.

  8. The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep.

    PubMed

    Alton, Eric W F W; Baker, Alison; Baker, Eilidh; Boyd, A Christopher; Cheng, Seng H; Coles, Rebecca L; Collie, D David S; Davidson, Heather; Davies, Jane C; Gill, Deborah R; Gordon, Catherine; Griesenbach, Uta; Higgins, Tracy; Hyde, Stephen C; Innes, J Alastair; McCormick, Dominique; McGovern, Michael; McLachlan, Gerry; Porteous, David J; Pringle, Ian; Scheule, Ronald K; Shaw, Darren J; Smith, Sionagh; Sumner-Jones, Stephanie G; Tennant, Peter; Vrettou, Christina

    2013-12-01

    Clinically effective gene therapy for Cystic Fibrosis has been a goal for over 20 years. A plasmid vector (pGM169) that generates persistent expression and reduced host inflammatory responses in mice has raised prospects for translation to the clinic. The UK CF Gene Therapy Consortium is currently evaluating long-term repeated delivery of pGM169 complexed with the cationic lipid GL67A in a large Multidose Trial. This regulatory-compliant evaluation of aerosol administration of nine doses of pGM169/GL67A at monthly intervals, to the sheep lung, was performed in preparation for the Multidose Trial. All sheep tolerated treatment well with no adverse effects on haematology, serum chemistry, lung function or histopathology. Acute responses were observed in relation to bronchoalveolar cellularity comprising increased neutrophils and macrophage numbers 1 day post-delivery but these increases were transient and returned to baseline. Importantly there was no cumulative inflammatory effect or lung remodelling with successive doses. Molecular analysis confirmed delivery of pGM169 DNA to the airways and pGM169-specific mRNA was detected in bronchial brushing samples at day 1 following doses 1, 5 and 9. In conclusion, nine doses of pGM169/GL67A were well tolerated with no significant evidence of toxicity that would preclude adoption of a similar strategy in CF patients. PMID:24090839

  9. Opioid induced nausea and vomiting.

    PubMed

    Smith, Howard S; Laufer, Andras

    2014-01-01

    Opioids are broad spectrum analgesics that are an integral part of the therapeutic armamentarium to combat pain in the palliative care population. Unfortunately, among the adverse effects of opioids that may be experienced along with analgesia is nausea, vomiting, and/or retching. Although it is conceivable that in the future, using combination agents (opioids combined with agents which may nullify emetic effects), currently nausea/vomiting remains a significant issue for certain patients. However, there exists potential current strategies that may be useful in efforts to diminish the frequency and/or intensity of opioid-induced nausea/vomiting (OINV).

  10. Two opioid forms of stress analgesia: studies of tolerance and cross-tolerance.

    PubMed

    Terman, G W; Lewis, J W; Liebeskind, J C

    1986-03-12

    We have previously reported that stress analgesia sensitive to and insensitive to opiate antagonists can be differentially produced in rats by varying the severity or temporal pattern of inescapable footshock. In these studies, we give further evidence for the opioid and non-opioid bases of these paradigms of stress analgesia. We find that naloxone-sensitive analgesia demonstrates tolerance with repeated stress and cross-tolerance with morphine, whereas naloxone-insensitive analgesia demonstrates neither of these characteristics. Moreover, different forms of opioid, but not non-opioid, stress analgesia manifest cross-tolerance with each other. These data are discussed in terms of the similarities and differences between two forms of opioid stress analgesia.

  11. Structural and functional interactions between six-transmembrane μ-opioid receptors and β2-adrenoreceptors modulate opioid signaling

    PubMed Central

    Samoshkin, Alexander; Convertino, Marino; Viet, Chi T.; Wieskopf, Jeffrey S.; Kambur, Oleg; Marcovitz, Jaclyn; Patel, Pinkal; Stone, Laura S.; Kalso, Eija; Mogil, Jeffrey S.; Schmidt, Brian L.; Maixner, William; Dokholyan, Nikolay V.; Diatchenko, Luda

    2015-01-01

    The primary molecular target for clinically used opioids is the μ-opioid receptor (MOR). Besides the major seven-transmembrane (7TM) receptors, the MOR gene codes for alternatively spliced six-transmembrane (6TM) isoforms, the biological and clinical significance of which remains unclear. Here, we show that the otherwise exclusively intracellular localized 6TM-MOR translocates to the plasma membrane upon coexpression with β2-adrenergic receptors (β2-ARs) through an interaction with the fifth and sixth helices of β2-AR. Coexpression of the two receptors in BE(2)-C neuroblastoma cells potentiates calcium responses to a 6TM-MOR ligand, and this calcium response is completely blocked by a selective β2-antagonist in BE(2)-C cells, and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and β2-AR ligands leads to substantial analgesic synergy and completely reverses opioid-induced hyperalgesia in rodent behavioral models. Together, our results provide evidence that the heterodimerization of 6TM-MOR with β2-AR underlies a molecular mechanism for 6TM cellular signaling, presenting a unique functional responses to opioids. This signaling pathway may contribute to the hyperalgesic effects of opioids that can be efficiently blocked by β2-AR antagonists, providing a new avenue for opioid therapy. PMID:26657998

  12. Remifentanil-acute opioid tolerance and opioid-induced hyperalgesia: a systematic review.

    PubMed

    Kim, Sang Hun; Stoicea, Nicoleta; Soghomonyan, Suren; Bergese, Sergio D

    2015-01-01

    The use of opioids may seem to be a double-edged sword; they provide straight analgesic and antihyperalgesic effects initially, but subsequently are associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) that have been reported in experimental studies and clinical observations. It has been suggested that opioids can induce an acute tolerance and hyperalgesia in dose- and/or time-dependent manners even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management in clinical anesthesia and in the intensive care units because of its rapid onset and offset. We reviewed articles analyzing AOT and/or OIH by remifentanil and focused on the following issues: (1) evidence of remifentanil inducing AOT and/or OIH and (2) importance of AOT and/or OIH in considering the reduction of remifentanil dosage or adopting preventive modulations. Twenty-four experimental and clinical studies were identified using electronic searches of MEDLINE (PubMed, Ovid, Springer, and Elsevier). However, the development of AOT and OIH by remifentanil administration remains controversial. There is no sufficient evidence to support or refute the existence of OIH in humans.

  13. The opioid system majorly contributes to preference for fat emulsions but not sucrose solutions in mice.

    PubMed

    Sakamoto, Kazuhiro; Okahashi, Tatsuya; Matsumura, Shigenobu; Okafuji, Yoko; Adachi, Shin-ichi; Tsuzuki, Satoshi; Inoue, Kazuo; Fushiki, Tohru

    2015-01-01

    Rodents show a stronger preference for fat than sucrose, even if their diet is isocaloric. This implies that the preference mechanisms for fat and sucrose differ. To compare the contribution of the opioid system to the preference of fat and sucrose, we examined the effects of mu-, delta-, kappa-, and non-selective opioid receptor antagonists on the preference of sucrose and fat, assessed by a two-bottle choice test and a licking test, in mice naïve to sucrose and fat ingestion. Administration of non-selective and mu-selective opioid receptor antagonists more strongly inhibited the preference of fat than sucrose. While the preference of fat was reduced to the same level as water by the antagonist administration that of sucrose was still greater than water. Our results suggest that the preference of fat relies strongly on the opioid system, while that of sucrose is regulated by other mechanisms in addition to the opioid system.

  14. Patterns and Correlates of Prescription Opioid Use in OEF/OIF Veterans with Chronic Non-Cancer Pain

    PubMed Central

    Macey, Tara A.; Morasco, Benjamin J.; Duckart, Jonathan P.; Dobscha, Steven K.

    2013-01-01

    Objectives Little is known about the treatment Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans receive for chronic non-cancer pain (CNCP). We sought to describe the prevalence of prescription opioid use, types and doses of opioids received, and identify correlates of receiving prescription opioids for CNCP among OEF/OIF veterans. Design Retrospective review of VA administrative data. Setting Ambulatory clinics within a VA regional healthcare network. Patients OEF/OIF veterans who had at least 3 elevated pain screening scores within a 12-month period in 2008. Within this group, those prescribed opioids (n=485) over the next 12 months were compared to those not prescribed opioids (n=277). In addition, patients receiving opioids short term (<90 days, n=284) were compared to patients receiving them long-term (≥90 consecutive days, n=201). Results Of 762 OEF/OIF veterans with CNCP, 64% were prescribed at least one opioid medication over the 12 months following their index dates. Of those prescribed an opioid, 59% were prescribed opioids short-term and 41% were prescribed opioids long-term. The average morphine-equivalent opioid dose for short-term users was 23.7 mg (SD=20.5) compared with 40.8 mg (SD=36.1) for long-term users (p<0.001). Fifty-one percent of long-term opioid users were prescribed short-acting opioids only and one-third were also prescribed sedative-hypnotics. In adjusted analyses, diagnoses of low back pain, migraine headache, post-traumatic stress disorder, and nicotine use disorder were associated with an increased likelihood of receiving an opioid prescription. Conclusion Prescription opioid use is common among OEF/OIF veterans with CNCP and is associated with several pain diagnoses and medical conditions. PMID:21899715

  15. Mu Opioid Receptor Gene: New Point Mutations in Opioid Addicts

    PubMed Central

    Dinarvand, Amin; Goodarzi, Ali; Vousooghi, Nasim; Hashemi, Mehrdad; Dinarvand, Rasoul; Ostadzadeh, Fahimeh; Khoshzaban, Ahad; Zarrindast, Mohammad-Reza

    2014-01-01

    Introduction Association between single-nucleotide polymorphisms (SNPs) in mu opioid receptor gene and drug addiction has been shown in various studies. Here, we have evaluated the existence of polymorphisms in exon 3 of this gene in Iranian population and investigated the possible association between these mutations and opioid addiction. Methods 79 opioid-dependent subjects (55 males, 24 females) and 134 non-addict or control individuals (74 males, 60 females) participated in the study. Genomic DNA was extracted from volunteers’ peripheral blood and exon 3 of the mu opioid receptor gene was amplified by polymerase chain reaction (PCR) whose products were then sequenced. Results Three different heterozygote polymorphisms were observed in 3 male individuals: 759T > C and 877G > A mutations were found in 2 control volunteers and 1043G > C substitution was observed in an opioid-addicted subject. Association between genotype and opioid addiction for each mutation was not statistically significant. Discussion It seems that the sample size used in our study is not enough to confirm or reject any association between 759T > C, 877G > A and 1043G > C substitutions in exon 3 of the mu opioid receptor gene and opioid addiction susceptibility in Iranian population. PMID:25436079

  16. The beta-lactam antibiotic, ceftriaxone, inhibits the development of opioid-induced hyperalgesia in mice.

    PubMed

    Chen, Zhijun; He, Ying; Wang, Zaijie Jim

    2012-02-16

    The glutamate transporter GLT-1 is primarily responsible for glutamate clearance in the spinal cord. beta-Lactam antibiotics have been shown to attenuate neuropathic pain behaviors by promoting GLT-1 expression and function in the CNS. The present study tested the hypothesis that ceftriaxone, a prototype beta-lactam antibiotic, can prevent the development of opioid-induced hyperalgesia (OIH) in mice. Repeated morphine administration produced mechanical allodynia and thermal hyperalgesia, signs of OIH, and reduced spinal GLT-1 expression in mice. Ceftriaxone (200mg/kg/d, i.p., for 7 d) inhibited OIH. Correlating with the behavioral effects, ceftriaxone reversed downregulation of GLT-1 expression that was induced by OIH. These results suggest that ceftriaxone inhibited the development of OIH by up-regulating spinal GLT-1 expression.

  17. The impact of the opioids fentanyl and morphine on nociception and bone destruction in a murine model of bone cancer pain.

    PubMed

    El Mouedden, Mohammed; Meert, Theo Frans

    2007-05-01

    Chronic pain resulting from metastasis into skeleton of certain neoplastic diseases remains poorly understood and relatively resistant to analgesic treatment. Opioids are the principal axis in drug therapy for this type of pain, especially at the end stage of cancer. Our aim was to examine whether, fentanyl as well as morphine, two potent analgesic opioids commonly used to treat cancer pain, would inhibit pain and bone lesion-related responses in a murine model of bone cancer pain. Repeated administration of equianalgesic doses of fentanyl (0.16 mg/kg s.c. once a day) and morphine (20 mg/kg s.c. once a day) initiated at day 1 (prophylactic treatment) or at day 7 (curative treatment) after tumor cell inoculation in the femoral cavity consistently decreased bone pain symptoms and tumor growth-induced bone destruction (micro-CT bone structure parameters). Both fentanyl and morphine treatments resulted in clear antinociceptive properties as well as reductions in cancer cell-induced bone lesions. The present results demonstrate that fentanyl, and to some lesser degree morphine, has potential benefits in the treatment and development of bone cancer pain. As such, chronic administration of high doses of certain opioids like fentanyl may have clinical utility in the management of bone cancer pain.

  18. Argon prevents the development of locomotor sensitization to amphetamine and amphetamine-induced changes in mu opioid receptor in the nucleus accumbens.

    PubMed

    David, Hélène N; Dhilly, Martine; Poisnel, Géraldine; Degoulet, Mickael; Meckler, Cédric; Vallée, Nicolas; Blatteau, Jean-Éric; Risso, Jean-Jacques; Lemaire, Marc; Debruyne, Danièle; Abraini, Jacques H

    2014-01-01

    Systemic administration of γ-amino-butyric acid type A (GABA-A) and benzodiazepine receptor agonists has been reported to block the development of locomotor sensitization to amphetamine. Here, we investigated whether the non-anesthetic noble gas argon, shown to possess agonistic properties at these receptors, may block the acquisition of amphetamine-induced locomotor sensitization and mu opioid receptor activation in the nucleus accumbens. Rats were pretreated with saline solution or amphetamine (1 mg/kg) from day 1 to day 3 and then exposed, immediately after injection of amphetamine, to medicinal air or argon at 75 vol% (with the remainder being oxygen). After a 3-day period of withdrawal, rats were challenged with amphetamine on day 7. Rats pretreated with amphetamine and argon had lower locomotor activity (U = 5, P < 0.005) and mu opioid receptor activity in the nucleus accumbens (U = 0, P < 0.001) than rats pretreated with amphetamine and air. In contrast, argon had effect on locomotor and mu receptor activity neither in rats pretreated with saline and challenged with amphetamine (acute amphetamine) nor in rats pretreated and challenged with saline solution (controls). These results indicate that argon inhibits the development of both locomotor sensitization and mu opioid receptor activation induced by repeated administration of amphetamine.

  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 effect of repeated administration of carbetocin (Depotocin, Spofa) in the first days postpartum on levels of thyroxine, triiodothyronine, 17 beta-estradiol, progesterone and on fertilization].

    PubMed

    Bekeová, E; Krajnicáková, M; Hendrichovský, V; Maracek, I

    1992-07-01

    Application of new procedures in the sphere of the control of sexual functions requires an extension of present knowledge of postparturient endocrinium or endogenic factors comprised in postparturient physiology of sexual activity. According to recent data, oxytocin, besides its uterotonic and luteolytic activity, acts as an ovarian factor in the local intrafollicular regulation of stereidogenesis and as a modulator of uterine secretion of prostaglandines. Based on present knowledge of oxytocin effects, this study was aimed at investigation of the influence of repeated carbetocin (Depotocin inj. Spofa) administration on the dynamics of changes in thyroxine (T4), triiodothyronine (T3), 17 beta-estradiol (E2), progesterone (P4) concentrations and their mutual correlations from the 36th hour till the 51st day after parturition. Simultaneous study of a possible delayed influence of applied carbetocin on conception of ewes after oestrus evocation on day 51 after lambing was carried out. Nineteen ewes of the Slovak Merino breed, lambed in the first decade of February, were assigned to the experimental (n = 9) and to the control group (n = 10). Experimental ewes were subjected to repeated postparturient carbetocin treatment at the dose 0.07 mg per animal. The first dose was applied i. m. in 24 hours, and the second in 72 hours after parturition. On day 51 oestrus was induced in nine ewes of each group by combined treatment with chlorsuperlutin (Agelin, vaginal pessaries, Spofa) and PMSG (500 I.U./animal). On the day of PMSG application ewes were housed together with rams for the period of the next six days. Samples of blood were taken 24 hours before parturition (-1st day), up to 36 h after parturition and on days 4, 7, 14, 17, 21, 25, 34, 42 and 51 after parturition. Concentrations of T4, T3, E2 and P4 were determined by commercial kits RIA-test-T4; RIA-test-T3; RIA-test-ESTRA and RIA-test-PROG (URVJT Kosice). Animal of the control group showed variations of T4

  1. Opioid neurotransmission in the post-ictal analgesia: involvement of mu(1)-opioid receptor.

    PubMed

    Coimbra, N C; Freitas, R L; Savoldi, M; Castro-Souza, C; Segato, E N; Kishi, R; Weltson, A; Resende, G C

    2001-06-01

    Pentylenetetrazol (PTZ), a non-competitive antagonist that blocks GABA-mediated Cl(-) flux, was used in the present work to induce seizures in animals. The aim of this work is to study the neurochemical basis of the antinociception induced by convulsions elicited by peripheral administration of PTZ (64 mg/kg). The analgesia was measured by the tail-flick test, in eight rats per group. Convulsions were followed by significative increase in the tail-flick latencies (TFL), for at least 120 min of the post-ictal period. Peripheral administration of naltrexone (5 mg/kg, 10 mg/kg and 20 mg/kg) caused a significant decrease in the TFL in seizing animals, as compared to controls. These data were corroborated with peripheral administration of naloxonazine (10 mg/kg and 20 mg/kg), a mu(1)-opioid blocker, in the same doses used for non-specific antagonist. These results indicate that endogenous opioids may be involved in the post-ictal analgesia. The involvement of mu(1)-opioid receptor was also considered.

  2. Regulation of μ and δ opioid receptor functions: involvement of cyclin-dependent kinase 5

    PubMed Central

    Beaudry, H; Mercier-Blais, A-A; Delaygue, C; Lavoie, C; Parent, J-L; Neugebauer, W; Gendron, L

    2015-01-01

    Background and Purpose Phosphorylation of δ opioid receptors (DOP receptors) by cyclin-dependent kinase 5 (CDK5) was shown to regulate the trafficking of this receptor. Therefore, we aimed to determine the role of CDK5 in regulating DOP receptors in rats treated with morphine or with complete Freund's adjuvant (CFA). As μ (MOP) and DOP receptors are known to be co-regulated, we also sought to determine if CDK5-mediated regulation of DOP receptors also affects MOP receptor functions. Experimental Approach The role of CDK5 in regulating opioid receptors in CFA- and morphine-treated rats was studied using roscovitine as a CDK inhibitor and a cell-penetrant peptide mimicking the second intracellular loop of DOP receptors (C11-DOPri2). Opioid receptor functions were assessed in vivo in a series of behavioural experiments and correlated by measuring ERK1/2 activity in dorsal root ganglia homogenates. Key Results Chronic roscovitine treatment reduced the antinociceptive and antihyperalgesic effects of deltorphin II (Dlt II) in morphine- and CFA-treated rats respectively. Repeated administrations of C11-DOPri2 also robustly decreased Dlt II-induced analgesia. Interestingly, DAMGO-induced analgesia was significantly increased by roscovitine and C11-DOPri2. Concomitantly, in roscovitine-treated rats the Dlt II-induced ERK1/2 activation was decreased, whereas the DAMGO-induced ERK1/2 activation was increased. An acute roscovitine treatment had no effect on Dlt II- or DAMGO-induced analgesia. Conclusions and Implications Together, our results demonstrate that CDK5 is a key player in the regulation of DOP receptors in morphine- and CFA-treated rats and that the regulation of DOP receptors by CDK5 is sufficient to modulate MOP receptor functions through an indirect process. PMID:25598508

  3. Opioid hypofunction in Parkinson's disease.

    PubMed

    Sandyk, R; Gillman, M A

    1985-02-01

    Loss of dopaminergic neuronal function has been the most consistent biochemical abnormality found in Parkinson's disease. Hypofunction of other transmitter systems has also been demonstrated in this disease. Recently, an opioid-dopamine link has been demonstrated. This paper provides evidence supporting an opioid system hypofunction in Parkinson's disease.

  4. Evolution of vertebrate opioid receptors

    PubMed Central

    Dreborg, Susanne; Sundström, Görel; Larsson, Tomas A.; Larhammar, Dan

    2008-01-01

    The opioid peptides and receptors have prominent roles in pain transmission and reward mechanisms in mammals. The evolution of the opioid receptors has so far been little studied, with only a few reports on species other than tetrapods. We have investigated species representing a broader range of vertebrates and found that the four opioid receptor types (delta, kappa, mu, and NOP) are present in most of the species. The gene relationships were deduced by using both phylogenetic analyses and chromosomal location relative to 20 neighboring gene families in databases of assembled genomes. The combined results show that the vertebrate opioid receptor gene family arose by quadruplication of a large chromosomal block containing at least 14 other gene families. The quadruplication seems to coincide with, and, therefore, probably resulted from, the two proposed genome duplications in early vertebrate evolution. We conclude that the quartet of opioid receptors was already present at the origin of jawed vertebrates ≈450 million years ago. A few additional opioid receptor gene duplications have occurred in bony fishes. Interestingly, the ancestral receptor gene duplications coincide with the origin of the four opioid peptide precursor genes. Thus, the complete vertebrate opioid system was already established in the first jawed vertebrates. PMID:18832151

  5. SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], a novel mixed nociceptin/orphanin FQ/mu-opioid receptor partial agonist: analgesic and rewarding properties in mice.

    PubMed

    Khroyan, Taline V; Zaveri, Nurulain T; Polgar, Willma E; Orduna, Juan; Olsen, Cris; Jiang, Faming; Toll, Lawrence

    2007-02-01

    We identified a novel nociceptin/orphanin FQ (NOP)/mu-opioid receptor agonist, SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], with high binding affinity and partial agonist activity at both receptors. It was hypothesized that SR 16435 would produce antinociception and yet, unlike morphine, would have diminished rewarding properties and tolerance development. Antinociception was assessed in mice using the tail-flick assay, whereas behavioral and rewarding effects were assessed using the place conditioning (PC) paradigm. PC was established by pairing drug injections with a distinct compartment. Behavioral effects were measured after acute and repeated drug administration, and the test for PC was carried out 24 h after four drug- and vehicle-pairing sessions. SR 16435 produced an increase in tail-flick latency, but SR 16435-induced antinociception was lower than that observed with morphine. Given that naloxone blocked SR 16435-induced antinociception, it is highly likely that this effect was mediated by mu-opioid receptors. Compared with morphine, chronic SR 16435 treatment resulted in reduced development of tolerance to its antinociceptive effects. SR 16435-induced conditioned place preference (CPP) was evident, an effect that was probably mediated via mu-opioid receptors, as it was reversed by coadministration of naloxone. NOP agonist activity was also present, given that SR 16435 decreased global activity, and this effect was partially reversed with the selective NOP antagonist, SR 16430 [1-(cyclooctylmethyl)-4-(3-(trifluoromethyl)phenyl)piperidin-4-ol]. Naloxone, however, also reversed the SR 16435-induced decrease in activity, indicating that both opioid and NOP receptors mediate this behavior. In summary, the mixed NOP/mu-opioid partial agonist SR 16435 exhibited both NOP and mu-opioid receptor-mediated behaviors. PMID:17132815

  6. Oxycodone alters temporal summation but not conditioned pain modulation: preclinical findings and possible relations to mechanisms of opioid analgesia.

    PubMed

    Suzan, Erica; Midbari, Ayelet; Treister, Roi; Haddad, May; Pud, Dorit; Eisenberg, Elon

    2013-08-01

    Opioid analgesia is mediated primarily by modulating (inhibiting and enhancing) pain mechanisms at the spinal and supraspinal levels. Advanced psychophysical paradigms of temporal summation (TS) and conditioned pain modulation (CPM) likely represent pain mechanisms at both levels. Therefore, the study of opioid effects on TS and CPM can shed light on their analgesic mechanisms in humans. The current randomized, double-blind study tested the effects of oxycodone on the magnitude of both TS and CPM in 40 healthy subjects. TS was tested by measuring increments in pain intensity in response to 10 repetitive painful phasic heat stimuli. CPM was assessed by subtracting the response to a painful phasic heat stimulus administrated simultaneously with a conditioning cold pain stimulus from a painful phasic heat stimulus alone. These paradigms were tested before and at 60, 120, and 180 minutes after administration of a single oral dose of either oxycodone or an active placebo. Repeated-measures analysis of variance revealed significant effects of oxycodone, but not placebo, on the magnitude of TS (F=7.196, P<.001). Pairwise comparisons revealed that relative to baseline, TS was significantly reduced at 60 minutes (P=.008) and at 180 minutes (P=.017) after oxycodone administration. In contrast, no significant effects of either oxycodone (F=0.871, P=.458) or placebo (F=2.086, P=.106) on the magnitude of CPM were found. These results suggest that under the current experimental conditions, oxycodone exerted spinal, rather than supraspinal, analgesic effects. Furthermore, compared with CPM, TS seems more suitable for studying the mechanisms of opioid analgesia in humans.

  7. Gabapentinoid Insensitivity after Repeated Administration is Associated with Down-Regulation of the α(2)δ-1 Subunit in Rats with Central Post-Stroke Pain Hypersensitivity.

    PubMed

    Yang, Yan; Yang, Fei; Yang, Fan; Li, Chun-Li; Wang, Yan; Li, Zhen; Lu, Yun-Fei; Yu, Yao-Qing; Fu, Han; He, Ting; Sun, Wei; Wang, Rui-Rui; Chen, Jun

    2016-02-01

    The α2δ-1 subunit of the voltage-gated Ca(2+) channel (VGCC) is a molecular target of gabapentin (GBP), which has been used as a first-line drug for the relief of neuropathic pain. GBP exerts its anti-nociceptive effects by disrupting trafficking of the α2δ-1 subunit to the presynaptic membrane, resulting in decreased neurotransmitter release. We previously showed that GBP has an anti-allodynic effect in the first two weeks; but this is followed by insensitivity in the later stage after repeated administration in a rat model of central post-stroke pain (CPSP) hypersensitivity induced by intra-thalamic hemorrhage. To explore the mechanisms underlying GBP insensitivity, the cellular localization and time-course of expression of the α2δ-1 subunit in both the thalamus and spinal dorsal horn were studied in the same model. We found that the α2δ-1 subunit was mostly localized in neurons, but not astrocytes and microglia. The level of α2δ-1 protein increased in the first two weeks after injury but then decreased in the third week, when GBP insensitivity occurred. Furthermore, the α2δ-1 down-regulation was likely caused by later neuronal loss in the injured thalamus through a mechanism other than apoptosis. In summary, the present results suggest that the GBP receptor α2δ-1 is mainly expressed in thalamic neurons in which it is up-regulated in the early stage of CPSP but this is followed by dramatic down-regulation, which is likely associated with GBP insensitivity after long-term use. PMID:26781878

  8. Inducibility of c-Fos protein in visuo-motor system and limbic structures after acute and repeated administration of nicotine in the rat.

    PubMed

    Mathieu-Kia, A M; Pages, C; Besson, M J

    1998-08-01

    To identify neuroanatomical substrates affected by nicotine, we have studied its effects after acute and repeated administration through the c-Fos protein inducibility in various brain structures. Ninety minutes after acute nicotine (0.35 mg/kg, s.c.) the number of c-Fos-like immunoreactive nuclei was consistently increased in visuo-motor structures such as the superior colliculus, the medial terminal nucleus of accessory optic tract, and the nucleus of the optic tract. The anteroventral and lateroposterior thalamic nuclei, connected with the retina and involved in limbic processing, showed a c-Fos induction. c-Fos was preferentially induced in terminal fields of neurons of the ventral tegmental area such as the nucleus accumbens, the central amygdala, the lateral habenula, the lateral septum, as well as the cingulate, medial prefrontal, orbital and piriform cortices. In chronically treated rats (0.35 mg/kg s.c., 3 x day for 14 days), the last nicotine injection given on the 15th day was still able to induce 90 minutes later c-Fos protein in visuo-motor, retino-limbic, subcortical, and cortical limbic structures. Moreover, this chronic treatment produced an additional recruitment of c-Fos-positive nuclei in the cingulate cortex, the core and the ventral shell of the nucleus accumbens. c-Fos induction after nicotine differs from that reported after other addictive drugs in terms of pattern and chronic inducibility, indicating that different mechanisms are involved for maintaining this transcription factor. In addition to a preferential sensitivity of mesolimbic dopaminergic neurons to nicotine, activation of visuo-limbic and limbic regions could be relevant for understanding some context-dependent and addictive behaviors produced by nicotine.

  9. Detection of diazepam in urine, hair and preserved oral fluid samples with LC-MS-MS after single and repeated administration of Myolastan and Valium.

    PubMed

    Laloup, Marleen; Fernandez, Maria Del Mar Ramirez; Wood, Michelle; Maes, Viviane; De Boeck, Gert; Vanbeckevoort, Yvan; Samyn, Nele

    2007-08-01

    Sedative agents are used to facilitate sexual assault due to their ability to render the victim passive, submissive and unable to resist. The primary pharmacological effect of the benzodiazepine tetrazepam is muscle relaxation, whereas the benzodiazepine diazepam acts on the central nervous system (CNS) exerting mainly sedation effects. Therefore, contrary to tetrazepam, diazepam is an often-abused drug, which can potentially be used as a date-rape drug. In this study, we describe the detection of low amounts of diazepam in Myolastan (Sanofi-Synthelabo S.A., Brussels, Belgium) and Epsipam (Will-Pharma, Wavre, Belgium) 50 mg tablet preparations by LC-MS-MS, GC-FID and HPLC-DAD. Considering the important forensic implication of this finding, a study was conducted with volunteers receiving a single or repeated dosage of Myolastan. Urine, hair and preserved oral fluid samples were analysed using a previously described sensitive and specific LC-MS-MS detection method allowing for the simultaneous quantification of tetrazepam, diazepam, nordiazepam, oxazepam and temazepam. This study demonstrates that diazepam can be observed in urine samples even after a single dose of Myolastan. In addition, maintaining therapy for 1 week results in the detection of both diazepam and nordiazepam in urine samples and of diazepam in the first hair segment. Importantly, comparing urine and hair samples after a single intake of diazepam versus the single and 1 week administration of Myolastan shows that the possible metabolic conversion of tetrazepam to diazepam is a more plausible explanation for the detection of diazepam in biological samples after the intake of Myolastan. As such, these results reveal that the presence of diazepam and/or nordiazepam in biological samples from alleged drug-facilitated assault cases should be interpreted with care. PMID:17468852

  10. The effect of repeated administrations of llama ovulation-inducing factor (OIF/NGF) during the peri-ovulatory period on corpus luteum development and function in llamas.

    PubMed

    Fernández, A; Ulloa-Leal, C; Silva, M; Norambuena, C; Adams, G P; Guerra, M; Ratto, M H

    2014-10-01

    The objective of the study was to test the hypothesis that repeated administrations of OIF/NGF during the peri-ovulatory period (pre-ovulatory, ovulatory, early post-ovulatory), will enhance the luteotrophic effect in llamas. Female llamas were examined daily by transrectal ultrasonography in B- and Doppler-mode using a scanner equipped with a 7.5-MHz linear-array transducer to monitor ovarian follicle and luteal dynamics. When a growing follicle ≥7mm was detected, llamas were assigned randomly to one of the three groups and given 1mg of purified OIF/NGF im (intramuscular) (a) pre-ovulation (single dose; n=12), (b) pre-ovulation and at the time of ovulation (2 doses, n=10), or (c) pre-ovulation, at the time of ovulation, and 24h after ovulation (3 doses, n=10). The pre-ovulatory follicle diameter at the time of treatment, ovulation rate and the first day of CL detection did not differ (P=0.3) among groups. However, maximum CL diameter was greatest (P=0.003) in llamas in the 2-dose group, and smallest in the 3-dose group. Accordingly, the 2 dose-group had the largest day-to-day profile for CL diameter (P<0.01), area of CL vascularization (<0.01), and plasma progesterone concentration (P=0.01) compared to the other groups. Interestingly, the luteal response to 3-doses of OIF/NGF during the peri-ovulatory period was not different from a single dose. In conclusion, OIF/NGF isolated from llama seminal plasma is luteotrophic and the effect on CL size and function is affected by the number and timing of treatments during the peri-ovulatory period.

  11. Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists

    PubMed Central

    Murányi, Marianna; Cinar, Resat; Kékesi, Orsolya; Birkás, Erika; Fábián, Gabriella; Bozó, Beáta; Zentai, András; Tóth, Géza; Kicsi, Emese Gabriella; Mácsai, Mónika; Szabó, Gyula; Szücs, Mária

    2013-01-01

    Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid2-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the “so-called biased agonism” or “functional selectivity”. PMID:24350273

  12. Clinical implications of opioid pharmacogenetics.

    PubMed

    Argoff, Charles E

    2010-01-01

    The peer-reviewed literature yields a plethora of examples of variability in patient's responses to medications. The rapidly progressing field of pharmacogenetics offers insight into the variation in responses observed clinically, and in particular for the variability observed among patients administered mu opioid analgesics. Genetic variation leads to interperson variability in drug absorption, distribution, metabolism, and excretion, processes that have an important impact on the observed efficacy and toxicity of a drug. In particular, single-nucleotide polymorphisms (SNPs) in the gene encoding the mu opioid receptor have been linked to the variability in responses to opioids, whereas SNPs within metabolic enzymes that process and eliminate opioids and their metabolites also have an important effect on an individual's response to opioid medications as do SNPs that affect the bioavailability of opioids. In current clinical practice, given the best available evidence, to optimize pain medications each patient is, in effect, given their own analgesic trial. In the near future, pharmacogenetic approaches may be implemented to best predict which medicine from the outset may be most appropriate for an individual-the therapy with the most sustained efficacy and the best side effect profile. In the meantime, pharmacogenetic studies on mu opioid analgesics have provided a molecular foundation supporting opioid rotation in cases in which opioid therapy loses efficacy or becomes associated with intolerable side effects. As more pharmacogenetic research links specific polymorphisms to the pharmacologic effects of specific opioid analgesics, clinicians will continue to improve their understanding of how to prescribe these medications more effectively. PMID:20026961

  13. Intravenous Oxycodone, Hydrocodone and Morphine in Recreational Opioid Users: Abuse Potential and Relative Potencies

    PubMed Central

    Stoops, William W.; Hatton, Kevin W.; Lofwall, Michelle R.; Nuzzo, Paul A.; Walsh, Sharon L.

    2010-01-01

    Rationale Nonmedical use and abuse of prescription opioids is an increasing public health problem. Intravenous (IV) administration of opioid analgesics intended for oral use is not uncommon, yet little is known about the relative abuse potential of these drugs when administered intravenously to recreational opioid abusers without physical dependence. Methods This inpatient study employed a double-blind, randomized, within-subject, placebo-controlled design to examine the relative abuse potential of IV doses of oxycodone, hydrocodone and morphine. Nine healthy adult participants reporting recreational opioid use and histories of IV opioid use completed 11 experimental sessions, including one active-dose practice session. IV doses were infused over 5-min and included three identical doses of each opioid (5, 10 and 20 mg/10 ml) and saline placebo. Physiological, subjective and performance effects were collected before and for 6 h after drug administration. Results All three opioids produced prototypical mu agonist effects (e.g., miosis; increased ratings of liking) that were generally dose-related. Pharmacodynamic effects were observed within 5 min of IV administration. Physiological effects were more prolonged than subjective effects for all three drugs. While the magnitude of effects was generally comparable across drugs and qualitatively similar, valid potency assays indicated the following potency relationship: oxycodone > morphine > hydrocodone. Conclusions There were modest potency differences between oxycodone, hydrocodone and morphine, but their overall profile of effects was similar, indicating significant abuse potential when administered intravenously. PMID:20665209

  14. Non-analgesic effects of opioids: opioid-induced nausea and vomiting: mechanisms and strategies for their limitation.

    PubMed

    Coluzzi, Flaminia; Rocco, Alessandra; Mandatori, Ilenia; Mattia, Consalvo

    2012-01-01

    Nausea and vomiting are common gastrointestinal symptoms following opioid administration, for either chronic or acute pain management. As a consequence, patients' dissatisfaction has a negative impact on treatment efficacy. A number of mechanisms have been identified, involving both central and peripheral sites. This article will review the pathophysiology of opioid-induced nausea and vomiting and the various pharmacological treatments currently available for its management. Preventive strategies and therapeutic approaches are evaluated in the perioperative setting and in chronic pain. Newer drugs include second generation serotonin receptor antagonists (palonosetron) and neurokinin-1 (NK-1) antagonists (aprepitant).

  15. Opioid-Induced Androgen Deficiency (OPIAD): Diagnosis, Management, and Literature Review.

    PubMed

    O'Rourke, Timothy K; Wosnitzer, Matthew S

    2016-10-01

    Opioid-induced androgen deficiency (OPIAD) was initially recognized as a possible consequence of opioid use roughly four decades ago. Long-acting opioid use carries risks of addiction, tolerance, and systemic side effects including hypogonadotropic hypogonadism with consequent testosterone depletion leading to multiple central and peripheral effects. Hypogonadism is induced through direct inhibitory action of opioids on receptors within the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes as well as testosterone production within the testes. Few studies have systematically investigated hormonal changes induced by long-term opioid administration or the effects of testosterone replacement therapy (TRT) in patients with OPIAD. Clomiphene citrate, a selective estrogen receptor modulator (SERM), is a testosterone enhancement treatment which upregulates endogenous hypothalamic function. This review will focus on the pathophysiology, diagnosis, and management of OPIAD, including summary of literature evaluating OPIAD treatment with TRT, and areas of future investigation. PMID:27586511

  16. Magnesium ions and opioid agonist activity in streptozotocin-induced hyperalgesia.

    PubMed

    Bujalska, Magdalena; Malinowska, Ewelina; Makulska-Nowak, Helena; Gumułka, Stanisław Witold

    2008-01-01

    Streptozotocin-induced hyperglycemia accompanied by a chronic decrease in the nociceptive threshold is considered a useful model of experimental hyperalgesia. We examined (1) the effect of the opioid receptor agonists and (2) the effect of the magnesium ions (Mg(2+)) on the antinociceptive action of opioid agonists in a diabetic neuropathic pain model. When administered alone, opioid agonists like morphine (5 mg/kg i.p.) and fentanyl (0.0625 mg/kg i.p.), as well as the partial agonist buprenorphine (0.075 mg/kg) had only little effect on streptozotocin-induced hyperalgesia. However, pretreatment with Mg(2+) at a dose of 40 mg magnesium sulfate/kg i.p. markedly enhanced the analgesic activity of all three investigated opioids. Practical aspects of co-administration of magnesium and opioids in diabetic neuropathy are discussed. PMID:18701828

  17. Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access

    PubMed Central

    2015-01-01

    Opioid overdose and mortality have increased at an alarming rate prompting new public health initiatives to reduce drug poisoning. One initiative is to expand access to the opioid antidote naloxone. Naloxone has a long history of safe and effective use by organized healthcare systems and providers in the treatment of opioid overdose by paramedics/emergency medicine technicians, emergency medicine physicians and anesthesiologists. The safety of naloxone in a prehospital setting administered by nonhealthcare professionals has not been formally established but will likely parallel medically supervised experiences. Naloxone dose and route of administration can produce variable intensity of potential adverse reactions and opioid withdrawal symptoms: intravenous administration and higher doses produce more adverse events and more severe withdrawal symptoms in those individuals who are opioid dependent. More serious adverse reactions after naloxone administration occur rarely and may be confounded by the effects of other co-intoxicants and the effects of prolonged hypoxia. One component of the new opioid harm reduction initiative is to expand naloxone access to high-risk individuals (addicts, abusers, or patients taking high-dose or extended-release opioids for pain) and their close family or household contacts. Patients or their close contacts receive a naloxone prescription to have the medication on their person or in the home for use during an emergency. Contacts are trained on overdose recognition, rescue breathing and administration of naloxone by intramuscular injection or nasal spraying of the injection prior to the arrival of emergency medical personnel. The safety profile of naloxone in traditional medical use must be considered in this new context of outpatient prescribing, dispensing and treatment of overdose prior to paramedic arrival. New naloxone delivery products are being developed for this prehospital application of naloxone in treatment of opioid

  18. GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity.

    PubMed

    Brackley, Allison Doyle; Gomez, Ruben; Akopian, Armen N; Henry, Michael A; Jeske, Nathaniel A

    2016-09-01

    Opioids remain the standard for analgesic care; however, adverse effects of systemic treatments contraindicate long-term administration. While most clinical opioids target mu opioid receptors (MOR), those that target the delta class (DOR) also demonstrate analgesic efficacy. Furthermore, peripherally restrictive opioids represent an attractive direction for analgesia. However, opioid receptors including DOR are analgesically incompetent in the absence of inflammation. Here, we report that G protein-coupled receptor kinase 2 (GRK2) naively associates with plasma membrane DOR in peripheral sensory neurons to inhibit analgesic agonist efficacy. This interaction prevents optimal Gβ subunit association with the receptor, thereby reducing DOR activity. Importantly, bradykinin stimulates GRK2 movement away from DOR and onto Raf kinase inhibitory protein (RKIP). protein kinase C (PKC)-dependent RKIP phosphorylation induces GRK2 sequestration, restoring DOR functionality in sensory neurons. Together, these results expand the known function of GRK2, identifying a non-internalizing role to maintain peripheral DOR in an analgesically incompetent state. PMID:27568556

  19. Novel opioid cyclic tetrapeptides: Trp isomers of CJ-15,208 exhibit distinct opioid receptor agonism and short-acting κ opioid receptor antagonism

    PubMed Central

    Ross, Nicolette C; Reilley, Kate J; Murray, Thomas F; Aldrich, Jane V; McLaughlin, Jay P

    2012-01-01

    BACKGROUND AND PURPOSE The κ opioid receptor antagonists demonstrate potential for maintaining abstinence from psychostimulant abuse, but existing non-peptide κ-receptor selective antagonists show exceptionally long activity. We hypothesized that the L- and D-Trp isomers of CJ-15,208, a natural cyclic tetrapeptide reported to be a κ-receptor antagonist in vitro, would demonstrate short-acting, dose-dependent antagonism in vivo, preventing reinstatement of cocaine-seeking behaviour. EXPERIMENTAL APPROACH Affinity, selectivity and efficacy of the L-Trp and D-Trp isomers for opioid receptors were assessed in vitro in radioligand and GTPγS binding assays. Opioid receptor agonist and antagonist activities were characterized in vivo following i.c.v. administration with the 55°C warm water tail-withdrawal assay. The D-Trp isomer, which demonstrated primarily κ-receptor selective antagonist activity, was further evaluated for its prevention of stress- and drug-induced reinstatement of extinguished cocaine conditioned place preference (CPP). KEY RESULTS The two isomers showed similar affinity and selectivity for κ receptors (Ki 30–35 nM) as well as κ receptor antagonism in vitro. As expected, the D-Trp cyclic tetrapeptide exhibited minimal agonist activity and induced dose-dependent κ-receptor selective antagonism lasting less than 18 h in vivo. Pretreatment with this peptide prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine CPP. In contrast, the L-Trp cyclic tetrapeptide unexpectedly demonstrated mixed opioid agonist/antagonist activity. CONCLUSIONS AND IMPLICATIONS The L-Trp and the D-Trp isomers of CJ-15,208 demonstrate stereospecific opioid activity in vivo. The relatively brief κ opioid receptor antagonism, coupled with the prevention of stress-induced reinstatement of extinguished cocaine-seeking behaviour, suggests the D-Trp isomer could be used therapeutically to maintain abstinence from psychostimulant abuse. PMID

  20. Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens

    PubMed Central

    David, H N; Dhilly, M; Degoulet, M; Poisnel, G; Meckler, C; Vallée, N; Blatteau, J-É; Risso, J-J; Lemaire, M; Debruyne, D; Abraini, J H

    2015-01-01

    We investigated the effects of the noble gas argon on the expression of locomotor sensitization to amphetamine and amphetamine-induced changes in dopamine release and mu-opioid neurotransmission in the nucleus accumbens. We found (1) argon blocked the increase in carrier-mediated dopamine release induced by amphetamine in brain slices, but, in contrast, potentiated the decrease in KCl-evoked dopamine release induced by amphetamine, thereby suggesting that argon inhibited the vesicular monoamine transporter-2; (2) argon blocked the expression of locomotor and mu-opioid neurotransmission sensitization induced by repeated amphetamine administration in a short-term model of sensitization in rats; (3) argon decreased the maximal number of binding sites and increased the dissociation constant of mu-receptors in membrane preparations, thereby indicating that argon is a mu-receptor antagonist; (4) argon blocked the expression of locomotor sensitization and context-dependent locomotor activity induced by repeated administration of amphetamine in a long-term model of sensitization. Taken together, these data indicate that argon could be of potential interest for treating drug addiction and dependence. PMID:26151922

  1. Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens.

    PubMed

    David, H N; Dhilly, M; Degoulet, M; Poisnel, G; Meckler, C; Vallée, N; Blatteau, J-É; Risso, J-J; Lemaire, M; Debruyne, D; Abraini, J H

    2015-01-01

    We investigated the effects of the noble gas argon on the expression of locomotor sensitization to amphetamine and amphetamine-induced changes in dopamine release and mu-opioid neurotransmission in the nucleus accumbens. We found (1) argon blocked the increase in carrier-mediated dopamine release induced by amphetamine in brain slices, but, in contrast, potentiated the decrease in KCl-evoked dopamine release induced by amphetamine, thereby suggesting that argon inhibited the vesicular monoamine transporter-2; (2) argon blocked the expression of locomotor and mu-opioid neurotransmission sensitization induced by repeated amphetamine administration in a short-term model of sensitization in rats; (3) argon decreased the maximal number of binding sites and increased the dissociation constant of mu-receptors in membrane preparations, thereby indicating that argon is a mu-receptor antagonist; (4) argon blocked the expression of locomotor sensitization and context-dependent locomotor activity induced by repeated administration of amphetamine in a long-term model of sensitization. Taken together, these data indicate that argon could be of potential interest for treating drug addiction and dependence. PMID:26151922

  2. The antiallodynic action of nortriptyline and terbutaline is mediated by β(2) adrenoceptors and δ opioid receptors in the ob/ob model of diabetic polyneuropathy.

    PubMed

    Choucair-Jaafar, Nada; Salvat, Eric; Freund-Mercier, Marie-José; Barrot, Michel

    2014-02-10

    Peripheral polyneuropathy is a frequent complication of diabetes. One of its consequences is neuropathic pain which is often chronic and difficult to treat. This pain management classically involves anticonvulsant drugs or tricyclic antidepressant drugs (TCA). We have previously shown that β2 adrenoceptors and δ opioid receptors are critical for TCA action in a traumatic model of neuropathic pain. In the present work, we used the obese leptin deficient mice (ob/ob) which are a genetic model of type 2 diabetes in order to study the treatment of diabetic polyneuropathy. ob/ob mice with hyperglycemia develop tactile bilateral allodynia. We investigated the action of the TCA nortriptyline and the β2 adrenoceptor agonist terbutaline on this neuropathic allodynia. The consequences of acute and chronic treatments were tested, and mechanical allodynia was assessed by using von Frey hairs. Chronic but not acute treatment with nortriptyline alleviates allodynia caused by the diabetic neuropathy. This effect depends on β2 adrenoceptors but not on α2 adrenoceptors, as shown by the blockade with repeated co-administration of the β2 adrenoceptor antagonist ICI118551 but not with repeated co-administration of the α2 adrenoceptor antagonist yohimbine. Direct stimulation of β2 adrenoceptors appears sufficient to relieve allodynia, as shown with chronic terbutaline treatment. δ but not mu opioid receptors seem important to these action since acute naltrindole, but not acute naloxonazine, reverses the effect of chronic nortriptyline or terbutaline treatment.

  3. Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens.

    PubMed

    David, H N; Dhilly, M; Degoulet, M; Poisnel, G; Meckler, C; Vallée, N; Blatteau, J-É; Risso, J-J; Lemaire, M; Debruyne, D; Abraini, J H

    2015-07-07

    We investigated the effects of the noble gas argon on the expression of locomotor sensitization to amphetamine and amphetamine-induced changes in dopamine release and mu-opioid neurotransmission in the nucleus accumbens. We found (1) argon blocked the increase in carrier-mediated dopamine release induced by amphetamine in brain slices, but, in contrast, potentiated the decrease in KCl-evoked dopamine release induced by amphetamine, thereby suggesting that argon inhibited the vesicular monoamine transporter-2; (2) argon blocked the expression of locomotor and mu-opioid neurotransmission sensitization induced by repeated amphetamine administration in a short-term model of sensitization in rats; (3) argon decreased the maximal number of binding sites and increased the dissociation constant of mu-receptors in membrane preparations, thereby indicating that argon is a mu-receptor antagonist; (4) argon blocked the expression of locomotor sensitization and context-dependent locomotor activity induced by repeated administration of amphetamine in a long-term model of sensitization. Taken together, these data indicate that argon could be of potential interest for treating drug addiction and dependence.

  4. 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

  5. PreBotzinger complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression.

    PubMed

    Montandon, Gaspard; Qin, Wuxuan; Liu, Hattie; Ren, Jun; Greer, John J; Horner, Richard L

    2011-01-26

    The analgesic properties of the opium poppy Papever somniferum were first mentioned by Hippocrates around 400 BC, and opioid analgesics remain the mainstay of pain management today. These drugs can cause the serious side-effect of respiratory depression that can be lethal with overdose, however the critical brain sites and neurochemical identity of the neurons mediating this depression are unknown. By locally manipulating neurotransmission in the adult rat, we identify the critical site of the medulla, the preBötzinger complex, that mediates opioid-induced respiratory depression in vivo. Here we show that opioids at the preBötzinger complex cause respiratory depression or fatal apnea, with anesthesia and deep-sleep being particularly vulnerable states for opioid-induced respiratory depression. Importantly, we establish that the preBötzinger complex is fully responsible for respiratory rate suppression following systemic administration of opioid analgesics. The site in the medulla most sensitive to opioids corresponds to a region expressing neurokinin-1 receptors, and we show in rhythmically active brainstem section in vitro that neurokinin-1 receptor-expressing preBötzinger complex neurons are selectively inhibited by opioids. In summary, neurokinin-1 receptor-expressing preBötzinger complex neurons constitute the critical site mediating opioid-induced respiratory rate depression, and the key therapeutic target for its prevention or reversal.

  6. Prescription opioid use and misuse

    PubMed Central

    Srivastava, Anita; Kahan, Meldon; Jiwa, Ashifa

    2012-01-01

    Abstract Objective To evaluate the feasibility and effectiveness of a multifaceted educational intervention to improve the opioid prescribing practices of rural family physicians in a remote First Nations community. Design Prospective cohort study. Setting Sioux Lookout, Ont. Participants Family physicians. Interventions Eighteen family physicians participated in a 1-year study of a series of educational interventions on safe opioid prescribing. Interventions included a main workshop with a lecture and interactive case discussions, an online chat room, video case conferencing, and consultant support. Main outcome measures Responses to questionnaires at baseline and after 1 year on knowledge, attitudes, and practices related to opioid prescribing. Results The main workshop was feasible and was well received by primary care physicians in remote communities. At 1 year, physicians were less concerned about getting patients addicted to opioids and more comfortable with opioid dosing. Conclusion Multifaceted education and consultant support might play an important role in improving family physician comfort with opioid prescribing, and could improve the treatment of chronic pain while minimizing the risk of addiction. PMID:22611608

  7. Respiratory depression in the intoxicated trauma patient: are opioids to blame?

    PubMed

    Shenk, Eleni; Barton, Cassie A; Mah, Nathan D; Ran, Ran; Hendrickson, Robert G; Watters, Jennifer

    2016-02-01

    Providing effective pain management to acutely intoxicated trauma patients represents a challenge of balancing appropriate pain management with the risk of potential respiratory depression from opioid administration. The objective of this study was to quantify the incidence of respiratory depression in trauma patients acutely intoxicated with ethanol who received opioids as compared with those who did not and identify potential risk factors for respiratory depression in this population. Retrospective medical record review was conducted for subjects identified via the trauma registry who were admitted as a trauma activation and had a detectable serum ethanol level upon admission. Risk factors and characteristics compared included demographics, Injury Severity Score, Glasgow Coma Score, serum ethanol level upon arrival, urine drug screen results, incidence of respiratory depression, and opioid and other sedative medication use. A total of 233 patients were included (78.5% male). Patients who received opioids were more likely to have a higher Injury Severity Score and initial pain score on admission as compared with those who did not receive opioids. Blood ethanol content was higher in patients who did not receive opioids (0.205 vs 0.237 mg/dL, P = .015). Patients who did not receive opioids were more likely to be intubated within 4 hours of admission (1.7% vs 12.1%, P = .02). Opioid administration was not associated with increased risk of respiratory depression (19.7% vs 22.4%, P = .606). Increased cumulative fentanyl dose was associated with increased risk of respiratory depression. Increased cumulative fentanyl dose, but not opioid administration alone, was found to be a risk factor for respiratory depression. PMID:26614581

  8. Validation of a Brief Opioid Compliance Checklist for Patients with Chronic Pain

    PubMed Central

    Jamison, Robert N.; Martel, Marc O.; Edwards, Robert R.; Qian, Jing; Sheehan, Kerry Anne; Ross, Edgar L.

    2014-01-01

    There has been a need for a brief assessment tool to determine compliance with use of prescribed opioids for pain. The purpose of this study was to develop and begin the validation of a brief and simple compliance checklist (Opioid Compliance Checklist; OCC) for chronic pain patients prescribed long-term opioid therapy. A review of the literature of opioid therapy agreements led to a 12-item OCC that was repeatedly administered to 157 patients who were taking opioids for chronic pain and followed for six months. Validation of the OCC was conducted by identifying those patients exhibiting aberrant drug-related behavior as determined by any of the following: positive urine toxicology screen, a positive score on the Prescription Drug Use Questionnaire (PDUQ) interview or Current Opioid Misuse Measure (COMM), and/or ratings by staff on the Addiction Behavior Checklist (ABC). Of the original 12 items, 5 OCC items appeared to best predict subsequent aberrant behaviors based on multivariate logistic regression analyses (cross-validated AUC=.67). Although further testing is needed, these results suggest that the OCC is an easy-to-use, promising measure in monitoring opioid adherence among persons with chronic pain. PMID:25092233

  9. Compulsive-like responding for opioid analgesics in rats with extended access.

    PubMed

    Wade, Carrie L; Vendruscolo, Leandro F; Schlosburg, Joel E; Hernandez, Daniel O; Koob, George F

    2015-01-01

    The abuse of prescription opioids that are used for the treatment of chronic pain is a major public health concern, costing ∼$53.4 billion annually in lost wages, health-care costs, and criminal costs. Although opioids remain a first-line therapy for the treatment of severe chronic pain, practitioners remain cautious because of the potential for abuse and addiction. Opioids such as heroin are considered very rewarding and reinforcing, but direct and systematic comparisons of compulsive intake between commonly prescribed opioids and heroin in animal models have not yet been performed. In the present study, we evaluated the potential for compulsive-like drug seeking and taking, using intravenous self-administration of oxycodone, fentanyl, and buprenorphine in rats allowed long access sessions (12 h). We measured compulsive-like intake using an established escalation model and responding on a progressive ratio schedule of reinforcement. We compared the potential for compulsive-like self-administration of these prescription opioids and heroin, which has been previously established to induce increasing intake that models the transition to addiction in humans. We found that animals that self-administered oxycodone, fentanyl, or heroin, but not buprenorphine had similar profiles of escalation and increases in breakpoints. The use of extended access models of prescription opioid intake will help better understand the biological factors that underlie opioid dependence.

  10. Compulsive-Like Responding for Opioid Analgesics in Rats with Extended Access

    PubMed Central

    Wade, Carrie L; Vendruscolo, Leandro F; Schlosburg, Joel E; Hernandez, Daniel O; Koob, George F

    2015-01-01

    The abuse of prescription opioids that are used for the treatment of chronic pain is a major public health concern, costing ∼$53.4 billion annually in lost wages, health-care costs, and criminal costs. Although opioids remain a first-line therapy for the treatment of severe chronic pain, practitioners remain cautious because of the potential for abuse and addiction. Opioids such as heroin are considered very rewarding and reinforcing, but direct and systematic comparisons of compulsive intake between commonly prescribed opioids and heroin in animal models have not yet been performed. In the present study, we evaluated the potential for compulsive-like drug seeking and taking, using intravenous self-administration of oxycodone, fentanyl, and buprenorphine in rats allowed long access sessions (12 h). We measured compulsive-like intake using an established escalation model and responding on a progressive ratio schedule of reinforcement. We compared the potential for compulsive-like self-administration of these prescription opioids and heroin, which has been previously established to induce increasing intake that models the transition to addiction in humans. We found that animals that self-administered oxycodone, fentanyl, or heroin, but not buprenorphine had similar profiles of escalation and increases in breakpoints. The use of extended access models of prescription opioid intake will help better understand the biological factors that underlie opioid dependence. PMID:25060491

  11. Illicit Opioid Intoxication: Diagnosis and Treatment

    PubMed Central

    Fareed, A.; Stout, S.; Casarella, J.; Vayalapalli, S.; Cox, J.; Drexler, K.

    2011-01-01

    Opioid intoxications and overdose are associated with high rates of morbidity and mortality. Opioid overdose may occur in the setting of intravenous or intranasal heroin use, illicit use of diverted opioid medications, intentional or accidental misuse of prescription pain medications, or iatrogenic overdose. In this review, we focused on the epidemiology of illict opioid use in the United States and on the mechanism of action of opioid drugs. We also described the signs and symptoms, and diagnoses of intoxication and overdose. Lastly, we updated the reader about the most recent recommendations for treatment and prevention of opioid intoxications and overdose. PMID:22879747

  12. Increased gabaergic input to ventral tegmental area dopaminergic neurons associated with decreased cocaine reinforcement in mu-opioid receptor knockout mice.

    PubMed

    Mathon, D S; Lesscher, H M B; Gerrits, M A F M; Kamal, A; Pintar, J E; Schuller, A G P; Spruijt, B M; Burbach, J P H; Smidt, M P; van Ree, J M; Ramakers, G M J

    2005-01-01

    There is general agreement that dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and prefrontal cortex play a key role in drug reinforcement. The activity of these neurons is strongly modulated by the inhibitory and excitatory input they receive. Activation of mu-opioid receptors, located on GABAergic neurons in the VTA, causes hyperpolarization of these GABAergic neurons, thereby causing a disinhibition of VTA dopaminergic neurons. This effect of mu-opioid receptors upon GABA neurotransmission is a likely mechanism for mu-opioid receptor modulation of drug reinforcement. We studied mu-opioid receptor signaling in relation to cocaine reinforcement in wild-type and mu-opioid receptor knockout mice using a cocaine self-administration paradigm and in vitro electrophysiology. Cocaine self-administration was reduced in mu-opioid receptor knockout mice, suggesting a critical role of mu-opioid receptors in cocaine reinforcement. The frequency of spontaneous inhibitory post-synaptic currents onto dopaminergic neurons in the ventral tegmental area was increased in mu-opioid receptor knockout mice compared with wild-type controls, while the frequency of spontaneous excitatory post-synaptic currents was unaltered. The reduced cocaine self-administration and increased GABAergic input to VTA dopaminergic neurons in mu-opioid receptor knockout mice supports the notion that suppression of GABAergic input onto dopaminergic neurons in the VTA contributes to mu-opioid receptor modulation of cocaine reinforcement. PMID:15664692

  13. κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats.

    PubMed

    Nealey, Kathryn A; Smith, Alexander W; Davis, Seth M; Smith, Daniel G; Walker, Brendan M

    2011-01-01

    Previously, it was shown that ethanol-dependent animals display increased sensitivity to the general opioid receptor antagonist nalmefene compared to naltrexone. It was hypothesized that the dissociable effects of the two antagonists were attributable to a κ-opioid receptor mechanism. Nucleus accumbens dynorphin is upregulated following chronic ethanol exposure and such neuroadaptations could contribute to nalmefene's increased potency in ethanol-dependent animals. To test this hypothesis, male Wistar rats were trained to self-administer ethanol using an operant conditioning procedure. Animals were then implanted with bilateral intra-accumbens shell guide cannulae and assigned to either a chronic intermittent ethanol vapor-exposure condition (to induce dependence) or an air-exposed control group. Following a one-month exposure period, nalmefene, nor-binaltorphimine (nor-BNI; selective for κ-opioid receptors) or a combination of the selective opioid receptor antagonists CTOP and naltrindole (selective for the μ- and δ-opioid receptors, respectively) were site-specifically infused into the nucleus accumbens shell prior to ethanol self-administration sessions during acute withdrawal. Nalmefene and CTOP/naltrindole dose-dependently reduced ethanol self-administration in nondependent and dependent animals, whereas nor-BNI selectively attenuated ethanol self-administration in ethanol-dependent animals without affecting the self-administration of nondependent animals. Further analysis indentified that intra-accumbens shell nalmefene was more potent in ethanol-dependent animals and that the increased potency was attributable to a κ-opioid receptor mechanism. These data support the concept that dysregulation of DYN/κ-opioid receptor systems contributes to the excessive self-administration observed in dependent animals and suggest that pharmacotherapeutics for ethanol dependence that target κ-opioid receptors, in addition to μ- and δ-opioid receptors, are preferable

  14. Opioid-induced hyperalgesia: a review of epidemiology, mechanisms and management.

    PubMed

    Low, Yinghui; Clarke, Collin F; Huh, Billy K

    2012-05-01

    There has been a growing interest in opioid-induced hyperalgesia (OIH), which is an increased sensitivity to pain caused by opioid exposure. Multiple underlying pathways may contribute to the development of OIH, and the mechanism may vary with the duration of opioid exposure, dose, type and route of administration. In addition, the distinction between OIH, tolerance and withdrawal should be made in both the basic and clinical science literature so as to help translate findings to the clinical phenomenon and to help determine the best strategies to prevent or treat OIH.

  15. Non-opioid effects of N-methyl levallorphan in the anaesthetised rat.

    PubMed

    Douglas, H; Kitchen, I

    1990-01-01

    1. The effects of the quaternary opioid antagonist N-methyl levallorphan upon cardiovascular responses to non-opioid agonists has been studied in the urethane-anaesthetised rat. 2. N-methyl levallorphan showed an initial nicotinic agonist effect followed by pronounced ganglion blocking activity after intravenous administration. These effects are observed at doses only 2-fold higher than those required to block cardiovascular responses to [Met] enkephalin. 3. The narrow selectivity of N-methyl levallorphan makes this compound inappropriate for opioid antagonist studies where nicotinic receptors may be involved. PMID:1967586

  16. 42 CFR 8.11 - Opioid treatment program certification.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Substances Act (21 U.S.C. 823(g)(1)) to dispense opioid drugs in the treatment of opioid addiction. An OTP... opioid addiction. (2) To obtain certification from SAMHSA, an OTP must meet the Federal opioid treatment... governmental entities to regulate the use of opioid drugs in the treatment of opioid......

  17. Epigenetic regulation of spinal cord gene expression contributes to enhanced postoperative pain and analgesic tolerance subsequent to continuous opioid exposure

    PubMed Central

    Liang, De-Yong; Shi, Xiao-You; Sun, Yuan; Clark, J David

    2016-01-01

    Background Opioids have become the mainstay for treatment of moderate to severe pain and are commonly used to treat surgical pain. While opioid administration has been shown to cause opioid-induced hyperalgesia and tolerance, interactions between opioid administration and surgery with respect to these problematic adaptations have scarcely been addressed. Accumulating evidence suggests opioids and nociceptive signaling may converge on epigenetic mechanisms in spinal cord to enhance or prolong neuroplastic changes. Epigenetic regulation of Bdnf (brain-derived neurotrophic factor) and Pdyn (prodynorphin) genes may be involved. Results Four days of ascending doses of morphine treatment caused opioid-induced hyperalgesia and reduced opioid analgesic efficacy in mice. Both opioid-induced hyperalgesia and the reduced opioid analgesic efficacy were enhanced in mice that received hindpaw incisions. The expression of Bdnf and Pdyn (qPCR) was increased after morphine treatment and incision. Chromatin immunoprecipitation assays demonstrated that the Pdyn and Bdnf promoters were more strongly associated with acetylated H3K9 after morphine plus incision than in the morphine or incision alone groups. Selective tropomyosin-related kinase B (ANA-12) and κ-opioid receptor (nor-binaltorphimine) antagonists were administered intrathecally, both reduced hyperalgesia one or three days after surgery. Administration of ANA-12 or nor-binaltorphimine attenuated the decreased morphine analgesic efficacy on day 1, but only nor-binaltorphimine was effective on day 3 after incision in opioid-exposed group. Coadministration of histone acetyltransferase inhibitor anacardic acid daily with morphine blocked the development of opioid-induced hyperalgesia and attenuated incision-enhanced hyperalgesia in morphine-treated mice. Anacardic acid had similar effects on analgesic tolerance, showing the involvement of histone acetylation in the interactions detected. Conclusions Spinal epigenetic changes

  18. Repeated Superovulation via PMSG/hCG Administration Induces 2-Cys Peroxiredoxins Expression and Overoxidation in the Reproductive Tracts of Female Mice.

    PubMed

    Park, Sun-Ji; Kim, Tae-Shin; Kim, Jin-Man; Chang, Kyu-Tae; Lee, Hyun-Shik; Lee, Dong-Seok

    2015-12-01

    Superovulation induced by exogenous gonadotropin treatment (PMSG/hCG) increases the number of available oocytes in humans and animals. However, Superovulatory PMSG/hCG treatment is known to affect maternal environment, and these effects may result from PMSG/hCG treatment-induced oxidative stress. 2-Cys peroxiredoxins (2-Cys Prxs) act as antioxidant enzymes that protect cells from oxidative stress induced by various exogenous stimuli. Therefore, the objective of this study was to test the hypothesis that repeated PMSG/hCG treatment induces 2-Cys Prx expression and overoxidation in the reproductive tracts of female mice. Immunohistochemistry and western blotting analyses further demonstrated that, after PMSG/hCG treatment, the protein expression levels of 2-Cys Prxs increased most significantly in the ovaries, while that of Prx1 was most affected by PMSG/hCG stimulation in all tissues of the female reproductive tract. Repeated PMSG/hCG treatment eventually leads to 2-Cys Prxs overoxidation in all reproductive organs of female mice, and the abundance of the 2-Cys Prxs-SO2/3 proteins reported here supports the hypothesis that repeated superovulation induces strong oxidative stress and damage to the female reproductive tract. Our data suggest that excessive oxidative stress caused by repeated PMSG/hCG stimulation increases 2-Cys Prxs expression and overoxidation in the female reproductive organs. Intracellular 2-Cys Prx therefore plays an important role in maintaining the reproductive organ environment of female mice upon exogenous gonadotropin treatment.

  19. Repeated Superovulation via PMSG/hCG Administration Induces 2-Cys Peroxiredoxins Expression and Overoxidation in the Reproductive Tracts of Female Mice

    PubMed Central

    Park, Sun-Ji; Kim, Tae-Shin; Kim, Jin-Man; Chang, Kyu-Tae; Lee, Hyun-Shik; Lee, Dong-Seok

    2015-01-01

    Superovulation induced by exogenous gonadotropin treatment (PMSG/hCG) increases the number of available oocytes in humans and animals. However, Superovulatory PMSG/hCG treatment is known to affect maternal environment, and these effects may result from PMSG/hCG treatment-induced oxidative stress. 2-Cys peroxiredoxins (2-Cys Prxs) act as antioxidant enzymes that protect cells from oxidative stress induced by various exogenous stimuli. Therefore, the objective of this study was to test the hypothesis that repeated PMSG/hCG treatment induces 2-Cys Prx expression and overoxidation in the reproductive tracts of female mice. Immunohistochemistry and western blotting analyses further demonstrated that, after PMSG/hCG treatment, the protein expression levels of 2-Cys Prxs increased most significantly in the ovaries, while that of Prx1 was most affected by PMSG/hCG stimulation in all tissues of the female reproductive tract. Repeated PMSG/hCG treatment eventually leads to 2-Cys Prxs overoxidation in all reproductive organs of female mice, and the abundance of the 2-Cys Prxs-SO2/3 proteins reported here supports the hypothesis that repeated superovulation induces strong oxidative stress and damage to the female reproductive tract. Our data suggest that excessive oxidative stress caused by repeated PMSG/hCG stimulation increases 2-Cys Prxs expression and overoxidation in the female reproductive organs. Intracellular 2-Cys Prx therefore plays an important role in maintaining the reproductive organ environment of female mice upon exogenous gonadotropin treatment. PMID:26486164

  20. Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics.

    PubMed

    Betti, Cecilia; Starnowska, Joanna; Mika, Joanna; Dyniewicz, Jolanta; Frankiewicz, Lukasz; Novoa, Alexandre; Bochynska, Marta; Keresztes, Attila; Kosson, Piotr; Makuch, Wioletta; Van Duppen, Joost; Chung, Nga N; Vanden Broeck, Jozef; Lipkowski, Andrzej W; Schiller, Peter W; Janssens, Frans; Ceusters, Marc; Sommen, François; Meert, Theo; Przewlocka, Barbara; Tourwé, Dirk; Ballet, Steven

    2015-12-10

    Herein, the synthesis and biological evaluation of dual opioid agonists-neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the μ- and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds. PMID:26713106

  1. Peptide and non-peptide opioid-induced hyperthermia in rabbits

    NASA Technical Reports Server (NTRS)

    Kandasamy, S. B.; Williams, B. A.

    1983-01-01

    The intracerebroventricular administration of prototype nonpeptide opioid receptor (mu, kappa, and sigma) agonists, morphine, ketocyclazocine, and N-allyl-normetazocine was found to induce hyperthermia in rabbits. The similar administration of peptide opioids like beta-endorphin (BE), methionine-enkephalin (ME), and its synthetic analogue D-ala2-methionine-enkephalinamide (DAME) was also found to cause hyperthermia. Results indicate that only the liver-like transport system is important to the ventricular inactivation of BE and DAME. Prostaglandins and norepinephrine were determined not to be involved in peptide and nonpeptide opioid-induced hyperthermia. In addition, cAMP was not required since a phosphodiesterase inhibitor, theophylline, did not accentuate the hyperthermia due to peptide and nonpeptide opioids. Naloxone-sensitive receptors were found to be involved in the induction of hyperthermia by morphine, BE, ME, and DAME since naloxone attenuated them. However, the hyperthermic response to ketocyclazocine and N-allyl-normetazocine was not antagonized by naloxone.

  2. Abuse-deterrent formulations of prescription opioid analgesics in the management of chronic noncancer pain.

    PubMed

    Hale, Martin E; Moe, Derek; Bond, Mary; Gasior, Maciej; Malamut, Richard

    2016-10-01

    Misuse, abuse and diversion of prescription opioid analgesics represent a global public health concern. The development of abuse-deterrent formulations (ADFs) of prescription opioid analgesics is an important step toward reducing abuse and diversion of these medications, as well as potentially limiting medical consequences when misused or administered in error. ADFs aim to hinder extraction of the active ingredient, prevent administration through alternative routes and/or make abuse of the manipulated product less attractive, less rewarding or aversive. However, opioid ADFs may still be abused via the intended route of administration by increasing the dose and/or dosing frequency. The science of abuse deterrence and the regulatory landscape are still relatively new and evolving. This paper reviews the current status of opioid ADFs, with particular focus on different approaches that can be used to deter abuse, regulatory considerations and implications for clinical management.

  3. Reward systems and food intake: role of opioids.

    PubMed

    Gosnell, B A; Levine, A S

    2009-06-01

    Humans eat for many reasons, including the rewarding qualities of foods. A host of neurotransmitters have been shown to influence eating behavior and some of these appear to be involved in reward-induced eating. Endogenous opioid peptides and their receptors were first reported more than 30 years ago, and studies suggesting a role of opioids in the regulation of food intake date back nearly as far. Opioid agonists and antagonists have corresponding stimulatory and inhibitory effects on feeding. In addition to studies aimed at identifying the relevant receptor subtypes and sites of action within the brain, there has been a continuing interest in the role of opioids on diet/taste preferences, food reward, and the overlap of food reward with others types of reward. Data exist that suggest a role for opioids in the control of appetite for specific macronutrients, but there is also evidence for their role in the stimulation of intake based on already-existing diet or taste preferences and in controlling intake motivated by hedonics rather than by energy needs. Finally, various types of studies indicate an overlap between mechanisms mediating drug reward and palatable food reward. Preference or consumption of sweet substances often parallels the self-administration of several drugs of abuse, and under certain conditions, the termination of intermittent access to sweet substances produces symptoms that resemble those observed during opiate withdrawal. The overconsumption of readily available and highly palatable foods likely contributes to the growing rates of obesity worldwide. An understanding of the role of opioids in mediating food reward and promoting the overconsumption of palatable foods may provide insights into new approaches for preventing obesity.

  4. EMS runs for suspected opioid overdose: Implications for surveillance and prevention

    PubMed Central

    Knowlton, Amy; Weir, Brian; Hazzard, Frank; Olsen, Yngvild; McWilliams, Junette; Fields, Julie; Gaasch, Wade

    2013-01-01

    Objective Opioid (including prescription opiate) abuse and overdose rates in the US have surged in the past decade. The dearth and limitations of opioid abuse and overdose surveillance systems impede the development of interventions to address this epidemic. We explored evidence to support the validity of emergency medical services (EMS) data on naloxone administration as a possible proxy for estimating incidence of opioid overdose. Methods We reviewed data from Baltimore City Fire Department EMS patient records matched with dispatch records over a thirteen month time period (2008-2009), and census 2008 data. We calculated incidence rates and patient demographic and temporal patterns of naloxone administration, and examined patient evaluation data associated with naloxone administration. Results were compared to the demographic distributions of the EMS patient and city population and to prior study findings. Results Of 116,910 EMS incidents during the study period for patients 15 years and older, EMS providers administered naloxone 1,297 times (1.1% of incidents), an average of 100 administrations per month. Overall incidence was 1.87 administrations per 1,000 population per year. Findings indicated naloxone administration peaked in summer months (31% of administrations), weekends (32%), and late afternoon (4-5:00pm [8%]); and there was a trend toward peaking in the first week of the month. The incidence of suspected opioid overdose was highest among males, whites, and those in the 45-54 year age group. Findings on temporal patterns were comparable to findings from prior studies. Demographic patterns of suspected opioid overdose were similar to medical examiner reports of demographic patterns of fatal drug or alcohol related overdoses in Baltimore in 2008-9 (88% of which involved opioids). The findings on patient evaluation data suggest some inconsistencies with previously recommended clinical indications of opioid overdose. Conclusions While our findings suggest

  5. 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

  6. Characteristics and Correlates of Men and Women with Prescription Opioid Dependence

    PubMed Central

    Back, Sudie E.; Lawson, Katie; Singleton, Lauren; Brady, Kathleen T.

    2011-01-01

    Despite the fact that important gender differences in drug and alcohol use have been previously reported, little research to date has focused on gender differences with regard to nonmedical prescription opioid use. This study preliminarily examined the presenting characteristics and correlates (e.g., age of onset, route of administration, motives for using, method of introduction) of men and women with prescription opioid dependence. Participants were 24 (12 men, 12 women) non-treatment seeking individuals at least 18 years of age with current (i.e., past 12 months) prescription opioid dependence who participated in an in-depth interview. The average age of onset of prescription opioid use was 22.2 years (SD = 8.5). In comparison to men, women were approximately six years older when they initiated prescription opioid use, but were only three years older when they began to use prescription opioids regularly (i.e., weekly), suggesting an accelerated course of disease progression among women. Over half of the sample (61.5%) endorsed chewing and almost half (45.8%) endorsed crushing and snorting prescription opioids. Men were significantly more likely than women to crush and snort prescription opioids (75.0% vs. 16.7%; p = 0.01). Women were significantly more likely than men to be motivated to use prescription opioids in order to cope with interpersonal stress, and to use them first thing in the morning (ps = 0.04). Concomitant alcohol and other drug use were common among both men and women. The findings highlight clinically relevant gender differences and may help enhance the design of gender-sensitive screening and treatment interventions for prescription opioids. PMID:21514061

  7. Medical and Nonmedical Use of Prescription Opioids among High School Seniors in the United States

    PubMed Central

    McCabe, Sean Esteban; West, Brady T.; Teter, Christian J.; Boyd, Carol J.

    2012-01-01

    Objective To determine the prevalence of medical and nonmedical use of prescription opioids among high school seniors in the United States, and to assess substance use behaviors based on medical and nonmedical use of prescription opioids. Design Nationally representative samples of high school seniors (modal age 18) were surveyed during the spring of their senior year via self-administered questionnaires. Setting Data were collected in public and private high schools. Participants The sample consisted of 7,374 students from three independent cohorts (2007-09). Main Outcome Measures Self-reports of medical and nonmedical use of prescription opioids and other substance use. Results An estimated 17.6% of high school seniors reported lifetime medical use of prescription opioids, while 12.9% reported nonmedical use of prescription opioids. Gender differences in the medical and nonmedical use were minimal, while racial/ethnic differences were extensive. Over 37% of nonmedical users reported intranasal administration of prescription opioids. An estimated 80% of nonmedical users with an earlier history of medical use had obtained prescription opioids from a prescription they had previously. The odds of substance use behaviors were greater among individuals who reported any history of nonmedical use of prescription opioids relative to those who reported medical use only. Conclusions Nearly one in every four high school seniors in the United States has ever had some exposure to prescription opioids either medically or nonmedically. The quantity of prescription opioids and number of refills prescribed to adolescents should be carefully considered and closely monitored to reduce subsequent nonmedical use of leftover medication. PMID:22566521

  8. Trends in use of opioids for chronic non-cancer pain among individuals with mental health and substance use disorders: the TROUP study

    PubMed Central

    Edlund, Mark J.; Martin, Bradley C.; Devries, Andrea; Fan, Ming-Yu; Braden, Jennifer Brennan; Sullivan, Mark D.

    2010-01-01

    Objectives Use of prescription opioids for chronic pain is increasing, as is abuse of these medications, though the nature of the link between these trends is unclear. These increases may be most marked in patients with mental health (MH) and substance use disorders (SUDs). We analyzed trends between 2000 and 2005 in opioid prescribing among individuals with non-cancer pain conditions (NCPC), with and without MH and SUDs. Methods Secondary data analysis of longitudinal administrative data from two dissimilar populations: a national, commercially-insured population, and Arkansas Medicaid enrollees. We examined these opioid outcomes: (1) Rates of any prescription opioid use in the past year, (2) rates of chronic use of prescription opioids (greater than 90 days in the past year), (3) mean days supply of opioids, (4) mean daily opioid dose in morphine equivalents, and (5) percentage of total opioid dose that was Schedule II opioids. Results In 2000, among individuals with NCPC, chronic opioid use was more common among those with a MH or SUD than those without in commercially insured (8% versus 3%, p<0.001) and Arkansas Medicaid (20% versus 13%, p<0.001). Between 2000 and 2005, in commercially insured, rates of chronic opioid use increased by 34.9% among individuals with an MH or SUD, and 27.8% among individuals without these disorders. In Arkansas Medicaid chronic opioid use increased 55.4% among individuals with an MH or SUD, and 39.8% among those without. Discussion Chronic use of prescription opioids for NCPC is much higher and growing faster in patients with MH and SUDs than those without these diagnoses. Clinicians should monitor use of prescription opioids in these vulnerable groups to determine whether opioids are substituting for or interfering with appropriate mental health and substance abuse treatment. PMID:20026946

  9. Prescribed opioids in primary care: cross-sectional and longitudinal analyses of influence of patient and practice characteristics

    PubMed Central

    Foy, Robbie; Leaman, Ben; McCrorie, Carolyn; Petty, Duncan; House, Allan; Bennett, Michael; Carder, Paul; Faulkner, Simon; Glidewell, Liz; West, Robert

    2016-01-01

    Objectives To examine trends in opioid prescribing in primary care, identify patient and general practice characteristics associated with long-term and stronger opioid prescribing, and identify associations with changes in opioid prescribing. Design Trend, cross-sectional and longitudinal analyses of routinely recorded patient data. Setting 111 primary care practices in Leeds and Bradford, UK. Participants We observed 471 828 patient-years in which all patients represented had at least 1 opioid prescription between April 2005 and March 2012. A cross-sectional analysis included 99 847 patients prescribed opioids between April 2011 and March 2012. A longitudinal analysis included 49 065 patient-years between April 2008 and March 2012. We excluded patients with cancer or treated for substance misuse. Main outcome measures Long-term opioid prescribing (4 or more prescriptions within 12 months), stronger opioid prescribing and stepping up to or down from stronger opioids. Results Opioid prescribing in the adult population almost doubled for weaker opioids over 2005–2012 and rose over sixfold for stronger opioids. There was marked variation among general practices in the odds of patients stepping up to stronger opioids compared with those not stepping up (range 0.31–3.36), unexplained by practice-level variables. Stepping up to stronger opioids was most strongly associated with being underweight (adjusted OR 3.26, 1.49 to 7.17), increasing polypharmacy (4.15, 3.26 to 5.29 for 10 or more repeat prescriptions), increasing numbers of primary care appointments (3.04, 2.48 to 3.73 for over 12 appointments in the year) and referrals to specialist pain services (5.17, 4.37 to 6.12). Compared with women under 50 years, men under 50 were less likely to step down once prescribed stronger opioids (0.53, 0.37 to 0.75). Conclusions While clinicians should be alert to patients at risk of escalated opioid prescribing, much prescribing variation may be attributable to

  10. Common Surgeries Raise Risk for Opioid Dependence

    MedlinePlus

    ... fullstory_159815.html Common Surgeries Raise Risk for Opioid Dependence: Study Doctors should explore alternatives for pain ... have an elevated risk of growing dependent on opioid painkillers, a new study finds. These prescription painkillers ...

  11. Opioid pharmacokinetic drug-drug interactions.

    PubMed

    Overholser, Brian R; Foster, David R

    2011-09-01

    Pharmacokinetic drug-drug interactions (DDIs) involving opioid analgesics can be problematic. Opioids are widely used, have a narrow therapeutic index, and can be associated with severe toxicity. The purpose of this review is to describe pharmacokinetic DDIs associated with opioids frequently encountered in managed care settings (morphine, codeine, oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, tramadol, and methadone). An introduction to the pharmacokinetic basis of DDIs is provided, and potential DDIs associated with opioids are reviewed. Opioids metabolized by the drug metabolizing enzymes of the cytochrome P450 (CYP450) system (codeine, oxycodone, hydrocodone, fentanyl, tramadol, and methadone) are associated with numerous DDIs that can result in either a reduction in opioid effect or excess opioid effects. Conversely, opioids that are not metabolized by that system (morphine, oxymorphone, and hydromorphone) tend to be involved in fewer CYP450-associated pharmacokinetic DDIs.

  12. Pain Raises Risk of Opioid Addiction

    MedlinePlus

    ... fullstory_160033.html Pain Raises Risk of Opioid Addiction Men and younger people had higher odds of ... had a 41 percent higher risk of opioid addiction than those with no pain. That increased risk ...

  13. Opioids by Injection May Drive HIV Outbreaks

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_159978.html Opioids by Injection May Drive HIV Outbreaks Indiana case ... cooked down the extended-release form of the opioid pain pill oxymorphone (Opana ER). The result was ...

  14. Parenthood and opioid dependence

    PubMed Central

    Pihkala, Heljä; Sandlund, Mikael

    2015-01-01

    Introduction Many patients in maintenance treatment programs for opioid dependence are parents to underage children. Objective The aim of this study was to explore how parents who are regular patients in maintenance treatment perceive their parenthood. Methods The study used a qualitative approach. The informants were recruited by staff at a substance abuse clinic in Sweden. Criteria for inclusion were participation in the local maintenance treatment program, having a child or children younger than 18 years, and being in contact with the child or children. Data were collected in 2012–2013 by in-depth interviews of seven fathers and five mothers and analyzed using concepts and procedures of qualitative content analysis. Results The central findings of the study were: 1) the parents’ concerns about possible future discrimination against their children, ie, stigma by association; and 2) the patients’ own parents’ role as the most important support in parenthood. Conclusion The issue of anticipated discrimination against the children of parents undergoing maintenance treatment might be an aspect to consider in the development of interventions and support. Considering the role of the patients’ own parents also seems important. PMID:25709518

  15. Effects of Acute and Repeated Administration of Staphylococcal Enterotoxin A On Morris Water Maze Learning, Corticosterone and Hippocampal IL-1β and TNFα

    PubMed Central

    Woodruff, Randall T.; Schorpp, Kristen M.; Lawrenczyk, Agniesczka J.; Chakraborty, Trisha; Kusnecov, Alexander W.

    2014-01-01

    Staphylococcal enterotoxin A (SEA) is a bacterial superantigen that induces pronounced T cell expansion and cytokine production. In addition, SEA activates the HPA axis and forebrain regions relevant to cognitive functions. Since learning-related cognitive changes have not been assessed in response to SEA, spatial learning in the morris water maze (MWM) was determined in male C57BL/6J mice subjected to acute or repeated injections of 5 μg SEA or Saline. Injections were given 2 hrs prior to 4–5 days of hidden platform sessions. Animals were then rested for 1 month and given retraining without further injections. In addition, splenic IL-1β, IL-2 and TNFα, plasma corticosterone, and hippocampal IL-1β and TNFα were measured after the regimen of treatment used in the behavioral experiments. The results showed no learning impairment following acute or repeated SEA challenge. Moreover, when retested one month later, and without further injections, the SEA group showed more rapid relearning of the MWM. This suggested that coincidental superantigenic T cell activation and training served to promote long-term improvement in recovery of learning. Furthermore, repeated SEA challenge continued to drive increases in plasma corticosterone, but with a compensatory reduction in hippocampal IL-1β. However, while hippocampal TNFα was reduced after acute and repeated SEA treatment, this was not statistically significant. In view of the importance of modest glucocorticoid elevations and hippocampal IL-1β in promoting contextual learning, the data point to the hypothesis that SEA promotes long-term plasticity by restraining disruptive increases in hippocampal IL-1β, and possibly TNFα, during learning. PMID:20946950

  16. Enhanced central serotonin release from slices of rat hypothalamus following repeated nialamide administration: evidence supporting the overactive serotonin receptor theory of depression

    SciTech Connect

    Offord, S.J.

    1986-01-01

    Researchers are suggesting unipolar affective disorders may be related to an abnormality in biogenic amine receptor-sensitivity. This abnormality may be a result of a dysfunction in central serotonin (5-HT) release mechanisms. 5-HT neurotransmission is modulated by presynaptic autoreceptors, which are members of the 5-HT/sub 1/ receptor subtype. The autoreceptor is thought to play an important role in the homeostasis of the central 5-HT synapse and could be a site at which some antidepressants mediate their therapeutic effect. The number of 5-HT/sub 1/ type receptor binding sites are reduced and behavior mediated by this receptor is abolished following repeated injections of monoamine oxidase inhibitor type antidepressants. These changes did not occur following a single injection. It was hypothesized that repeated treatment with a monoamine oxidase inhibitor would reduce the sensitivity of 5-HT autoreceptors and enhance 5-HT release. Rats were pretreated with single or repeated (twice daily for 7 days) intraperitoneal injections of nialamide (40 mg/kg) or chlorimipramine (10 mg/kg) and the ability of the autoreceptor agonist to inhibit potassium-induced /sup 3/H-5-HT release was evaluated using an in vitro superfusion system. These changes in 5-HT autoreceptor activity are consistent with other reports evaluating monoamine oxidase inhibitors on 5-HT/sub 1/ type receptors. It is hypothesized that the changes in 5-HT neurotransmission are related to the antidepressant mechanism of monoamine oxidase inhibitors.

  17. Opioid-induced central immune signaling: implications for opioid analgesia

    PubMed Central

    Grace, Peter M.; Maier, Steven F.; Watkins, Linda R.

    2015-01-01

    Despite being the mainstay of pain management, opioids are limited in their clinical utility by adverse effects, such as tolerance and paradoxical hyperalgesia. Research of the past 15 years has extended beyond neurons, to implicate central nervous system immune signaling in these adverse effects. This article will provide an overview of these central immune mechanisms in opioid tolerance and paradoxical hyperalgesia, including those mediated by toll like receptor 4, purinergic, ceramide and chemokine signaling. Challenges for the future, as well as new lines of investigation will be highlighted. PMID:25833219

  18. Opioids in Preclinical and Clinical Trials

    NASA Astrophysics Data System (ADS)

    Nagase, Hiroshi; Fujii, Hideaki

    Since 1952, when Gates determined the stereo structure of morphine, numerous groups have focused on discovering a nonnarcotic opioid drug [1]. Although several natural, semisynthetic, and synthetic opioid ligands (alkaloids and peptides) have been developed in clinical studies, very few were nonnarcotic opioid drugs [2]. One of the most important studies in the opioid field appeared in 1976, when Martin and colleagues [3] established types of opioid receptors (these are now classified into μ, δ, and κ types). Later, Portoghese discovered a highly selective μ type opioid receptor antagonist, β-funaltrexamine [4]. This led to the finding that the μ type opioid receptor was correlated to drug dependence [5]. Consequently, δ, and particularly κ, opioid agonists were expected to lead to ideal opioid drugs. Moreover, opioid antagonists were evaluated for the treatment of symptoms related to undesirable opioid system activation. In this chapter, we provide a short survey of opioid ligands in development and describe the discovery of the two most promising drugs, TRK-851 [6] and TRK-820 (nalfurafine hydrochloride) [7].

  19. Synthetic opioids and arrhythmia risk: a new paradigm?

    PubMed

    Schuller, Joseph L; Krantz, Mori J

    2012-09-01

    The most commonly prescribed class of medications in the United States for chronic severe pain is opioid analgesics. Due to their low cost and widespread availability, the synthetic opioids are popular choices among clinicians and patients. However, there is an increasingly recognized risk of QT prolongation with several drugs in this class, and recently propoxyphene (Darvon) was withdrawn from the market by the Food and Drug Administration (FDA) due to, in part, the risk of QT prolongation and ventricular arrhythmias Updated Epidemiological Review of Propoxyphene Safety. [FDA Alert]. Rockville, MD: U.S. Food and Drug Administration; 2010. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM234383.pdf on 5 May 2012 .

  20. Effects of ginsenosides on opioid-induced hyperalgesia in mice.

    PubMed

    Li, Peng; Tang, Minke; Li, Hui; Huang, Xinjie; Chen, Lei; Zhai, Haifeng

    2014-07-01

    Opioid-induced hyperalgesia (OIH) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use. OIH can limit the clinical use of opioid analgesics and complicate withdrawal from opioid addiction. In this study, we investigated the effects of Re, Rg1, and Rb1 ginsenosides, the bioactive components of ginseng, on OIH. OIH was achieved in mice after subcutaneous administration of morphine for 7 consecutive days three times per day. During withdrawal (days 8 and 9), these mice were administered Re, Rg1, or Rb1 intragastrically two times per day. On the test day (day 10), mice were subjected to the thermal sensitivity test and the acetic acid-induced writhing test. Re (300 mg/kg) inhibited OIH in both the thermal sensitivity test and the acetic acid-induced writhing test. However, the Rg1 and Rb1 ginsenosides failed to prevent OIH in either test. Furthermore, Rg1 showed a tendency to aggravate OIH in the acetic acid-induced writhing test. Our data suggested that the ginsenoside Re, but not Rg1 or Rb1, may contribute toward reversal of OIH.

  1. Micronized Organic Magnesium Salts Enhance Opioid Analgesia in Rats

    PubMed Central

    Bujalska-Zadrożny, Magdalena; Kulik, Kamila; Ordak, Michał; Sasinowska-Motyl, Małgorzata; Gąsińska, Emilia; de Corde, Anna; Kowalczyk, Agnieszka; Sacharczuk, Mariusz; Naruszewicz, Marek

    2016-01-01

    Purpose As previously reported, magnesium sulphate administered parenterally significantly increased an opioid antinociception in different kinds of pain. Since the typical form of magnesium salts are poorly and slowly absorbed from the gastrointestinal tract we examined whether their micronized form could increase opioids induced antinociception. Methods In behavioural studies on rats morphine, tramadol and oxycodone together with magnesium (lactate dihydrate, hydroaspartate, chloride) in micronized (particles of size D90 < 50 μm) and conventional forms were used. Changes in pain thresholds were determined using mechanical stimuli. The intestinal absorption of two forms of magnesium lactate dihydrate (at the doses of 7.5 or 15 mg ions) in the porcine gut sac model were also compared. Results Micronized form of magnesium lactate dihydrate or hydroaspartate but not chloride (15 mg of magnesium ions kg-1) enhanced the analgesic activity of orally administered opioids, significantly faster and more effective in comparison to the conventional form of magnesium salts (about 40% for oxycodone administered together with a micronized form of magnesium hydroaspartate). Moreover, in vitro studies of transport across porcine intestines of magnesium ions showed that magnesium salts administered in micronized form were absorbed from the intestines to a greater extent than the normal form of magnesium salts. Conclusions The co-administration of micronized magnesium organic salts with opioids increased their synergetic analgesic effect. This may suggest an innovative approach to the treatment of pain in clinical practice. PMID:27792736

  2. Selective review and commentary on emerging pharmacotherapies for opioid addiction.

    PubMed

    Ling, Walter; Mooney, Larissa; Zhao, Min; Nielsen, Suzanne; Torrington, Matthew; Miotto, Karen

    2011-01-01

    Pharmacotherapies for opioid addiction under active development in the US include lofexidine (primarily for managing withdrawal symptoms) and Probuphine®, a distinctive mode of delivering buprenorphine for six months, thus relieving patients, clinicians, and regulatory personnel from most concerns about diversion, misuse, and unintended exposure in children. In addition, two recently approved formulations of previously proven medications are in early phases of implementation. The sublingual film form of buprenorphine + naloxone (Suboxone®) provides a less divertible, more quickly administered, more child-proof version than the buprenorphine + naloxone sublingual tablet. The injectable depot form of naltrexone (Vivitrol®) ensures consistent opioid receptor blockade for one month between administrations, removing concerns about medication compliance. The clinical implications of these developments have attracted increasing attention from clinicians and policymakers in the US and around the world, especially given that human immunodeficiency virus/acquired immunodeficiency syndrome and other infectious diseases are recognized as companions to opioid addiction, commanding more efforts to reduce opioid addiction. While research and practice improvement efforts continue, reluctance to adopt new medications and procedures can be expected, especially considerations in the regulatory process and in the course of implementation. Best practices and improved outcomes will ultimately emerge from continued development efforts that reflect input from many quarters. PMID:24474855

  3. Regulation of plasma motilin by opioids in the dog.

    PubMed

    Poitras, P; Boivin, M; Lahaie, R G; Trudel, L

    1989-07-01

    In the first part of this study, we compared the effects of morphine and trimebutine, two opioid receptor agonists, on small intestinal motility and plasma motilin in dogs. Morphine (100 micrograms/kg iv for 10 min) induced first a typical vomiting myoelectric profile followed subsequently by a migrating electrical activity mimicking phase III of the migrating myoelectric complex; trimebutine (5 mg/kg iv for 10 min) initiated only a migrating phase III-like activity. Despite their different initial contractile effects, both agents induced a significant and similar rise in plasma motilin that preceded the beginning of the premature phase III. In the second portion of the study, naloxone, an opioid receptor antagonist, was infused to verify the influence of endogenous opiates on plasma motilin and on the migrating motor complex. Naloxone (2 mg/kg, then 0.5 mg.kg-1.h-1 iv) delayed significantly the cyclic recurrence of plasma motilin peak increases and of the phase IIIs. In some animals, where naloxone abolished the phase IIIs, the amplitude of the motilin peak increases was significantly diminished. These results suggest 1) that opioid administration increases plasma levels of motilin by a mechanism that is independent of the intestinal contractile activity, and 2) that endogenous opioids could be physiological inducers of plasma motilin increases in the conscious dog. PMID:2546442

  4. Repeated administration of phytocannabinoid Δ(9)-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner.

    PubMed

    Tai, S; Hyatt, W S; Gu, C; Franks, L N; Vasiljevik, T; Brents, L K; Prather, P L; Fantegrossi, W E

    2015-12-01

    These studies probed the relationship between intrinsic efficacy and tolerance/cross-tolerance between ∆(9)-THC and synthetic cannabinoid drugs of abuse (SCBs) by examining in vivo effects and cellular changes concomitant with their repeated administration in mice. Dose-effect relationships for hypothermic effects were determined in order to confirm that SCBs JWH-018 and JWH-073 are higher efficacy agonists than ∆(9)-THC in mice. Separate groups of mice were treated with saline, sub-maximal hypothermic doses of JWH-018 or JWH-073 (3.0mg/kg or 10.0mg/kg, respectively) or a maximally hypothermic dose of 30.0mg/kg ∆(9)-THC once per day for 5 consecutive days while core temperature and locomotor activity were monitored via biotelemetry. Repeated administration of all drugs resulted in tolerance to hypothermic effects, but not locomotor effects, and this tolerance was still evident 14 days after the last drug administration. Further studies treated mice with 30.0mg/kg ∆(9)-THC once per day for 4 days, then tested with SCBs on day 5. Mice with a ∆(9)-THC history were cross-tolerant to both SCBs, and this cross-tolerance also persisted 14 days after testing. Select brain regions from chronically treated mice were examined for changes in CB1 receptor expression and function. Expression and function of hypothalamic CB1Rs were reduced in mice receiving chronic drugs, but cortical CB1R expression and function were not altered. Collectively, these data demonstrate that repeated ∆(9)-THC, JWH-018 and JWH-073 can induce long-lasting tolerance to some in vivo effects, which is likely mediated by region-specific downregulation and desensitization of CB1Rs.

  5. Presence and bioavailability of bisphenol A in the uterus of rats and mice following single and repeated dietary administration at low doses.

    PubMed

    Pollock, Tyler; deCatanzaro, Denys

    2014-11-01

    This research examined the distribution of low dietary doses of bisphenol A (BPA). When female rats received 50μg/kg (14)C-BPA orally, radioactivity was distributed throughout the body, with especial presence in the uterus. Pre-treatment with estradiol or the estrogen antagonist ICI 182,780 significantly reduced radioactivity in the uterus. The majority of BPA at the uterus was determined to be aglycone (receptor-active) via GC-MS. Subsequently, mice given 0.5, 5, or 50μg/kg (14)C-BPA showed more radioactivity in the uterus than in other non-metabolic tissues. When female mice received 1, 7, or 28 daily doses of 50μg/kg (14)C-BPA, then were measured 24h after the last dose, significantly more radioactivity was detected in the uterus, liver, and kidney following repeated doses. Collectively, these data provide evidence for the in vivo interaction of BPA with estrogen receptors. They also indicate elevated presence of BPA in reproductive tissues after repeated low doses.

  6. Effects of single or repeated administration of a carbamate, propoxur, and an organophosphate, DDVP, on jejunal cholinergic activities and contractile responses in rats.

    PubMed

    Kobayashi, H; Sato, I; Akatsu, Y; Fujii, S; Suzuki, T; Matsusaka, N; Yuyama, A

    1994-01-01

    Wistar rats were injected once or repeatedly for 10 days with dichlorvos (DDVP, 5 mg kg-1), propoxur (10 mg kg-1), oxotremorine (0.1 mg kg-1) or atropine (5 mg kg-1). Animals were killed 20 min or 24 h after single or consecutive injections, respectively, for determinations of cholinergic activities and contractile responses to acetylcholine (ACh) of the jejunum. Single treatments: while DDVP and propoxur decreased acetylcholinesterase (AChE) activity, oxotremorine and atropine did not. Although DDVP, propoxur and oxotremorine increased levels of ACh, atropine decreased them. Contractile responses to ACh were enhanced by DDVP and reduced by oxotremorine and atropine. The Bmax value of binding of [3H]quinuclidinyl benzylate (QNB) to muscarinic ACh receptors was decreased by atropine. Consecutive treatments: DDVP and oxotremorine decreased AChE activity markedly and slightly, respectively. Although DDVP and oxotremorine increased levels of ACh, propoxur decreased them. Without affecting the contractile responses, DDVP caused a reduction and propoxur and atropine caused an increase in the Bmax value for binding of [3H]QNB. Both the contractile responses and the value of Bmax for binding of [3H]-QNB were decreased by oxotremorine. In summary, propoxur and DDVP showed similar effects mainly through their anticholinesterase properties in the case of single injection, but DDVP had similar effects to those of oxotremorine and propoxur had similar effects to those of atropine in the case of repeated injection.

  7. Lithium chloride administration prevents spatial learning and memory impairment in repeated cerebral ischemia-reperfusion mice by depressing apoptosis and increasing BDNF expression in hippocampus.

    PubMed

    Fan, Mingyue; Jin, Wei; Zhao, Haifeng; Xiao, Yining; Jia, Yanqiu; Yin, Yu; Jiang, Xin; Xu, Jing; Meng, Nan; Lv, Peiyuan

    2015-09-15

    Lithium has been reported to have neuroprotective effects, but the preventive and treated role on cognition impairment and the underlying mechanisms have not been determined. In the present study, C57Bl/6 mice were subjected to repeated bilateral common carotid artery occlusion to induce the learning and memory deficits. 2 mmol/kg or 5 mmol/kg of lithium chloride (LiCl) was injected intraperitoneally per day before (for 7 days) or post (for 28 days) the operation. This repeated cerebral ischemia-reperfusion (IR) induced dynamic overexpression of ratio of Bcl-2/Bax and BDNF in hippocampus of mice. LiCl pretreatment and treatment significantly decreased the escape latency and increased the percentage of time that the mice spent in the target quadrant in Morris water maze. 2 mmol/kg LiCl evidently reversed the morphologic changes, up-regulated the survival neuron count and increased the BDNF gene and protein expression. 5 mmol/kg pre-LiCl significantly increased IR-stimulated reduce of Bcl-2/Bax and p-CREB/CREB. These results described suggest that pre-Li and Li treatment may induce a pronounced prevention on cognitive impairment. These effects may relay on the inhibition of apoptosis and increasing BDNF and p-CREB expression.

  8. Toward a systematic approach to opioid rotation

    PubMed Central

    Smith, Howard S; Peppin, John F

    2014-01-01

    Patients requiring chronic opioid therapy may not respond to or tolerate the first opioid prescribed to them, necessitating rotation to another opioid. They may also require dose increases for a number of reasons, including worsening disease and increased pain. Dose escalation to restore analgesia using the primary opioid may lead to increased adverse events. In these patients, rotation to a different opioid at a lower-than-equivalent dose may be sufficient to maintain adequate tolerability and analgesia. In published trials and case series, opioid rotation is performed either using a predetermined substitute opioid with fixed conversion methods, or in a manner that appears to be no more systematic than trial and error. In clinical practice, opioid rotation must be performed with consideration of individual patient characteristics, comorbidities (eg, concurrent psychiatric, pulmonary, renal, or hepatic illness), and concurrent medications, using flexible dosing protocols that take into account incomplete opioid cross-tolerance. References cited in this review were identified via a search of PubMed covering all English language publications up to May 21, 2013 pertaining to opioid rotation, excluding narrative reviews, letters, and expert opinion. The search yielded a total of 129 articles, 92 of which were judged to provide relevant information and subsequently included in this review. Through a review of this literature and from the authors’ empiric experience, this review provides practical information on performing opioid rotation in clinical practice. PMID:25378948

  9. Non-analgesic effects of opioids: opioids and the endocrine system.

    PubMed

    Elliott, Jennifer A; Opper, Susan E; Agarwal, Sonali; Fibuch, Eugene E

    2012-01-01

    Opioids are among the oldest known and most widely used analgesics. The application of opioids has expanded over the last few decades, especially in the treatment of chronic non-malignant pain. This upsurge in opioid use has been accompanied by the increasingly recognized occurrence of opioid-associated endocrinopathy. This may arise after exposure to enteral, parenteral, or neuraxial opioids. Opioid-associated endocrinopathy consists primarily of hypothalamic-pituitary-gonadal axis or hypothalamic-pituitary-adrenal axis dysfunction and may manifest with symptoms of hypogonadism, adrenal dysfunction, and other hormonal disturbances. Additionally, opioid related endocrine dysfunction may be coupled with such disorders as osteoporosis and mood disturbances including depression. Undesirable changes in pain sensitivity such as opioid-induced hyperalgesia, and reduced potency of opioid analgesia may also be potential consequences of chronic opioid consumption. Few studies to date have been able to establish what degree of opioid exposure, in terms of dose or duration of therapy, may predispose patients to opioid-associated endocrinopathy. This article will review the currently available literature concerning opioid-associated endocrinopathy and will provide recommendations for the evaluation, monitoring, and management of opioid-associated endocrinopathy and its other accompanying undesired effects.

  10. Using behavioral economics to predict opioid use during prescription opioid dependence treatment

    PubMed Central

    Worley, Matthew J.; Shoptaw, Steven J.; Bickel, Warren K.; Ling, Walter

    2015-01-01

    Background Research grounded in behavioral economics has previously linked addictive behavior to disrupted decision-making and reward-processing, but these principles have not been examined in prescription opioid addiction, which is currently a major public health problem. This study examined whether pre-treatment drug reinforcement value predicted opioid use during outpatient treatment of prescription opioid addiction. Methods Secondary analyses examined participants with prescription opioid dependence who received 12 weeks of buprenorphine-naloxone and counseling in a multi-site clinical trial (N = 353). Baseline measures assessed opioid source and indices of drug reinforcement value, including the total amount and proportion of income spent on drugs. Weekly urine drug screens measured opioid use. Results Obtaining opioids from doctors was associated with lower pre-treatment drug spending, while obtaining opioids from dealers/patients was associated with greater spending. Controlling for demographics, opioid use history, and opioid source frequency, patients who spent a greater total amount (OR = 1.30, p < .001) and a greater proportion of their income on drugs (OR = 1.31, p < .001) were more likely to use opioids during treatment. Conclusions Individual differences in drug reinforcement value, as indicated by pre-treatment allocation of economic resources to drugs, reflects propensity for continued opioid use during treatment among individuals with prescription opioid addiction. Future studies should examine disrupted decision-making and reward-processing in prescription opioid users more directly and test whether reinforcer pathology can be remediated in this population. PMID:25622776

  11. An exploration of opioid medication management for non-malignant pain in primary care

    PubMed Central

    Foell, Jens

    2015-01-01

    The present study aimed to explore how prescription of opioid medication for chronic non-malignant pain (CNMP) is managed in primary care. We used audit as a research tool, and one general practitioner (GP) practice in West London acted as an exemplar. Of the practice population with CNMP, 1% had repeat prescription of at least 12 months duration for opioid analgesics at the time of data collection. These 1% are on highly controlled opioids. Our study showed the following: (1) long-term opioid prescription appears to follow a fluctuating course as opposed to staying the same; (2) we found that medication reviews were done in most cases (85.7%), but the quality of the process is difficult to assess and ascertain; and (3) we identified two incidences where opioid contract was implemented. In both cases, contracts were used as a last chance warning for patients who were already problematic, suggesting that opioid contracts served as a disciplinary tool rather than a preventative measure. Our findings highlight a need for a more structured and specific review of analgesic medication, and a need for a simple and effective way to identify patients at high risk of developing problematic use, to ensure better monitoring and early presentations. PMID:26516575

  12. Co-occurring prescription opioid use problems and posttraumatic stress disorder symptom severity

    PubMed Central

    Meier, Andrea; Lambert-Harris, Chantal; McGovern, Mark P.; Xie, Haiyi; An, Melissa; McLeman, Bethany

    2016-01-01

    Background Prescription opioids are the most rapidly growing category of abused substances, and result in significant morbidity, mortality and healthcare costs. Co-occurring with psychiatric disorders, persons with prescription opioid problems have negative treatment outcomes. Data are needed on the prevalence of co-occurring prescription opioid abuse and specific disorders, such as posttraumatic stress disorder (PTSD), to better inform clinical practice. Objective: To determine prevalence rates of current co-occurring prescription opioid use problems and PTSD symptom severity among patients in community addiction treatment settings. Methods We abstracted administrative and chart information on 573 new admissions to three addictive treatment agencies during 2011. Systematic data were collected on PTSD symptoms, substance use, and patient demographics. Results Prescription opioid use was significantly associated with co-occurring PTSD symptom severity (OR: 1.42, p < 0.05). Use of prescription opioids in combination with sedatives (OR: 3.81, p < 0.01) or cocaine (OR: 2.24, p < 0.001) also were associated with PTSD severity. The odds of having co-occurring PTSD symptoms and prescription opioid use problem were nearly three times greater among females versus males (OR: 2.63, p < 0.001). Younger patients (18–34 years old) also were at higher risk (OR: 1.86, p < 0.01). Conclusions Prescription opioid use problems are a risk factor for co-occurring PTSD symptom severity. Being female or younger increase the likelihood of this co-morbidity. Further research is needed to confirm these finding, particularly using more rigorous diagnostic procedures. These data suggest that patients with prescription opioid use problems should be carefully evaluated for PTSD symptoms. PMID:24809229

  13. The role of naloxegol in the management of opioid-induced bowel dysfunction.

    PubMed

    Leppert, Wojciech; Woron, Jaroslaw

    2016-09-01

    Opioid-induced constipation (OIC) and other gastrointestinal (GI) symptoms of opioid-induced bowel dysfunction (OIBD) significantly deteriorate patients' quality of life and may lead to noncompliance with opioid schedule and undertreatment of pain. Although traditional oral laxatives are the first-line treatment of OIC, they do not address OIBD pathophysiology, and display numerous adverse effects. OIC treatment includes prokinetics (lubiprostone), opioid switch, and changing route of opioid administration. Targeted management of OIBD comprises the use of purely peripherally acting μ-opioid receptor antagonists (PAMORA): naloxegol and methylnaltrexone. Naloxegol (NKTR-118) is a polymer conjugate of the opioid antagonist naloxone. The polyethylene glycol limits naloxegol capacity to cross the blood-brain barrier (BBB). Naloxegol is substrate for the P-glycoprotein (P-gp) transporter. The central nervous system penetration of naloxegol is negligible due to reduced permeability and its increased efflux across the BBB, related to P-gp transporter. Naloxegol antagonizes μ- and κ-opioid receptors and displays low affinity to δ-opioid receptors in the GI tract, thereby decreasing OIBD symptoms without reversing central analgesic effects. Naloxegol is metabolised through CYP3A4 to six metabolites, with the majority of the dose (68%) excreted with faeces and less (16%) with urine. The dose of naloxegol equals 25 mg administered orally once daily on a fasting condition. Mild or moderate hepatic impairment has no impact on naloxegol dosing; naloxegol was not studied and is not recommended in patients with hepatic failure. Dose reduction (12.5 mg once daily) and caution is recommended in patients with moderate-to-severe renal impairment. Efficacy (bowel movement in 42-49% of patients not responsive to laxatives) and safety of naloxegol were confirmed in studies conducted in patients with OIC and nonmalignant pain. Naloxegol may be useful for cancer patients with OIC

  14. Clinical care for opioid-using pregnant and postpartum women: the role of obstetric providers.

    PubMed

    Jones, Hendrée E; Deppen, Krisanna; Hudak, Mark L; Leffert, Lisa; McClelland, Carol; Sahin, Leyla; Starer, Jacquelyn; Terplan, Mishka; Thorp, John M; Walsh, James; Creanga, Andreea A

    2014-04-01

    We review clinical care issues that are related to illicit and therapeutic opioid use among pregnant women and women in the postpartum period and outline the major responsibilities of obstetrics providers who care for these patients during the antepartum, intrapartum, and postpartum periods. Selected patient treatment issues are highlighted, and case examples are provided. Securing a strong rapport and trust with these patients is crucial for success in delivering high-quality obstetric care and in coordinating services with other specialists as needed. Obstetrics providers have an ethical obligation to screen, assess, and provide brief interventions and referral to specialized treatment for patients with drug use disorders. Opioid-dependent pregnant women often can be treated effectively with methadone or buprenorphine. These medications are classified as pregnancy category C medications by the Food and Drug Administration, and their use in the treatment of opioid-dependent pregnant patients should not be considered "off-label." Except in rare special circumstances, medication-assisted withdrawal during pregnancy should be discouraged because of a high relapse rate. Acute pain management in this population deserves special consideration because patients who use opioids can be hypersensitive to pain and because the use of mixed opioid-agonist/antagonists can precipitate opioid withdrawal. In the absence of other indications, pregnant women who use opioids do not require more intense medical care than other pregnant patients to ensure adequate treatment and the best possible outcomes. Together with specialists in pain and addiction medicine, obstetricians can coordinate comprehensive care for pregnant women who use opioids and women who use opioids in the postpartum period.

  15. The role of naloxegol in the management of opioid-induced bowel dysfunction

    PubMed Central

    Leppert, Wojciech; Woron, Jaroslaw

    2016-01-01

    Opioid-induced constipation (OIC) and other gastrointestinal (GI) symptoms of opioid-induced bowel dysfunction (OIBD) significantly deteriorate patients’ quality of life and may lead to noncompliance with opioid schedule and undertreatment of pain. Although traditional oral laxatives are the first-line treatment of OIC, they do not address OIBD pathophysiology, and display numerous adverse effects. OIC treatment includes prokinetics (lubiprostone), opioid switch, and changing route of opioid administration. Targeted management of OIBD comprises the use of purely peripherally acting μ-opioid receptor antagonists (PAMORA): naloxegol and methylnaltrexone. Naloxegol (NKTR-118) is a polymer conjugate of the opioid antagonist naloxone. The polyethylene glycol limits naloxegol capacity to cross the blood–brain barrier (BBB). Naloxegol is substrate for the P-glycoprotein (P-gp) transporter. The central nervous system penetration of naloxegol is negligible due to reduced permeability and its increased efflux across the BBB, related to P-gp transporter. Naloxegol antagonizes μ- and κ-opioid receptors and displays low affinity to δ-opioid receptors in the GI tract, thereby decreasing OIBD symptoms without reversing central analgesic effects. Naloxegol is metabolised through CYP3A4 to six metabolites, with the majority of the dose (68%) excreted with faeces and less (16%) with urine. The dose of naloxegol equals 25 mg administered orally once daily on a fasting condition. Mild or moderate hepatic impairment has no impact on naloxegol dosing; naloxegol was not studied and is not recommended in patients with hepatic failure. Dose reduction (12.5 mg once daily) and caution is recommended in patients with moderate-to-severe renal impairment. Efficacy (bowel movement in 42–49% of patients not responsive to laxatives) and safety of naloxegol were confirmed in studies conducted in patients with OIC and nonmalignant pain. Naloxegol may be useful for cancer patients with OIC

  16. SCOPE of Pain: An Evaluation of an Opioid Risk Evaluation and Mitigation Strategy Continuing Education Program

    PubMed Central

    Zisblatt, Lara; Ng, Pamela; Hayes, Sean M.; Peloquin, Sophie; Hardesty, Ilana; White, Julie L.

    2016-01-01

    Objective. Due to the high prevalence of prescription opioid misuse, the US Food and Drug Administration (FDA) mandated a Risk Evaluation and Mitigation Strategy (REMS) requiring manufacturers of extended-release/long-acting (ER/LA) opioid analgesics to fund continuing education based on a FDA Blueprint. This article describes the Safe and Competent Opioid Prescribing Education (SCOPE of Pain) program, an ER/LA opioid analgesic REMS program, and its impact on clinician knowledge, confidence, attitudes, and self-reported clinical practice. Method. Participants of the 3-h SCOPE of Pain training completed pre-, immediate post- and 2-month post-assessments. Subjects. The primary target group (n = 2,850), and a subset (n = 476) who completed a 2-month post-assessment, consisted of clinicians licensed to prescribe ER/LA opioid analgesics, who care for patients with chronic pain and who completed the 3-h training between February 28, 2013 and June 13, 2014. Results. Immediately post-program, there was a significant increase in correct responses to knowledge questions (60% to 84%, P ≤ 0.02) and 87% of participants planned to make practice changes. At 2-months post-program, there continued to be a significant increase in correct responses to knowledge questions (60% to 69%, P ≤ 0.03) and 67% reported increased confidence in applying safe opioid prescribing care and 86% reported implementing practice changes. There was also an improvement in alignment of desired attitudes toward safe opioid prescribing. Conclusions. The SCOPE of Pain program improved knowledge, attitudes, confidence, and self-reported clinical practice in safe opioid prescribing. This national REMS program holds potential to improve the safe use of opioids for the treatment of chronic pain. PMID:26304703

  17. Dextrorphan binds to opioid receptors in guinea-pig brain membranes and is an antagonist at opioid receptors in myenteric plexus.

    PubMed Central

    Goldstein, A; Naidu, A

    1990-01-01

    Dextrorphan (+)-tartrate, purified by repeated crystallization to remove all traces of the enantiomer levorphanol, binds to mu, delta, and kappa sites on guinea-pig brain membranes with lower affinities (by a factor of 400-3200) than levorphanol. In the guinea-pig ileum myenteric plexus longitudinal muscle preparation (GPI), dextrorphan, at 100-200 microM, inhibits the electrically stimulated twitch, but this action is not blocked or reversed by naloxone; both (+)- and (-)-naloxone produce similar non-opioid twitch inhibition at comparable concentrations. At 10-20 microM, dextrorphan blocks and reverses the twitch inhibition due to mu and kappa agonists, but the blockade can be overcome only partially by increasing the agonist concentration. We conclude that dextrorphan is an opioid ligand with low affinity and with antagonist effect on opioid receptors in the GPI. PMID:2155421

  18. [Neurotoxicity of intrathecally administrated agents].

    PubMed

    Malinovsky, J M; Pinaud, M

    1996-01-01

    Spinal anaesthetics can induce histopathologic lesions and regional haemodynamic alterations in the spinal cord. There are numerous causes of neurologic lesions, including direct trauma of the spinal cord and nerve roots during puncture or catheter insertion, compromised spinal cord perfusion and direct neurotoxic effect. Histopathologic lesions are localized either in meninges (meningitis or arachnoiditis) or in neuraxis (myelitis or axonal degeneration). Neurotoxicity can result from decrease in neuronal blood supply, elicited by high concentrations of the solutions, long duration exposure to local anaesthetics, and the use of adjuvants. They have been implicated in the occurrence of cauda equina syndrome after continuous spinal anaesthesia using hyperbaric solution of lidocaine and tetracaine given through small diameter catheters. Selective spinal analgesia is induced by spinal opioids without motor blockade except for meperidine. Complications occurred in patients after high doses of morphine, which were related to one of its metabolites, morphine-3-glucuronide. Preservative-free opioid solutions are to be preferred for spinal anaesthesia. There is no report of neurotoxicity neither in animal studies, nor in humans, using spinal clonidine. In order to reduce the incidence of neurotoxicity, some safety rules should be followed. The lowest efficient dose of local anaesthetics must be given. Incomplete blockade should not necessarily lead to a reinjection. Large volume of hyperbaric lidocaine or repeated injections of such solutions must be avoided as well as preservative-containing solutions. The administration of new compounds by the spinal route must be supported by data of spinal neuropharmacology and the lack of neurotoxicity must have been previously checked with animal studies.

  19. Reduced striatal dopamine transporter density associated with working memory deficits in opioid-dependent male subjects: a SPECT study.

    PubMed

    Liang, Chih-Sung; Ho, Pei-Shen; Yen, Che-Hung; Yeh, Yi-Wei; Kuo, Shin-Chang; Huang, Chang-Chih; Chen, Chun-Yen; Shih, Mei-Chen; Ma, Kuo-Hsing; Huang, San-Yuan

    2016-01-01

    Research on the effects of repeated opioid use on striatal dopamine transporters has yielded inconsistent results, possibly confounded by a history of methamphetamine or methadone exposure in opioid-dependent individuals. Previous studies have shown that striatal dopamine transporter density is positively correlated with the cognitive performance of healthy volunteers. This study aimed to investigate changes in striatal dopamine transporter density and their functional significance in opioid-dependent individuals. Single-photon emission computed tomography with [(99m) Tc]TRODAT-1 as a ligand was used to measure striatal dopamine transporter levels in 20 opioid-dependent individuals and 20 age- and sex-matched healthy controls. Opioid-dependent individuals had no history of methamphetamine or methadone use. The Wisconsin Card Sorting Test (WCST) was performed to assess neurocognitive function. We found that compared with healthy controls, opioid-dependent individuals showed a significant reduction in striatal dopamine transporter density. They also showed poorer performance on the WCST in terms of the trials administered, total errors, perseverative responses, perseverative errors, and non-perseverative errors. Striatal dopamine transporter levels negatively correlated with non-perseverative errors not only in opioid-dependent individuals but also in healthy controls. These findings suggest that in human, repeated opioid exposure reduces striatal dopamine transporter density, which can be associated with non-perseverative errors. Non-perseverative errors may be one of the more sensitive parameters in WCST to identify working memory deficits associated with striatal dopamine transporter reduction. Moreover, we suggest that whether opioid-associated neurotoxicity is reversible depends on the brain region. PMID:25439653

  20. Opioid receptors in the gastrointestinal tract

    PubMed Central

    Holzer, Peter

    2011-01-01

    Opium is arguably one of the oldest herbal medicines, being used as analgesic, sedative and antidiarrheal drug for thousands of years. These effects mirror the actions of the endogenous opioid system and are mediated by the principal μ-, κ- and δ-opioid receptors. In the gut, met-enkephalin, leu-enkephalin, β-endorphin and dynorphin occur in both neurons and endocrine cells. When released, opioid peptides activate opioid receptors on the enteric circuitry controlling motility and secretion. As a result, inhibition of gastric emptying, increase in sphincter tone, induction of stationary motor patterns and blockade of peristalsis ensue. Together with inhibition of ion and fluid secretion, these effects cause constipation, one of the most frequent and troublesome adverse reactions of opioid analgesic therapy. Although laxatives are most frequently used to ameliorate opioid-induced bowel dysfunction, their efficacy is unsatisfactory. Specific antagonism of peripheral opioid receptors is a more rational approach. This goal is addressed by the use of opioid receptor antagonists with limited absorption such as oral prolonged-release naloxone and opioid receptor antagonists that do not penetrate the blood-brain barrier such as methylnaltrexone and alvimopan. Preliminary evidence indicates that peripherally restricted opioid receptor antagonists may act as prokinetic drugs in their own right. PMID:19345246

  1. "Weak" opioid analgesics. Codeine, dihydrocodeine and tramadol: no less risky than morphine.

    PubMed

    2016-02-01

    So-called weak opioid analgesics are often used to treat severe pain, or when paracetamol or a nonsteroidal anti-inflammatory drug (NSAID) proves inadequate. But are weak opioids any more effective than paracetamol or NSAIDs on nociceptive pain, and are they better tolerated than morphine? To answer these questions, we conducted a review of literature using the standard Prescrire methodology. The potency of codeine and tramadol is strongly influenced by the cytochrome P450 isoenzyme CYP2D6 genotype, which varies widely from one person to another. This explains reports of overdosing or underdosing after administration of standard doses of the two drugs. The potency of morphine and that of buprenorphine, an opioid receptor agonist-antagonist, appears to be independent of CYP2D6 activity. All "weak" opioids can have the same dose-dependent adverse effects as morphine. There is no evidence that, at equivalent analgesic efficacy, weak opioids carry a lower risk of addiction than low-dose morphine. Respiratory depression can occur in ultrarapid metabolisers after brief exposure to standard doses of codeine or tramadol. Similar cases have been reported with dihydrocodeine in patients with renal failure. In addition, tramadol can cause a serotonin syndrome, hypoglycaemia, hyponatraemia and seizures. Several trials have compared different weak opioids in patients with post-operative pain. A single dose of a weak opioid, possibly combined with paracetamol, has greater analgesic efficacy than paracetamol alone but is not more effective than an NSAID alone. There is a dearth of evidence on weak opioids in patients with chronic pain. Available trials fail to show that a weak opioid has markedly superior analgesic efficacy to paracetamol or an NSAID. Sublingual buprenorphine at analgesic doses appears less likely to cause respiratory depression, but it seems to have weak analgesic efficacy. In practice, when opioid therapy is needed, there is no evidence that codeine

  2. Activation of delta-opioid receptor contributes to the antinociceptive effect of oxycodone in mice.

    PubMed

    Yang, Pao-Pao; Yeh, Geng-Chang; Yeh, Teng-Kuang; Xi, Jinghua; Loh, Horace H; Law, Ping-Yee; Tao, Pao-Luh

    2016-09-01

    Oxycodone has been used clinically for over 90 years. While it is known that it exhibits low affinity for the multiple opioid receptors, whether its pharmacological activities are due to oxycodone activation of the opioid receptor type or due to its active metabolite (oxymorphone) that exhibits high affinity for the mu-opioid receptors remains unresolved. Ross and Smith (1997) reported the antinociceptive effects of oxycodone (171nmol, i.c.v.) are induced by putative kappa-opioid receptors in SD rat while others have reported oxycodone activities are due to activation of mu- and/or delta-opioid receptors. In this study, using male mu-opioid receptor knock-out (MOR-KO) mice, we examined whether delta-opioid receptor was involved in oxycodone antinociception. Systemic subcutaneous (s.c.) administration of oxycodone (above 40mg/kg) could induce a small but significant antinociceptive effect in MOR-KO mice by the tail flick test. Delta-opioid receptor antagonist (naltrindole, 10mg/kg or 20mg/kg, i.p.) could block this effect. When oxycodone was injected directly into the brain of MOR-KO mice by intracerebroventricular (i.c.v.) route, oxycodone at doses of 50nmol or higher could induce similar level of antinociceptive responses to those observed in wild type mice at the same doses by i.c.v. Delta-opioid receptor antagonists (naltrindole at 10nmol or ICI 154,129 at 20μg) completely blocked the supraspinal antinociceptive effect of oxycodone in MOR-KO mice. Such oxycodone antinociceptive responses were probably not due to its active metabolites oxymorphone because (a) the relative low level of oxymorphone was found in the brain after systemically or centrally oxycodone injection using LC/MS/MS analysis; (b) oxymorphone at a dose that mimics the level detected in the mice brain did not show any significant antinocieption effect; (c) oxycodone exhibits equal potency as oxymorphone albeit being a partial agonist in regulating [Ca(2+)]I transients in a clonal cell line

  3. Will abuse-deterrent formulations of opioid analgesics be successful in achieving their purpose?

    PubMed

    Bannwarth, Bernard

    2012-09-10

    During the last 2 decades, there has been a dramatic increase in the use of strong opioids for chronic non-cancer pain. This increase has been accompanied by a steep increase in abuse, misuse, and both fatal and non-fatal overdoses involving prescription opioids. The situation is already alarming in the US. Prescription opioid-related harm is a complex, multifactorial issue that requires a multifaceted solution. In this respect, formulations of opioid analgesics designed to resist or deter abuse may be a useful component of a comprehensive opioid risk minimization programme. Such formulations have or are being developed. Abuse-resistant opioids include those that use some kind of physical barrier to prevent tampering with the formulation. Abuse-deterrent opioids are not necessarily resistant to tampering, but contain substances that are designed to make the formulation less attractive to abusers. This article focuses on two products intended to deter abuse that were reviewed by the US Food and Drug Administration (FDA). The first (Embeda®) consists of extended-release morphine with sequestered naltrexone, an opioid antagonist that is released if the tablet is compromised by chewing or crushing. Although Embeda® exhibited abuse-deterrent features, its label warns that it can be abused in a manner similar to other opioid agonists. Furthermore, tampering with Embeda® will result in the release of naltrexone, which may precipitate withdrawal in opioid-tolerant individuals. In March 2011, all dosage forms of Embeda® were recalled because the product failed to meet routine stability standards, and its return date to the market is currently unknown. The second product (Acurox®) was intended to be both tamper resistant and abuse deterrent. It consisted of an immediate-release oxycodone tablet with subtherapeutic niacin as an aversive agent and used a gel-forming ingredient designed to inhibit inhalation and prevent extraction of the drug for injection. The new drug

  4. "Weak" opioid analgesics. Codeine, dihydrocodeine and tramadol: no less risky than morphine.

    PubMed

    2016-02-01

    So-called weak opioid analgesics are often used to treat severe pain, or when paracetamol or a nonsteroidal anti-inflammatory drug (NSAID) proves inadequate. But are weak opioids any more effective than paracetamol or NSAIDs on nociceptive pain, and are they better tolerated than morphine? To answer these questions, we conducted a review of literature using the standard Prescrire methodology. The potency of codeine and tramadol is strongly influenced by the cytochrome P450 isoenzyme CYP2D6 genotype, which varies widely from one person to another. This explains reports of overdosing or underdosing after administration of standard doses of the two drugs. The potency of morphine and that of buprenorphine, an opioid receptor agonist-antagonist, appears to be independent of CYP2D6 activity. All "weak" opioids can have the same dose-dependent adverse effects as morphine. There is no evidence that, at equivalent analgesic efficacy, weak opioids carry a lower risk of addiction than low-dose morphine. Respiratory depression can occur in ultrarapid metabolisers after brief exposure to standard doses of codeine or tramadol. Similar cases have been reported with dihydrocodeine in patients with renal failure. In addition, tramadol can cause a serotonin syndrome, hypoglycaemia, hyponatraemia and seizures. Several trials have compared different weak opioids in patients with post-operative pain. A single dose of a weak opioid, possibly combined with paracetamol, has greater analgesic efficacy than paracetamol alone but is not more effective than an NSAID alone. There is a dearth of evidence on weak opioids in patients with chronic pain. Available trials fail to show that a weak opioid has markedly superior analgesic efficacy to paracetamol or an NSAID. Sublingual buprenorphine at analgesic doses appears less likely to cause respiratory depression, but it seems to have weak analgesic efficacy. In practice, when opioid therapy is needed, there is no evidence that codeine

  5. Repeated administration of AC-5216, a ligand for the 18 kDa translocator protein, improves behavioral deficits in a mouse model of post-traumatic stress disorder.

    PubMed

    Qiu, Zhi-Kun; Zhang, Li-Ming; Zhao, Nan; Chen, Hong-Xia; Zhang, You-Zhi; Liu, Yan-Qin; Mi, Tian-Yue; Zhou, Wen-Wen; Li, Yang; Yang, Ri-Fang; Xu, Jiang-Ping; Li, Yun-Feng

    2013-08-01

    Post-traumatic stress disorder (PTSD) is a severely disabling anxiety disorder that may occur following exposure to a serious traumatic event. It is a psychiatric condition that can afflict anyone who has experienced a life-threatening or violent event. Previous studies have shown that changes in 18 kDa translocator protein (TSPO) expression (or function), a promising target for treating neurological disorders without benzodiazepine-like side effects, may correlate with PTSD. However, few studies have investigated the anti-PTSD effects of TSPO ligands. AC-5216, a ligand for TSPO, induces anxiolytic- and anti-depressant-like effects in animal models. The present study aimed to determine whether AC-5216 ameliorates PTSD behavior in mice. Following the training session consisting of exposure to inescapable electric foot shocks, animals were administered AC-5216 daily during the behavioral assessments, i.e., situational reminders (SRs), the open field (OF) test, the elevated plus-maze (EPM) test, and the staircase test (ST). The results indicated that exposure to foot shocks induced long-term behavioral deficiencies in the mice, including freezing and anxiety-like behavior, which were significantly ameliorated by repeated treatment with AC-5216 but without any effect on spontaneous locomotor activity or body weight. In summary, this study demonstrated the anti-PTSD effects of AC-5216 treatment, suggesting that TSPO may represent a therapeutic target for anti-PTSD drug discovery and that TSPO ligands may be a promising new class of drugs for the future treatment of PTSD.

  6. Correlation between decreased motor activity and dopaminergic degeneration in the ventrolateral putamen in monkeys receiving repeated MPTP administrations: a positron emission tomography study.

    PubMed

    Nagai, Yuji; Minamimoto, Takafumi; Ando, Kiyoshi; Obayashi, Shigeru; Ito, Hiroshi; Ito, Nobuhiko; Suhara, Tetsuya

    2012-05-01

    Parkinson's disease (PD) patients have remarkably reduced levels of dopaminergic biomarkers in the caudal putamen. However, the relationship between motor impairments and the localization of intrastriatal dopaminergic degeneration in monkey PD models remains unclear. To identify the striatal areas with dopaminergic dysfunction responsible for motor impairments, we measured changes in both general motor activity and in vivo dopaminergic biomarkers in three cynomolgus monkeys that repeatedly received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), starting in the normal state and continuing until after tremor appearance. Binding of dopamine transporters (DAT) and D(2) receptors were measured by positron emission tomography (PET) using [(11)C]PE2I and [(11)C]raclopride, respectively. Region-of-interest-based regression analysis demonstrated the degree of general motor activity reduction to be explained by striatal DAT binding but not by D(2) receptor binding. Furthermore, voxel-based analysis revealed a significant correlation between reduced general motor activity and decreased DAT binding, specifically in the ventrolateral putamen, which corresponds to the area receiving upper body motor inputs from the primary motor cortex. These results suggest that specific functional deficits in PD models are closely related to the degeneration of dopaminergic terminals in the striatal subregion responsible for these functions and that the level of deficit is dependent on the degree of degeneration.

  7. Repeated administration of almonds increases brain acetylcholine levels and enhances memory function in healthy rats while attenuates memory deficits in animal model of amnesia.

    PubMed

    Batool, Zehra; Sadir, Sadia; Liaquat, Laraib; Tabassum, Saiqa; Madiha, Syeda; Rafiq, Sahar; Tariq, Sumayya; Batool, Tuba Sharf; Saleem, Sadia; Naqvi, Fizza; Perveen, Tahira; Haider, Saida

    2016-01-01

    Dietary nutrients may play a vital role in protecting the brain from age-related memory dysfunction and neurodegenerative diseases. Tree nuts including almonds have shown potential to combat age-associated brain dysfunction. These nuts are an important source of essential nutrients, such as tocopherol, folate, mono- and poly-unsaturated fatty acids, and polyphenols. These components have shown promise as possible dietary supplements to prevent or delay the onset of age-associated cognitive dysfunction. This study investigated possible protective potential of almond against scopolamine induced amnesia in rats. The present study also investigated a role of acetylcholine in almond induced memory enhancement. Rats in test group were orally administrated with almond suspension (400 mg/kg/day) for four weeks. Both control and almond-treated rats were then divided into saline and scopolamine injected groups. Rats in the scopolamine group were injected with scopolamine (0.5 mg/kg) five minutes before the start of each memory test. Memory was assessed by elevated plus maze (EPM), Morris water maze (MWM) and novel object recognition (NOR) task. Cholinergic function was determined in terms of hippocampal and frontal cortical acetylcholine content and acetylcholinesterase activity. Results of the present study suggest that almond administration for 28 days significantly improved memory retention. This memory enhancing effect of almond was also observed in scopolamine induced amnesia model. Present study also suggests a role of acetylcholine in the attenuation of scopolamine induced amnesia by almond.

  8. Strategies to Reduce the Tampering and Subsequent Abuse of Long-acting Opioids: Potential Risks and Benefits of Formulations With Physical or Pharmacologic Deterrents to Tampering

    PubMed Central

    Stanos, Steven P.; Bruckenthal, Patricia; Barkin, Robert L.

    2012-01-01

    Increased prescribing of opioid analgesics for chronic noncancer pain may reflect acceptance that opioid benefits outweigh risks of adverse events for a broadening array of indications and patient populations; however, a parallel increase in the abuse, misuse, and diversion of prescription opioids has resulted. There is an urgent need to reduce opioid tampering and subsequent abuse without creating barriers to safe, effective analgesia. Similar to the “magic bullet” concept of antibiotic development (kill the bacteria without harming the patient), the idea behind reformulating opioid analgesics is to make them more difficult to tamper with and abuse by drug abusers but innocuous to the compliant patient. As antibiotics exploit differences in bacterial and human physiology, tamper-resistant formulations depend on differences in the way drug abusers and compliant patients consume opioids. Most opioid abusers tamper with tablets to facilitate oral, intranasal, or intravenous administration, whereas compliant patients usually take intact tablets. Pharmaceutical strategies to deter opioid abuse predominantly focus on tablet tampering, incorporating physical barriers (eg, crush resistance) or embedded chemicals that render tampered tablets inert, unusable, or noxious. Deterring tampering and abuse of intact tablets is more challenging. At present, only a few formulations with characteristics designed to oppose tampering for abuse have received approval by the US Food and Drug Administration, and none has been permitted to include claims of abuse deterrence or tamper resistance in their labeling. This review discusses the potential benefits, risks, and limitations associated with available tamper-resistant opioids and those in development. PMID:22766088

  9. Opioid modulation of song in male zebra finches (Taenopygia guttata).

    PubMed

    Khurshid, Nazia; Jayaprakash, Navin; Hameed, L Shahul; Mohanasundaram, Sivaraj; Iyengar, Soumya

    2010-04-01

    Endogenous opioids are known to modulate motivated behaviors. Male zebra finches produce a highly motivated behavior (directed song) to court females and also sing in isolation (undirected song). We found that adult male zebra finches sang significantly fewer directed and undirected songs after administration of low doses (2.5 mg/kg body weight) of the general opioid antagonist naloxone, even though the order of syllables in songs was not altered. Surprisingly, high doses of naloxone (10 mg/kg body weight) dramatically decreased the production of undirected songs but had no significant effects on directed songs. There were no changes in the number of calls during directed or undirected song, movement, stereotyped behaviors including pecking and preening, feeding or drinking behaviors after naloxone administration. We also found that treating zebra finches with naloxone led to a decrease in tonality (goodness of pitch), frequency and amplitude modulation and an increase in the length of intersyllable intervals. Our results suggest that the opioid system can differentially modulate directed and undirected song as well as the acoustic characteristics of birdsong, perhaps by acting on different components of the song control system.

  10. Direct and long-lasting effects elicited by repeated drug administration on 50-kHz ultrasonic vocalizations are regulated differently: implications for the study of the affective properties of drugs of abuse.

    PubMed

    Simola, Nicola; Frau, Lucia; Plumitallo, Antonio; Morelli, Micaela

    2014-03-01

    Several studies suggest that 50-kHz ultrasonic vocalizations (USVs) may indicate a positive affective state in rats, and these vocalizations are increasingly being used to investigate the properties of psychoactive drugs. Previous studies, however, have focused on dopaminergic psychostimulants and morphine, whereas little is known about how other drugs modulate 50-kHz USVs. To further elucidate the neuropharmacology of 50-kHz USVs, the present study characterized the direct and long-lasting effects of different drugs of abuse, by measuring the number of 50-kHz USVs and their 'trill' subtype emitted by adult male rats. Rats received repeated administrations of amphetamine (2 mg/kg, i.p.), 3,4-methylenedioxymethamphetamine (MDMA, 7.5 mg/kg, i.p.), morphine (7.5 mg/kg, s.c.), or nicotine (0.4 mg/kg, s.c.), on either consecutive or alternate days (five administrations in total) in a novel environment. Seven days later, rats were re-exposed to the drug-paired environment, subjected to USVs recording, and then challenged with the same drug. Finally, 7 d after the challenge, rats were repeatedly exposed to the drug-paired environment and vocalizations were measured. Amphetamine was the only drug to stimulate 50-kHz USVs and 'trill' subtype emission during administration and challenge. Conversely, all rats emitted 50-kHz USVs when re-exposed to the test cage, and this effect was most marked in morphine-treated rats, and less evident in nicotine-treated rats. This study demonstrates that the direct and long-lasting effects of drugs on 50-kHz USVs are regulated differently, providing a better understanding of the usefulness of these vocalizations in the study of psychoactive drugs.

  11. Direct and long-lasting effects elicited by repeated drug administration on 50-kHz ultrasonic vocalizations are regulated differently: implications for the study of the affective properties of drugs of abuse.

    PubMed

    Simola, Nicola; Frau, Lucia; Plumitallo, Antonio; Morelli, Micaela

    2014-03-01

    Several studies suggest that 50-kHz ultrasonic vocalizations (USVs) may indicate a positive affective state in rats, and these vocalizations are increasingly being used to investigate the properties of psychoactive drugs. Previous studies, however, have focused on dopaminergic psychostimulants and morphine, whereas little is known about how other drugs modulate 50-kHz USVs. To further elucidate the neuropharmacology of 50-kHz USVs, the present study characterized the direct and long-lasting effects of different drugs of abuse, by measuring the number of 50-kHz USVs and their 'trill' subtype emitted by adult male rats. Rats received repeated administrations of amphetamine (2 mg/kg, i.p.), 3,4-methylenedioxymethamphetamine (MDMA, 7.5 mg/kg, i.p.), morphine (7.5 mg/kg, s.c.), or nicotine (0.4 mg/kg, s.c.), on either consecutive or alternate days (five administrations in total) in a novel environment. Seven days later, rats were re-exposed to the drug-paired environment, subjected to USVs recording, and then challenged with the same drug. Finally, 7 d after the challenge, rats were repeatedly exposed to the drug-paired environment and vocalizations were measured. Amphetamine was the only drug to stimulate 50-kHz USVs and 'trill' subtype emission during administration and challenge. Conversely, all rats emitted 50-kHz USVs when re-exposed to the test cage, and this effect was most marked in morphine-treated rats, and less evident in nicotine-treated rats. This study demonstrates that the direct and long-lasting effects of drugs on 50-kHz USVs are regulated differently, providing a better understanding of the usefulness of these vocalizations in the study of psychoactive drugs. PMID:24138707

  12. Splice variation of the mu-opioid receptor and its effect on the action of opioids

    PubMed Central

    Droney, Joanne

    2014-01-01

    Summary points An individual’s response to opioids is influenced by a complex combination of genetic, molecular and phenotypic factors. Intra- and inter-individual variations in response to mu opioids have led to the suggestion that mu-opioid receptor subtypes exist. Scientists have now proven that mu-opioid receptor subtypes exist and that they occur through a mechanism promoting protein diversity, called alternative splicing. The ability of mu opioids to differentially activate splice variants may explain some of the clinical differences observed between mu opioids. This article examines how differential activation of splice variants by mu opioids occurs through alternative mu-opioid receptor binding, through differential receptor activation, and as a result of the distinct distribution of variants located regionally and at the cellular level. PMID:26516547

  13. Repeated stress exposure causes strain-dependent shifts in the behavioral economics of cocaine in rats.

    PubMed

    Groblewski, Peter A; Zietz, Chad; Willuhn, Ingo; Phillips, Paul E M; Chavkin, Charles

    2015-03-01

    Cocaine-experienced Wistar and Wistar Kyoto (WKY) rats received four daily repeated forced swim stress sessions (R-FSS), each of which preceded 4-hour cocaine self-administration sessions. Twenty-four hours after the last swim stress, cocaine valuation was assessed during a single-session threshold procedure. Prior exposure to R-FSS significantly altered cocaine responding in Wistar, but not WKY, rats. Behavioral economic analysis of responding revealed that the Wistar rats that had received R-FSS exhibited an increase in the maximum price that they were willing to pay for cocaine (Pmax ). Pre-treatment with the long-lasting kappa opioid receptor (KOR) antagonist norbinaltorphimine prevented the stress-induced increase in Pmax . Thus, R-FSS exposure had strain-dependent effects on cocaine responding during the threshold procedure, and the stress effects on cocaine valuation exhibited by Wistar, but not WKY, required intact KOR signaling.

  14. Repeated amphetamine administration and long-term effects on 50-kHz ultrasonic vocalizations: possible relevance to the motivational and dopamine-stimulating properties of the drug.

    PubMed

    Simola, Nicola; Morelli, Micaela

    2015-03-01

    Ultrasonic vocalizations (USVs) of 50kHz are thought to indicate positive affective states in rats, and are increasingly being used to investigate the motivational properties of drugs of abuse. However, previous studies have observed that only dopaminergic psychostimulants of abuse, but not other addictive drugs, stimulate 50-kHz USVs immediately after their administration. This would suggest that 50-kHz USVs induced by addictive dopaminergic psychostimulants might reflect rewarding dopaminergic effect, rather than motivational effect. To elucidate this issue, our study compared the effects of the psychostimulant of abuse amphetamine and the dopamine receptor agonist apomorphine on 50-kHz USVs. Rats that received five drug administrations on alternate days in a novel test-cage were first re-exposed to the test-cage 7 days after treatment discontinuation to assess drug-conditioning, and then received a drug challenge. USVs were recorded throughout the experiments together with locomotor activity. To further clarify how amphetamine and apomorphine influenced 50-kHz USVs, rats were subdivided into "low" and "high" vocalizers, and time-dependence of drug effects was assessed. Amphetamine and apomorphine stimulated both 50-kHz USVs and locomotor activity, though they elicited dissimilar changes in these behaviors, depending on drug dose, rats׳ individual predisposition to vocalize, and time. Moreover, only amphetamine-treated rats displayed both sensitized 50-kHz USVs emission and conditioned vocalizations on test-cage re-exposure. These results indicate that the effects of amphetamine on 50-kHz USVs are not mimicked by a dopaminergic agonist with a low abuse potential, and may further support the usefulness of 50-kHz USVs in the study of the motivational properties of psychoactive drugs.

  15. Repeated amphetamine administration and long-term effects on 50-kHz ultrasonic vocalizations: possible relevance to the motivational and dopamine-stimulating properties of the drug.

    PubMed

    Simola, Nicola; Morelli, Micaela

    2015-03-01

    Ultrasonic vocalizations (USVs) of 50kHz are thought to indicate positive affective states in rats, and are increasingly being used to investigate the motivational properties of drugs of abuse. However, previous studies have observed that only dopaminergic psychostimulants of abuse, but not other addictive drugs, stimulate 50-kHz USVs immediately after their administration. This would suggest that 50-kHz USVs induced by addictive dopaminergic psychostimulants might reflect rewarding dopaminergic effect, rather than motivational effect. To elucidate this issue, our study compared the effects of the psychostimulant of abuse amphetamine and the dopamine receptor agonist apomorphine on 50-kHz USVs. Rats that received five drug administrations on alternate days in a novel test-cage were first re-exposed to the test-cage 7 days after treatment discontinuation to assess drug-conditioning, and then received a drug challenge. USVs were recorded throughout the experiments together with locomotor activity. To further clarify how amphetamine and apomorphine influenced 50-kHz USVs, rats were subdivided into "low" and "high" vocalizers, and time-dependence of drug effects was assessed. Amphetamine and apomorphine stimulated both 50-kHz USVs and locomotor activity, though they elicited dissimilar changes in these behaviors, depending on drug dose, rats׳ individual predisposition to vocalize, and time. Moreover, only amphetamine-treated rats displayed both sensitized 50-kHz USVs emission and conditioned vocalizations on test-cage re-exposure. These results indicate that the effects of amphetamine on 50-kHz USVs are not mimicked by a dopaminergic agonist with a low abuse potential, and may further support the usefulness of 50-kHz USVs in the study of the motivational properties of psychoactive drugs. PMID:25638025

  16. 78 FR 2676 - Draft Guidance for Industry on Abuse-Deterrent Opioids-Evaluation and Labeling; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-14

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Abuse-Deterrent Opioids-- Evaluation and Labeling; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing the availability of a draft guidance for...

  17. Endogenous opioids: a proximate reward mechanism for kin selection?

    PubMed

    D'Amato, F R; Pavone, F

    1993-07-01

    The kin selection theory predicts that individuals would behave differently toward one another, depending on their genetic relatedness. Proximate mechanisms have been postulated to exist helping the individual to discriminate what is good or bad for him. Opioids have been discovered to be involved in the mediation of reinforcement, in particular they underlay social emotion. In this study it is shown that pain sensitivity decreased in male mice interacting with siblings following 2 months of separation; this analgesic response was antagonized by naloxone administration. Interaction with unknown and unrelated subjects did not change the nociceptive threshold. These results suggest that interacting with kin is an adaptive situation reinforced, at the neural level, by the release of endogenous opioids.

  18. Fewer Injured Workers Getting Opioid Prescriptions in Some States

    MedlinePlus

    ... opioids in the 25 states in the study. Simultaneous use of opioids and sedating medications called benzodiazepines ... 1 percent to 9 percent of injured workers. Simultaneous use of opioids and muscle relaxants occurred among ...

  19. Is periconceptional opioid use safe?

    PubMed Central

    Chan, Felix; Koren, Gideon

    2015-01-01

    Abstract Question A patient in my practice who takes buprenorphine for chronic pain would like to conceive. Is it safe for her to continue taking her medication? Answer The literature regarding periconceptional opioid use is conflicted as to whether opioids pose an elevated risk of birth defects. Confounding factors such as socioeconomic status, stress, and alcohol consumption might play a role. The first trimester of pregnancy is the critical period of development for many organ systems in the embryo. A chemical or environmental insult is more likely to produce major congenital malformations such as neural tube defects or mental retardation if it occurs within this window. Medical practitioners should judiciously consider a risk-benefit analysis before making their decisions. PMID:26167561

  20. Autoradiographic localization of mu and delta opioid receptors in the mesocorticolimbic dopamine system

    SciTech Connect

    Dilts, R.P. Jr.

    1989-01-01

    In vitro autoradiographic techniques were coupled with selective chemical lesions of the A10 dopamine cells and intrinsic perikarya of the region to delineate the anatomical localization of mu and delta opioid receptors, as well as, neurotensin receptors. Mu opioid receptors were labeled with {sup 125}I-DAGO. Delta receptors were labeled with {sup 125}I-DPDPE. Neurotensin receptors were labeled with {sup 125}I-NT3. Unilateral lesions of the dopamine perikarya were produced by injections of 6-OHDA administered in the ventral mesencephalon. Unilateral lesions of intrinsic perikarya were induced by injections of quinolinic acid in to the A10 dopamine cell region. Unilateral lesions produced with 6-OHDA resulted in the loss of neurotensin receptors in the A10 region and within the terminal fields. Mu opioid receptors were unaffected by this treatment, but delta opioid receptors increased in the contralateral striatum and nucleus accumbens following 6-OHDA administration. Quinolinic acid produced a reduction of mu opioid receptors within the A10 region with a concomitant reduction in neurotensin receptors in both the cell body region and terminal fields. These results are consistent with a variety of biochemical and behavioral data which suggest the indirect modulation of dopamine transmission by the opioids. In contrast these results strongly indicate a direct modulation of the mesolimbic dopamine system by neurotensin.

  1. Individual variation in the motivational and neurobiological effects of an opioid cue.

    PubMed

    Yager, Lindsay M; Pitchers, Kyle K; Flagel, Shelly B; Robinson, Terry E

    2015-04-01

    A discrete cue associated with intravenous injections of cocaine acquires greater control over motivated behavior in some rats ('sign-trackers', STs) than others ('goal-trackers', GTs). It is not known, however, if such variation generalizes to cues associated with other drugs. We asked, therefore, whether a discrete cue (a light) associated with the intravenous administration of an opioid drug (the short-acting mu receptor agonist, remifentanil) acquires incentive motivational properties differently in STs and GTs, as indicated by tests of Pavlovian conditioned approach and conditioned reinforcement. Consistent with studies using cocaine, STs approached a classically conditioned opioid cue more readily than GTs, and in a test of conditioned reinforcement worked more avidly to get it. Interestingly, STs and GTs did not differ in the acquisition of a conditioned orienting response. In addition, the performance of conditioned approach behavior, but not conditioned orientation, was attenuated by pretreatment with the dopamine receptor antagonist, flupenthixol, into the core of the nucleus accumbens. Lastly, food and opioid cues engaged similar amygdalo-striatal-thalamic circuitry to a much greater extent in STs than GTs, as indicated by Fos expression. Taken together, these data demonstrate that, similar to food and cocaine cues: (1) a discrete opioid cue attains greater incentive motivational value in STs than GTs; (2) the attribution of incentive motivational properties to an opioid cue is dopamine dependent; and (3) an opioid cue engages the so-called 'motive circuit' only if it is imbued with incentive salience. PMID:25425322

  2. Endothelin ETA receptor antagonist reverses naloxone-precipitated opioid withdrawal in mice.

    PubMed

    Bhalla, Shaifali; Pais, Gwendolyn; Tapia, Melissa; Gulati, Anil

    2015-11-01

    Long-term use of opioids for pain management results in rapid development of tolerance and dependence leading to severe withdrawal symptoms. We have previously demonstrated that endothelin-A (ETA) receptor antagonists potentiate opioid analgesia and eliminate analgesic tolerance. This study was designed to investigate the involvement of central ET mechanisms in opioid withdrawal. The effect of intracerebroventricular administration of ETA receptor antagonist BQ123 on morphine and oxycodone withdrawal was determined in male Swiss Webster mice. Opioid tolerance was induced and withdrawal was precipitated by the opioid antagonist naloxone. Expression of ETA and ETB receptors, nerve growth factor (NGF), and vascular endothelial growth factor was determined in the brain using Western blotting. BQ123 pretreatment reversed hypothermia and weight loss during withdrawal. BQ123 also reduced wet shakes, rearing behavior, and jumping behavior. No changes in expression of vascular endothelial growth factor, ETA receptors, and ETB receptors were observed during withdrawal. NGF expression was unaffected in morphine withdrawal but significantly decreased during oxycodone withdrawal. A decrease in NGF expression in oxycodone- but not in morphine-treated mice could be due to mechanistic differences in oxycodone and morphine. It is concluded that ETA receptor antagonists attenuate opioid-induced withdrawal symptoms.

  3. Thienorphine is a potent long-acting partial opioid agonist: a comparative study with buprenorphine.

    PubMed

    Yu, Gang; Yue, Yong-Juan; Cui, Meng-Xun; Gong, Ze-Hui

    2006-07-01

    A strategy in the development of new treatment for opioid addiction is to find partial opioid agonists with properties of long duration of action and high oral bioavailability. In a search for such compounds, thienorphine, a novel analog of buprenorphine, was synthesized. Here, we reported that, like buprenorphine, thienorphine bound potently and nonselectively to mu-, delta-, and kappa-opioid receptors stably expressed in CHO (Chinese hamster ovary) cells and behaved as a partial agonist at mu-opioid receptor. However, some differences were observed between the pharmacological profiles of thienorphine and buprenorphine. In vitro, thienorphine was more potent than buprenorphine in inhibiting [3H]diprenorphine and stimulating guanosine 5'-O-(3-[35S]thio)triphosphate binding to rat mu-opioid receptor stably expressed in CHO cells. In vivo, thienorphine exhibited a less potent but more efficacious antinociceptive effect with an ED50 value of 0.25 mg/kg s.c. and more potent antimorphine effect with an ED50 value of 0.64 mg/kg intragastric, compared with buprenorphine. Additionally, the bioavailability of thienorphine was greatly higher than that of buprenorphine after oral administration. Moreover, compared with buprenorphine, thienorphine showed a similar long-lasting antinociceptive effect but a much longer antagonism of morphine-induced lethality (more than 15 days). These results indicate that thienorphine is a potent, long-acting partial opioid agonist with high oral bioavailability and may have possible application in treating addiction. PMID:16569757

  4. Repeated systemic administration of the nutraceutical alpha-linolenic acid exerts neuroprotective efficacy, an antidepressant effect and improves cognitive performance when given after soman exposure.

    PubMed

    Pan, Hongna; Piermartiri, Tetsade C B; Chen, Jun; McDonough, John; Oppel, Craig; Driwech, Wafae; Winter, Kristin; McFarland, Emylee; Black, Katelyn; Figueiredo, Taiza; Grunberg, Neil; Marini, Ann M

    2015-12-01

    Exposure to nerve agents results in severe seizures or status epilepticus caused by the inhibition of acetylcholinesterase, a critical enzyme that breaks down acetylcholine to terminate neurotransmission. Prolonged seizures cause brain damage and can lead to long-term consequences. Current countermeasures are only modestly effective against the brain damage supporting interest in the evaluation of new and efficacious therapies. The nutraceutical alpha-linolenic acid (LIN) is an essential omega-3 polyunsaturated fatty acid that has a wide safety margin. Previous work showed that a single intravenous injection of alpha-linolenic acid (500 nmol/kg) administered before or after soman significantly protected against soman-induced brain damage when analyzed 24h after exposure. Here, we show that administration of three intravenous injections of alpha-linolenic acid over a 7 day period after soman significantly improved motor performance on the rotarod, enhanced memory retention, exerted an anti-depressant-like activity and increased animal survival. This dosing schedule significantly reduced soman-induced neuronal degeneration in four major vulnerable brain regions up to 21 days. Taken together, alpha-linolenic acid reduces the profound behavioral deficits induced by soman possibly by decreasing neuronal cell death, and increases animal survival.

  5. Opioids for chronic noncancer pain

    PubMed Central

    2015-01-01

    The recent American Academy of Neurology position paper by Franklin, “Opioids for chronic noncancer pain,” suggests that the benefits of opioid treatment are very likely to be substantially outweighed by the risks and recommends avoidance of doses above 80–120 mg/day morphine equivalent. However, close reading of the primary literature supports a different conclusion: opioids have been shown in randomized controlled trials (RCTs) to be highly effective in the treatment of chronic nonmalignant pain; long-term follow-up studies have shown that this effectiveness can be maintained; and effectiveness has been limited in many clinical trials by failure to take into account high variability in dose requirements, failure to adequately treat depression, and use of suboptimal outcome measures. Frequency of side effects in many RCTs has been inflated by overly rapid dose titration and failure to appreciate the high interindividual variability in side effect profiles. The recent marked increase in incidence of opioid overdose is of grave concern, but there is good reason to believe that it has been somewhat exaggerated. Potential causes of overdose include inadequately treated depression; inadequately treated pain, particularly when compounded by hopelessness; inadvertent overdose; concurrent use of alcohol; and insufficient practitioner expertise. Effective treatment of pain can enable large numbers of patients to lead productive lives and improve quality of life. Effective alleviation of suffering associated with pain falls squarely within the physician's professional obligation. Existing scientific studies provide the basis for many improvements in pain management that can increase effectiveness and reduce risk. Many potentially useful areas of further research can be identified. PMID:26138946

  6. Development of a peptidomimetic antagonist of neuropeptide FF receptors for the prevention of opioid-induced hyperalgesia.

    PubMed

    Bihel, Frédéric; Humbert, Jean-Paul; Schneider, Séverine; Bertin, Isabelle; Wagner, Patrick; Schmitt, Martine; Laboureyras, Emilie; Petit-Demoulière, Benoît; Schneider, Elodie; Mollereau, Catherine; Simonnet, Guy; Simonin, Frédéric; Bourguignon, Jean-Jacques

    2015-03-18

    Through the development of a new class of unnatural ornithine derivatives as bioisosteres of arginine, we have designed an orally active peptidomimetic antagonist of neuropeptide FF receptors (NPFFR). Systemic low-dose administration of this compound to rats blocked opioid-induced hyperalgesia, without any apparent side-effects. Interestingly, we also observed that this compound potentiated opioid-induced analgesia. This unnatural ornithine derivative provides a novel therapeutic approach for both improving analgesia and reducing hyperalgesia induced by opioids in patients being treated for chronic pain.

  7. Chronic Pain and the Opioid Conundrum.

    PubMed

    Webster, Lynn R

    2016-06-01

    Opioids prescribed for chronic cancer and noncancer pain have been embroiled in public policy debates as to effectiveness and potential for contributing to society's problem with misuse, addiction, and overdose mortality. The conundrum of opioid prescribing is to determine who will most likely benefit from opioids and how medical practitioners may safely provide chronic opioid therapy, while also identifying patients who are unlikely to benefit or could divert illicit pharmaceuticals into society. Risk assessment and monitoring are essential to meet the standard of care, as is compliance with federal controlled substances law as well as state regulations. PMID:27208714

  8. The toxicity and distribution of iron oxide-zinc oxide core-shell nanoparticles in C57BL/6 mice after repeated subcutaneous administration.

    PubMed

    Yun, Jun-Won; Yoon, Jung-Hee; Kang, Byeong-Cheol; Cho, Nam-Hyuk; Seok, Seung Hyeok; Min, Seung-Kee; Min, Ji Hyun; Che, Jeong-Hwan; Kim, Young Keun

    2015-06-01

    Therapeutic cancer vaccines promote immune responses by delivering tumour-specific antigens. Recently, we developed iron oxide (Fe3 O4 )-zinc oxide (ZnO) core-shell nanoparticles (CSNPs) as carriers for antigen delivery into dendritic cells (DCs), and the CSNPs were injected subcutaneously into C57BL/6 mice to examine the systemic toxicity, tissue distribution and excretion of the CSNPs. The doses injected were 0, 4, 20 and 200 mg kg(-1) weekly for 4 weeks. No significant changes were observed after the CSNPs administration with respect to mortality, clinical observations, body weight, food intake, water consumption, urinalysis, haematology, serum biochemistry,and organ weights. A dose-dependent increase in granulomatous inflammation was observed at the injection site of the CSNP-treated animals, but no other histopathological lesions in other organs could be attributed to the CSNPs. The Zn concentration, which is an indicator for CSNPs, was not significantly higher in the sampled tissues, urine, or faeces after the CSNP injection. In contrast, the Zn concentration at the subcutaneous skin of the site injected with the CSNPs increased in a dose-dependent manner, along with a macroscopic deposition of the CSNPs. The CSNP residue at the injection site resulted in a foreign body response with the appearance of macrophage infiltration, but otherwise did not show any systemic distribution or toxicity at up to 200 mg kg(-1) during this study. In conclusion, CSNPs could be used as good antigen carriers for DC-based immunotherapy, although further study is needed to completely clear the residue of the CSNPs at the injection site.

  9. Gene expression changes induced by ochratoxin A in renal and hepatic tissues of male F344 rat after oral repeated administration

    SciTech Connect

    Arbillaga, Leire; Vettorazzi, Ariane; Gil, Ana G; Garcia-Jalon, Jose Antonio

    2008-07-15

    Ochratoxin A (OTA), a naturally occurring mycotoxin, is nephrotoxic in all animal species tested and is considered a potent renal carcinogen, particularly in male rats. Its mechanism of toxicity is still unknown, although oxidative stress appears to be a plausible mechanism. Therefore, the objective of this study was to identify the biological pathways that are modulated in vivo by OTA in male F344 rats in order to gain further insight into its mechanism of renal toxicity. Rats were gavaged daily with OTA (500 {mu}g/kg bw) and gene expression profiles in target and non-target organs were analyzed after 7 and 21 days administration. As was expected, a time-dependent increase of OTA concentrations was found in plasma, kidney and liver, with the concentrations found in both tissues being quite similar. However, histopathological examinations only revealed changes in kidney; signs of nephrotoxicity involving single cell necrosis and karyomegalic nuclei were observed in the treated rats. The number of differentially expressed genes in kidney was much higher than in liver (541 versus 11 at both time points). Several similarities were observed with other in vivo gene expression data. However, great differences were found with previous in vitro gene expression data, with the exception of DNA damage response which was not observed at mRNA level in any of our study conditions. Down-regulation was the predominant effect. Oxidative stress response pathway and genes involved in metabolism and transport were inhibited at both time points. RGN (regucalcin) - a gene implicated in calcium homeostasis - was strongly inhibited at both time points and genes implicated in cell survival and proliferation were up-regulated at day 21. Moreover, translation factors and annexin genes were up-regulated at both time points. Apart from oxidative stress, alterations of the calcium homeostasis and cytoskeleton structure may be present at the first events of OTA toxicity.

  10. The influence of divalent cations on the analgesic effect of opioid and non-opioid drugs.

    PubMed

    Assi, A A

    2001-06-01

    It is generally accepted that divalent cations are involved in the nociceptive pathway. The effect of systemic co-administration of magnesium sulfate and calcium channel blockers (nifedipine, verapamil) on the analgesic effect of opioid (mixed mu/kappa: butorphanol) and non-opioid drugs (paracetamol) was investigated. Albino mice and rats were used as experimental animals. Magnesium sulfate and calcium channel blockers were given i.p., 30 min before the administration of butorphanol tartrate and paracetamol. Analgesia was measured using "hot-plate" ( 52.5( composite function)C), "tail-flick" (radiant heat source), "writhing" (acetic acid, 1%, i.p.) and "tail-clip" tests. The pain threshold was evaluated before and after the administration (i.p.) of the different agents. The effect of the combined administration of different agents on behavior, blood pressure and heart rate, was also determined. Nifedipine (5 mg kg(-1), i.p.) and verapamil (10 mg kg(-1), i.p.) potentiated the analgesic effect of butorphanol tartrate (0.25-2 mg kg(-1), i.p.) in all tests (synergism) and enhanced analgesic effect of paracetamol (50-125 mg kg(-1), i.p.), only in acetic acid writhing and tail-clip tests. Magensium sulfate (2.5 mg kg(-1), i.p.) potentiated the analgesic effect of butorphanol, but not that of paracetamol. Co-administration of nifedipine and verapamil with either of butorphanol (0.25-2 mg kg(-1)) or paracetamol (50-125 mg kg(-1), i.p.) produced no significant effects on motor coordination, motor performance, locomotor activity, long-term memory or on the blood pressure and heart rate of experimental animals. Co-administration of magnesium sulfate, however, significantly induced sedation, inhibition of locomotor activity, motor performance and coordination, as well as impairing of long-term memory, as compared with butorphanol and paracetamol, administered alone. We conclude that the systemic co-administration of calcium channel blockers potentiated the analgesic effect of

  11. Time-Scheduled versus Pain-Contingent Opioid Dosing in Chronic Opioid Therapy

    PubMed Central

    Von Korff, Michael; Merrill, Joseph O.; Rutter, Carolyn M.; Sullivan, Mark; Campbell, Cynthia I.; Weisner, Constance

    2011-01-01

    Some expert guidelines recommend time-scheduled opioid dosing over pain-contingent dosing for patients receiving chronic opioid therapy (COT). The premise is that time-scheduled dosing results in more stable opioid blood levels and better pain relief, fewer side effects, less reinforcement of pain behaviors, and lower addiction risk. We report results of a survey of 1781 patients receiving COT for chronic non-cancer pain, in which 967 reported time-scheduled opioid dosing only and 325 reported pain-contingent opioid dosing only. Opioid-related problems and concerns were assessed with the Prescribed Opioids Difficulties Scale. We hypothesized that respondents using time-scheduled opioid dosing would report significantly fewer problems and concerns than those using pain-contingent dosing. Patients receiving time-scheduled dosing received substantially higher average daily opioid doses than those using pain-contingent dosing (97.2 vs. 37.2 milligrams average daily dose morphine equivalents, p<.0001). Contrary to expectation, time-scheduled opioid dosing was associated with higher levels of patient opioid control concerns than pain-contingent dosing (6.2 vs. 4.8, p=.008), after adjusting for patient and drug regimen differences. Opioid-related psychosocial problems were somewhat greater among patients using time-scheduled dosing, but this difference was non-significant after controlling for patient and drug regimen differences (5.9 versus 5.0, p=.14). Time-scheduled dosing typically involved higher dosage levels and was associated with higher levels of patient concerns about opioid use. Controlled comparative effectiveness research is needed to assess benefits and risks of time-scheduled opioid dosing relative to pain-contingent opioid dosing among COT patients in ambulatory care. PMID:21296498

  12. Prescription Opioid Duration, Dose, and Increased Risk of Depression in 3 Large Patient Populations

    PubMed Central

    Scherrer, Jeffrey F.; Salas, Joanne; Copeland, Laurel A.; Stock, Eileen M.; Ahmedani, Brian K.; Sullivan, Mark D.; Burroughs, Thomas; Schneider, F. David; Bucholz, Kathleen K.; Lustman, Patrick J.

    2016-01-01

    PURPOSE Recent results suggests the risk of a new onset of depression increases with longer duration of opioid analgesic use. It is unclear whether new-onset depression related to opioid analgesic use is a function of the dose prescribed or the duration of use or both. METHODS Using a retrospective cohort design, we collected patient data from 2000 to 2012 from the Veterans Health Administration (VHA), and from 2003 to 2012 from both Baylor Scott & White Health (BSWH) and the Henry Ford Health System (HFHS). Patients (70,997 VHA patients, 13,777 BSWH patients, and 22,981 HFHS patients) were new opioid users, aged 18 to 80 years, without a diagnosis of depression at baseline. Opioid analgesic use duration was defined as 1 to 30, 31 to 90, and more than 90 days, and morphine equivalent dose (MED) was defined as 1 to 50 mg/d, 51 to 100 mg/d, and greater than 100 mg/d of analgesic. Pain and other potential confounders were controlled for by inverse probability of treatment–weighted propensity scores. RESULTS New-onset depression after opioid analgesic use occurred in 12% of the VHA sample, 9% of the BSWH sample, and 11% of the HFHS sample. Compared with 1- to 30-day users, new-onset depression increased in those with longer opioid analgesic use. Risk of new-onset depression with 31 to 90 days of opioid analgesic use ranged from hazard ratio [HR] = 1.18 (95% CI, 1.10–1.25) in VHA to HR = 1.33 (95% CI, 1.16–1.52) in HFHS; in opioid analgesic use of more than 90 days, it ranged from HR = 1.35 (95% CI, 1.26–1.44) in VHA to HR = 2.05 (95% CI, 1.75–2.40) in HFHS. Dose was not significantly associated with a new onset of depression. CONCLUSIONS Opioid-related new onset of depression is associated with longer duration of use but not dose. Patients and practitioners should be aware that opioid analgesic use of longer than 30 days imposes risk of new-onset depression. Opioid analgesic use, not just pain, should be considered a potential source when patients report

  13. The role of opioid antagonist efficacy and constitutive opioid receptor activity in the opioid withdrawal syndrome in mice.

    PubMed

    Navani, Dipesh M; Sirohi, Sunil; Madia, Priyanka A; Yoburn, Byron C

    2011-10-01

    On the basis of efficacy, opioid antagonists are classified as inverse opioid agonists (e.g. naltrexone) or neutral opioid antagonists (e.g. 6β-naltrexol). This study examined the interaction between naltrexone and 6β-naltrexol in the precipitated opioid withdrawal syndrome in morphine dependent mice. Furthermore, the possible contribution of constitutive opioid receptor activity to precipitated withdrawal was evaluated using increasing levels of morphine dependence. In the first experiment, low doses of 6β-naltrexol antagonized naltrexone precipitated withdrawal while high doses acted additively. All doses of naltrexone increased 6β-naltrexol's potency to precipitate withdrawal. The next experiment examined changes in antagonist potency to precipitate withdrawal with increasing morphine dependence. Mice were exposed to morphine for 1-6 days and then withdrawal was precipitated. Naltrexone was more potent than 6β-naltrexol at all the time points. The ED(50) of both drugs decreased at the same rate suggesting that increased dependence produced no change in constitutive opioid receptor activity. Taken together these results indicate that the functional efficacy of 6β-naltrexol is dose-dependent and that constitutive opioid receptor activity did not change as opioid dependence increased from 1 to 6 days. PMID:21736895

  14. The role of opioid antagonist efficacy and constitutive opioid receptor activity in the opioid withdrawal syndrome in mice.

    PubMed

    Navani, Dipesh M; Sirohi, Sunil; Madia, Priyanka A; Yoburn, Byron C

    2011-10-01

    On the basis of efficacy, opioid antagonists are classified as inverse opioid agonists (e.g. naltrexone) or neutral opioid antagonists (e.g. 6β-naltrexol). This study examined the interaction between naltrexone and 6β-naltrexol in the precipitated opioid withdrawal syndrome in morphine dependent mice. Furthermore, the possible contribution of constitutive opioid receptor activity to precipitated withdrawal was evaluated using increasing levels of morphine dependence. In the first experiment, low doses of 6β-naltrexol antagonized naltrexone precipitated withdrawal while high doses acted additively. All doses of naltrexone increased 6β-naltrexol's potency to precipitate withdrawal. The next experiment examined changes in antagonist potency to precipitate withdrawal with increasing morphine dependence. Mice were exposed to morphine for 1-6 days and then withdrawal was precipitated. Naltrexone was more potent than 6β-naltrexol at all the time points. The ED(50) of both drugs decreased at the same rate suggesting that increased dependence produced no change in constitutive opioid receptor activity. Taken together these results indicate that the functional efficacy of 6β-naltrexol is dose-dependent and that constitutive opioid receptor activity did not change as opioid dependence increased from 1 to 6 days.

  15. Mesenchymal Stem Cells Reversed Morphine Tolerance and Opioid-induced Hyperalgesia.

    PubMed

    Hua, Zhen; Liu, LiPing; Shen, Jun; Cheng, Katherine; Liu, Aijun; Yang, Jing; Wang, Lina; Qu, Tingyu; Yang, HongNa; Li, Yan; Wu, Haiyan; Narouze, John; Yin, Yan; Cheng, Jianguo

    2016-08-24

    More than 240 million opioid prescriptions are dispensed annually to treat pain in the US. The use of opioids is commonly associated with opioid tolerance (OT) and opioid-induced hyperalgesia (OIH), which limit efficacy and compromise safety. The dearth of effective way to prevent or treat OT and OIH is a major medical challenge. We hypothesized that mesenchymal stem cells (MSCs) attenuate OT and OIH in rats and mice based on the understanding that MSCs possess remarkable anti-inflammatory properties and that both OT and chronic pain are associated with neuroinflammation in the spinal cord. We found that the development of OT and OIH was effectively prevented by either intravenous or intrathecal MSC transplantation (MSC-TP), which was performed before morphine treatment. Remarkably, established OT and OIH were significantly reversed by either intravenous or intrathecal MSCs when cells were transplanted after repeated morphine injections. The animals did not show any abnormality in vital organs or functions. Immunohistochemistry revealed that the treatments significantly reduced activation level of microglia and astrocytes in the spinal cord. We have thus demonstrated that MSC-TP promises to be a potentially safe and effective way to prevent and reverse two of the major problems of opioid therapy.

  16. Mesenchymal Stem Cells Reversed Morphine Tolerance and Opioid-induced Hyperalgesia

    PubMed Central

    Hua, Zhen; Liu, LiPing; Shen, Jun; Cheng, Katherine; Liu, Aijun; Yang, Jing; Wang, Lina; Qu, Tingyu; Yang, HongNa; Li, Yan; Wu, Haiyan; Narouze, John; Yin, Yan; Cheng, Jianguo

    2016-01-01

    More than 240 million opioid prescriptions are dispensed annually to treat pain in the US. The use of opioids is commonly associated with opioid tolerance (OT) and opioid-induced hyperalgesia (OIH), which limit efficacy and compromise safety. The dearth of effective way to prevent or treat OT and OIH is a major medical challenge. We hypothesized that mesenchymal stem cells (MSCs) attenuate OT and OIH in rats and mice based on the understanding that MSCs possess remarkable anti-inflammatory properties and that both OT and chronic pain are associated with neuroinflammation in the spinal cord. We found that the development of OT and OIH was effectively prevented by either intravenous or intrathecal MSC transplantation (MSC-TP), which was performed before morphine treatment. Remarkably, established OT and OIH were significantly reversed by either intravenous or intrathecal MSCs when cells were transplanted after repeated morphine injections. The animals did not show any abnormality in vital organs or functions. Immunohistochemistry revealed that the treatments significantly reduced activation level of microglia and astrocytes in the spinal cord. We have thus demonstrated that MSC-TP promises to be a potentially safe and effective way to prevent and reverse two of the major problems of opioid therapy. PMID:27554341

  17. Mesenchymal Stem Cells Reversed Morphine Tolerance and Opioid-induced Hyperalgesia.

    PubMed

    Hua, Zhen; Liu, LiPing; Shen, Jun; Cheng, Katherine; Liu, Aijun; Yang, Jing; Wang, Lina; Qu, Tingyu; Yang, HongNa; Li, Yan; Wu, Haiyan; Narouze, John; Yin, Yan; Cheng, Jianguo

    2016-01-01

    More than 240 million opioid prescriptions are dispensed annually to treat pain in the US. The use of opioids is commonly associated with opioid tolerance (OT) and opioid-induced hyperalgesia (OIH), which limit efficacy and compromise safety. The dearth of effective way to prevent or treat OT and OIH is a major medical challenge. We hypothesized that mesenchymal stem cells (MSCs) attenuate OT and OIH in rats and mice based on the understanding that MSCs possess remarkable anti-inflammatory properties and that both OT and chronic pain are associated with neuroinflammation in the spinal cord. We found that the development of OT and OIH was effectively prevented by either intravenous or intrathecal MSC transplantation (MSC-TP), which was performed before morphine treatment. Remarkably, established OT and OIH were significantly reversed by either intravenous or intrathecal MSCs when cells were transplanted after repeated morphine injections. The animals did not show any abnormality in vital organs or functions. Immunohistochemistry revealed that the treatments significantly reduced activation level of microglia and astrocytes in the spinal cord. We have thus demonstrated that MSC-TP promises to be a potentially safe and effective way to prevent and reverse two of the major problems of opioid therapy. PMID:27554341

  18. Sex differences in opioid analgesia and addiction: interactions among opioid receptors and estrogen receptors

    PubMed Central

    2013-01-01

    Opioids are widely used as the pain reliever and also notorious for being addictive drugs. Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear. Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids. The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated. We postulate that the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators. PMID:24010861

  19. Selectively Promiscuous Opioid Ligands: Discovery of High Affinity/Low Efficacy Opioid Ligands with Substantial Nociceptin Opioid Peptide Receptor Affinity

    PubMed Central

    2015-01-01

    Emerging clinical and preclinical evidence suggests that a compound displaying high affinity for μ, κ, and δ opioid (MOP, KOP, and DOP) receptors and antagonist activity at each, coupled with moderate affinity and efficacy at nociceptin opioid peptide (NOP) receptors will have utility as a relapse prevention agent for multiple types of drug abuse. Members of the orvinol family of opioid ligands have the desired affinity profile but have typically displayed substantial efficacy at MOP and or KOP receptors. In this study it is shown that a phenyl ring analogue (1d) of buprenorphine displays the desired profile in vitro with high, nonselective affinity for the MOP, KOP, and DOP receptors coupled with moderate affinity for NOP receptors. In vivo, 1d lacked any opioid agonist activity and was an antagonist of both the MOP receptor agonist morphine and the KOP receptor agonist ethylketocyclazocine, confirming the desired opioid receptor profile in vivo. PMID:24761755

  20. Modulation of MDMA-induced behavioral and transcriptional effects by the delta opioid antagonist naltrindole in mice

    PubMed Central

    Belkaï, Emilie; Scherrmann, Jean-Michel; Noble, Florence; Marie-Claire, Cynthia

    2009-01-01

    The delta opioid system is involved in the behavioral effects of various drugs of abuse. However, only few studies have focused on the possible interactions between the opioid system and the effects of MDMA. In order to examine the possible role of the delta opioid system in MDMA-induced behaviors in mice, locomotor activity and conditioned place preference were investigated in the presence of naltrindole, a selective delta opioid antagonist. Moreover, the consequences of acute and chronic MDMA administration on Penk (pro-enkephalin) and Pomc (pro-opioimelanocortin) gene expression were assessed by quantitative real-time PCR. The results showed that, after acute MDMA administration (9mg/kg; i.p.), naltrindole (5mg/kg, s.c.) was able to totally block MDMA-induced hyperlocomotion. Penk expression gene was not modulated by acute MDMA but a decrease of Pomc gene expression was observed that was not antagonized by naltrindole. Administration of the antagonist prevented the acquisition of MDMA-induced conditioned place preference, suggesting an implication of the delta opioid receptors in this behavior. Following chronic MDMA treatment only the level of Pomc was modulated. The observed increase was totally blocked by naltrindole pretreatment. All these results confirm the interactions between the delta opioid system (receptors and peptides) and the effects of MDMA. PMID:19523041

  1. Targeted Opioid Receptor Antagonists in the Treatment of Alcohol Use Disorders

    PubMed Central

    Niciu, Mark J.

    2015-01-01

    In 1994, the US Food and Drug Administration approved the μ-opioid receptor antagonist naltrexone to treat alcohol dependence. However, treatments requiring daily administration, such as naltrexone, are inconsistently adhered to in substance abusing populations, and constant medication exposure can increase risk of adverse outcomes, e.g., hepatotoxicity. This has fostered a ‘targeted’ or ‘as needed’ approach to opioid receptor antagonist treatment, in which medications are used only in anticipation of or during high-risk situations, including times of intense cravings. Initial studies of the ability of targeted naltrexone to reduce drinking-related outcomes were conducted in problem drinkers and have been extended into larger, multi-site, placebo-controlled investigations with positive results. Another μ-opioid receptor antagonist, nalmefene, has been studied on an ‘as-needed’ basis to reduce heavy drinking in alcohol-dependent individuals. These studies include three large multi-site trials in Europe of up to 1 year in duration, and serve as the basis for the recent approval of nalmefene by the European Medicines Agency as an ‘as-needed’ adjunctive treatment for alcohol dependence. We review potential moderators of opioid receptor antagonist treatment response including subjective assessments, objective clinical measures and genetic variants. In sum, the targeted or ‘as-needed’ approach to treatment with opioid antagonists is an efficacious harmreduction strategy for problem drinking and alcohol dependence. PMID:23881605

  2. Opioid neonatal abstinence syndrome: controversies and implications for practice.

    PubMed

    Wolff, Kim; Perez-Montejano, Raul

    2014-01-01

    The Opioid Neonatal Abstinence Syndrome (NAS) is a term used to describe a cluster of signs and symptoms seen in infants experiencing withdrawal from opioid drugs. Despite a substantial literature the relationship between maternal methadone dose, NAS and the method of assessment of NAS symptoms has not been agreed. The following review will address current and historical controversies surrounding these issues and will examine the evidence concerned with the evaluation of neonates exposed to methadone in utero. The key findings are as follows: A variety of NAS scales are used to assess the severity of neonatal withdrawal symptoms including locally adapted validated tools. Inconsistencies in the use of NAS scales have included the timing, duration and frequency of administration; the degree to which observers were trained to reliability; the use of NAS scales designed for term neonates to assess pre-term neonates who may have a qualitatively different expression of abstinence symptoms and; the research setting in which the tool was administered. There is a lack of research investigating the observant bias' effect upon scoring NAS, the basis for treatment decisions and the influence of concomitant maternal use of non-opioid drugs late in pregnancy. We also discuss the implications of the lack of recognition of NAS symptoms leading to possible under reporting and inappropriate, early neonatal discharge from hospital. In addition, this paper also discusses the merits and problems of conducting research in this area and highlights gaps in our knowledge and areas for further research.

  3. Does the kappa opioid receptor system contribute to pain aversion?

    PubMed Central

    Cahill, Catherine M.; Taylor, Anna M. W.; Cook, Christopher; Ong, Edmund; Morón, Jose A.; Evans, Christopher J.

    2014-01-01

    The kappa opioid receptor (KOR) and the endogenous peptide-ligand dynorphin have received significant attention due the involvement in mediating a variety of behavioral and neurophysiological responses, including opposing the rewarding properties of drugs of abuse including opioids. Accumulating evidence indicates this system is involved in regulating states of motivation and emotion. Acute activation of the KOR produces an increase in motivational behavior to escape a threat, however, KOR activation associated with chronic stress leads to the expression of symptoms indicative of mood disorders. It is well accepted that KOR can produce analgesia and is engaged in chronic pain states including neuropathic pain. Spinal studies have revealed KOR-induced analgesia in reversing pain hypersensitivities associated with peripheral nerve injury. While systemic administration of KOR agonists attenuates nociceptive sensory transmission, this effect appears to be a stress-induced effect as anxiolytic agents, including delta opioid receptor agonists, mitigate KOR agonist-induced analgesia. Additionally, while the role of KOR and dynorphin in driving the dysphoric and aversive components of stress and drug withdrawal has been well characterized, how this system mediates the negative emotional states associated with chronic pain is relatively unexplored. This review provides evidence that dynorphin and the KOR system contribute to the negative affective component of pain and that this receptor system likely contributes to the high comorbidity of mood disorders associated with chronic neuropathic pain. PMID:25452729

  4. Impact of chronic morphine on delta opioid receptor-expressing neurons in the mouse hippocampus.

    PubMed

    Erbs, E; Faget, L; Ceredig, R A; Matifas, A; Vonesch, J-L; Kieffer, B L; Massotte, D

    2016-01-28

    Delta opioid (DOP) receptors participate to the control of chronic pain and emotional responses. Recent data also identified their implication in spatial memory and drug-context associations pointing to a critical role of hippocampal delta receptors. To better appreciate the impact of repeated drug exposure on their modulatory activity, we used fluorescent knock-in mice that express a functional delta receptor fused at its carboxy-terminus with the green fluorescent protein in place of the native receptor. We then tested the impact of chronic morphine treatment on the density and distribution of delta receptor-expressing cells in the hippocampus. A decrease in delta receptor-positive cell density was observed in the CA1, CA3 and dentate gyrus without alteration of the distribution across the different GABAergic populations that mainly express delta receptors. This effect partly persisted after four weeks of morphine abstinence. In addition, we observed increased DOP receptor expression at the cell surface compared to saline-treated animals. In the hippocampus, chronic morphine administration thus induces DOP receptor cellular redistribution and durably decreases delta receptor-expressing cell density. Such modifications are likely to alter hippocampal physiology, and to contribute to long-term cognitive deficits.

  5. Opioid risk assessment in palliative medicine.

    PubMed

    Dale, Rebecca; Edwards, Jeremy; Ballantyne, Jane

    2016-03-01

    Pain management with opioids is an integral part of palliative medicine. As the doses and durations of opioid therapy increase, the inherent risks of opioid therapy rise. Although opioids are effective analgesics, they bring with them complex medical and psychological side effects. Aberrant behavior is dangerous and can be difficult to identify as it results in a splitting in the goals of treatment between the patient and providers. One effective strategy in preventing that situation is through the early identification of at-risk patients. There are several tools that can help identify patients at higher risk of addiction and aberrant behaviors during opioid therapy. Structured use of these tools in conjunction with the clinic exam, regular follow-up visits, and lab testing can further reduce patient risk and improve success in opioid therapy. This article will review the background behind a structured strategy for opioid risk assessment using the Opioid Risk Tool, SOAPP-R, and DIRE tools. In addition, example aberrant behaviors and follow-up strategies will be reviewed. It will be demonstrated that careful screening and follow-up allow risk factors to be recognized and addressed early. PMID:27058865

  6. Bi- or multifunctional opioid peptide drugs.

    PubMed

    Schiller, Peter W

    2010-04-10

    Strategies for the design of bi- or multifunctional drugs are reviewed. A distinction is made between bifunctional drugs interacting in a monovalent fashion with two targets and ligands containing two distinct pharmacophores binding in a bivalent mode to the two binding sites in a receptor heterodimer. Arguments are presented to indicate that some of the so-called "bivalent" ligands reported in the literature are unlikely to simultaneously interact with two binding sites. Aspects related to the development of bi- or multifunctional drugs are illustrated with examples from the field of opioid analgesics. The drug-like properties of the tetrapeptide Dmt(1)[DALDA] with triple action as a micro opioid agonist, norepinephrine uptake inhibitor and releaser of endogenous opioid peptides to produce potent spinal analgesia are reviewed. Rationales for the development of opioid peptides with mixed agonist/antagonist profiles as analgesics with reduced side effects are presented. Progress in the development of mixed micro opioid agonist/delta opioid antagonists with low propensity to produce tolerance and physical dependence is reviewed. Efforts to develop bifunctional peptides containing a micro opioid agonist and a cholecystokinin antagonist or an NK1 receptor antagonist as analgesics expected to produce less tolerance and dependence are also reviewed. A strategy to improve the drug-like properties of bifunctional opioid peptide analgesics is presented.

  7. Shedding "UV" light on endogenous opioid dependence.

    PubMed

    Tejeda, Hugo A; Bonci, Antonello

    2014-06-19

    Excessive sun tanning can result in addictive behavior. In this issue of Cell, Fell et al. utilize a combination of behavioral pharmacology and transgenic mice to demonstrate that chronic UV light exposure recruits p53 signaling in keratinocytes, subsequently increasing β-endorphin signaling at opioid receptors, and produces an endogenous opioid-dependent state.

  8. Opioid-Induced Hyperalgesia: A Diagnostic Dilemma.

    PubMed

    Carullo, Veronica; Fitz-James, Ingrid; Delphin, Ellise

    2015-01-01

    Opioids are utilized frequently for the treatment of moderate to severe acute pain in the perioperative setting, as well as in the treatment of cancer-related pain. When prescribing chronic opioid therapy to patients with chronic pain, it is crucial for the practitioner to be aware not only of the issues of tolerance and withdrawal, but also to have knowledge of the possibility for opioid-induced hyperalgesia (OIH). An understanding of the differences between tolerance and OIH when escalating opioid therapy allows the titration of opioid as well as nonopioid analgesics in order to obtain maximum control of both chronic and acute pain. A case study is described to highlight the importance of judicious utilization of opioids in the treatment of cancer-related pain. In this case, high-dose opioid therapy did not improve chronic pain and contributed to a hyperalgesic state in which a young man experienced severe intractable pain postoperatively after two routine thoracotomies, despite aggressive pharmacologic measures to manage his perioperative pain. Furthermore, it illustrates the potential advantages of opioid rotation to methadone when OIH is suspected.

  9. Shedding "UV" light on endogenous opioid dependence.

    PubMed

    Tejeda, Hugo A; Bonci, Antonello

    2014-06-19

    Excessive sun tanning can result in addictive behavior. In this issue of Cell, Fell et al. utilize a combination of behavioral pharmacology and transgenic mice to demonstrate that chronic UV light exposure recruits p53 signaling in keratinocytes, subsequently increasing β-endorphin signaling at opioid receptors, and produces an endogenous opioid-dependent state. PMID:24949960

  10. kappa-Opioid receptor signaling and brain reward function.

    PubMed

    Bruijnzeel, Adrie W

    2009-12-11

    The dynorphin-like peptides have profound effects on the state of the brain reward system and human and animal behavior. The dynorphin-like peptides affect locomotor activity, food intake, sexual behavior, anxiety-like behavior, and drug intake. Stimulation of kappa-opioid receptors, the endogenous receptor for the dynorphin-like peptides, inhibits dopamine release in the striatum (nucleus accumbens and caudate putamen) and induces a negative mood state in humans and animals. The administration of drugs of abuse increases the release of dopamine in the striatum and mediates the concomitant release of dynorphin-like peptides in this brain region. The reviewed studies suggest that chronic drug intake leads to an upregulation of the brain dynorphin system in the striatum and in particular in the dorsal part of the striatum/caudate putamen. This might inhibit drug-induced dopamine release and provide protection against the neurotoxic effects of high dopamine levels. After the discontinuation of chronic drug intake these neuroadaptations remain unopposed which has been suggested to contribute to the negative emotional state associated with drug withdrawal and increased drug intake. kappa-Opioid receptor agonists have also been shown to inhibit calcium channels. Calcium channel inhibitors have antidepressant-like effects and inhibit the release of norepinephrine. This might explain that in some studies kappa-opioid receptor agonists attenuate nicotine and opioid withdrawal symptomatology. A better understanding of the role of dynorphins in the regulation of brain reward function might contribute to the development of novel treatments for mood disorders and other disorders that stem from a dysregulation of the brain reward system.

  11. Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain.

    PubMed

    Labuz, Dominika; Celik, Melih Ö; Zimmer, Andreas; Machelska, Halina

    2016-01-01

    Neuropathic pain often results from peripheral nerve damage, which can involve immune response. Local leukocyte-derived opioid peptides or exogenous opioid agonists inhibit neuropathy-induced mechanical hypersensitivity in animal models. Since neuropathic pain can also be augmented by heat, in this study we investigated the role of opioids in the modulation of neuropathy-evoked heat hypersensitivity. We used a chronic constriction injury of the sciatic nerve in wild-type and opioid peptide-knockout mice, and tested opioid effects in heat and mechanical hypersensitivity using Hargreaves and von Frey tests, respectively. We found that although perineural exogenous opioid agonists, including peptidergic ligands, were effective, the endogenous opioid peptides β-endorphin, Met-enkephalin and dynorphin A did not alleviate heat hypersensitivity. Specifically, corticotropin-releasing factor, an agent triggering opioid peptide secretion from leukocytes, applied perineurally did not attenuate heat hypersensitivity in wild-type mice. Exogenous opioids, also shown to release opioid peptides via activation of leukocyte opioid receptors, were equally analgesic in wild-type and opioid peptide-knockout mice, indicating that endogenous opioids do not contribute to exogenous opioid analgesia in heat hypersensitivity. Furthermore, exogenously applied opioid peptides were ineffective as well. Conversely, opioid peptides relieved mechanical hypersensitivity. Thus, both opioid type and sensory modality may determine the outcome of neuropathic pain treatment. PMID:27605249

  12. Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain

    PubMed Central

    Labuz, Dominika; Celik, Melih Ö.; Zimmer, Andreas; Machelska, Halina

    2016-01-01

    Neuropathic pain often results from peripheral nerve damage, which can involve immune response. Local leukocyte-derived opioid peptides or exogenous opioid agonists inhibit neuropathy-induced mechanical hypersensitivity in animal models. Since neuropathic pain can also be augmented by heat, in this study we investigated the role of opioids in the modulation of neuropathy-evoked heat hypersensitivity. We used a chronic constriction injury of the sciatic nerve in wild-type and opioid peptide-knockout mice, and tested opioid effects in heat and mechanical hypersensitivity using Hargreaves and von Frey tests, respectively. We found that although perineural exogenous opioid agonists, including peptidergic ligands, were effective, the endogenous opioid peptides β-endorphin, Met-enkephalin and dynorphin A did not alleviate heat hypersensitivity. Specifically, corticotropin-releasing factor, an agent triggering opioid peptide secretion from leukocytes, applied perineurally did not attenuate heat hypersensitivity in wild-type mice. Exogenous opioids, also shown to release opioid peptides via activation of leukocyte opioid receptors, were equally analgesic in wild-type and opioid peptide-knockout mice, indicating that endogenous opioids do not contribute to exogenous opioid analgesia in heat hypersensitivity. Furthermore, exogenously applied opioid peptides were ineffective as well. Conversely, opioid peptides relieved mechanical hypersensitivity. Thus, both opioid type and sensory modality may determine the outcome of neuropathic pain treatment. PMID:27605249

  13. Tonic inhibitory control exerted by opioid peptides in the paraventricular nuclei of the hypothalamus on regional hemodynamic activity in rats.

    PubMed

    Lessard, Andrée; Bachelard, Hélène

    2002-07-01

    1. Systemic and regional cardiovascular changes were measured following bilateral microinjection of specific and selective opioid-receptor antagonists into the paraventricular nuclei of the hypothalamus (PVN) of awake, freely moving rats. 2. PVN microinjection of increasing doses of the specific opioid antagonist naloxone - methiodide (1 - 5.0 nmol), or a selective mu-opioid receptor antagonist, beta-funaltrexamine (0.05 - 0.5 nmol), evoked important cardiovascular changes characterized by small and transient increases in heart rate (HR) and mean arterial pressure (MAP), vasoconstriction in renal and superior mesenteric vascular beds and vasodilation in the hindquarter vascular bed. 3. No significant cardiovascular changes were observed following PVN administration of the highly selective delta-opioid-receptor antagonist, ICI 174864 (0.1 - 1 nmol), or the selective kappa-opioid-receptor antagonist, nor-binaltorphine (0.1 - 1 nmol). 4. Most of the cardiovascular responses to naloxone (3 nmol) and beta-funaltrexamine (0.5 nmol) were attenuated or abolished by an i.v. treatment with a specific vasopressin V(1) receptor antagonist. 5. These results suggest that endogenous opioid peptides and mu-type PVN opioid receptors modulate a tonically-active central depressor pathway acting on systemic and regional haemodynamic systems. Part of this influence could involve a tonic inhibition of vasopressin release.

  14. Tonic inhibitory control exerted by opioid peptides in the paraventricular nuclei of the hypothalamus on regional hemodynamic activity in rats

    PubMed Central

    Lessard, Andrée; Bachelard, Hélène

    2002-01-01

    Systemic and regional cardiovascular changes were measured following bilateral microinjection of specific and selective opioid-receptor antagonists into the paraventricular nuclei of the hypothalamus (PVN) of awake, freely moving rats.PVN microinjection of increasing doses of the specific opioid antagonist naloxone – methiodide (1 – 5.0 nmol), or a selective μ-opioid receptor antagonist, β-funaltrexamine (0.05 – 0.5 nmol), evoked important cardiovascular changes characterized by small and transient increases in heart rate (HR) and mean arterial pressure (MAP), vasoconstriction in renal and superior mesenteric vascular beds and vasodilation in the hindquarter vascular bed.No significant cardiovascular changes were observed following PVN administration of the highly selective δ-opioid-receptor antagonist, ICI 174864 (0.1 – 1 nmol), or the selective κ-opioid-receptor antagonist, nor-binaltorphine (0.1 – 1 nmol).Most of the cardiovascular responses to naloxone (3 nmol) and β-funaltrexamine (0.5 nmol) were attenuated or abolished by an i.v. treatment with a specific vasopressin V1 receptor antagonist.These results suggest that endogenous opioid peptides and μ-type PVN opioid receptors modulate a tonically-active central depressor pathway acting on systemic and regional haemodynamic systems. Part of this influence could involve a tonic inhibition of vasopressin release. PMID:12086985

  15. A Review of Opioid Overdose Prevention and Naloxone Prescribing: Implications for Translating Community Programming into Clinical Practice

    PubMed Central

    Mueller, Shane R.; Walley, Alexander Y.; Calcaterra, Susan L.; Glanz, Jason M.; Binswanger, Ingrid A.

    2015-01-01

    Background As physicians have increased opioid prescribing, overdose deaths from pharmaceutical opioids have substantially increased in the United States. Naloxone hydrochloride (naloxone), an opioid antagonist, is the standard of care for treatment of opioid induced respiratory depression. Since 1996, community-based programs have offered overdose prevention education and distributed naloxone for bystander administration to people who use opioids, particularly heroin. There is growing interest in translating overdose education and naloxone distribution (OEND) into conventional medical settings for patients who are prescribed pharmaceutical opioids. For this review, we summarized and classified existing publications on overdose education and naloxone distribution to identify evidence of effectiveness and opportunities for translation into conventional medical settings. Methods For this review, we searched English language PubMed for articles on naloxone based on primary data collection from humans, including feasibility studies, program evaluations, surveys, qualitative studies and studies comparing the effectiveness of different routes of naloxone administration. We also included cost-effectiveness studies. Results We identified 41 articles that represented 5 categories: evaluations of OEND programs, effects of OEND programs on experiences and attitudes of participants, willingness of medical providers to prescribe naloxone, comparisons of different routes of naloxone administration, and the cost-effectiveness of naloxone. Conclusions Existing research suggests that people who are at risk for overdose and other bystanders are willing and able to be trained to prevent overdoses and administer naloxone. Counseling patients about the risks of opioid overdose and prescribing naloxone is an emerging clinical practice which may reduce fatalities from overdose while enhancing the safe prescribing of opioids. PMID:25774771

  16. Increased Burden of Healthcare Utilization and Cost Associated with Opioid-Related Constipation Among Patients with Noncancer Pain

    PubMed Central

    Fernandes, Ancilla W.; Kern, David M.; Datto, Catherine; Chen, Yen-Wen; McLeskey, Charles; Tunceli, Ozgur

    2016-01-01

    Background Opioids are widely accepted as treatment for moderate to severe pain, and opioid-induced constipation is one of the most common side effects of opioids. This side effect negatively affects pain management and patients’ quality of life, which could result in increased healthcare utilization and costs. Objective To assess healthcare utilization and costs (all-cause, constipation-related, and pain-related) for individuals with and without opioid-induced constipation during the 12 months after initiation of opioid therapy for noncancer pain. Methods This retrospective cohort study was conducted using administrative claims data from HealthCore Integrated Research Environment between January 1, 2006, and June 30, 2014. The analysis was limited to patients aged ≥18 years who filled a prescription for continuous opioid treatment (≥28 days) for noncancer pain. Propensity scores were used to match opioid users with constipation (cohort 1) and opioid users without constipation (cohort 2), using a 1:1 ratio. Generalized linear models were used to estimate all-cause, constipation-related, and pain-related healthcare utilization and costs during the 12 months after the initiation of opioid therapy. Results After matching and balancing for all prespecified variables, 17,384 patients were retained in each cohort (mean age, 56 years; 63% female). Opioid users with constipation were twice as likely as those without constipation to have ≥1 inpatient hospitalizations (odds ratio, 2.28; 95% confidence interval [CI], 2.17–2.39) during the 12 months. The total mean adjusted overall costs per patient during the study period were $12,413 higher for patients with constipation versus those without it (95% CI, $11,726–$13,116). The total mean adjusted overall pain-related costs per patient were $6778 (95% CI, $6293–$7279) higher for the patients with constipation than those without. Among patients using opioids for noncancer pain, the annual mean constipation

  17. Patterns of opioid analgesic prescription among patients with osteoarthritis.

    PubMed

    Dominick, Kelli L; Bosworth, Hayden B; Dudley, Tara K; Waters, Sandra J; Campbell, Lisa C; Keefe, Francis J

    2004-01-01

    This study describes patterns of opioid analgesic prescription during a one-year period among a sample of patients with osteoarthritis (OA). The study sample included 3,061 patients with prior ICD-9 codes indicating a diagnosis of OA who were treated at a federal Veterans Affairs Medical Center. Specific opioid variables included: any opioid prescription, number of specific opioid drugs prescribed, total number of opioid prescriptions, total number of days supply of opioids, and daily opioid doses. We also examined relationships of demographic characteristics to opioid variables. Results revealed that 41% of patients received at least one opioid prescription. Opioids were prescribed significantly less frequently among African-Americans than Caucasians and the number of opioid prescriptions declined with increasing age. The mean annual supply of opioids was 104 days. Days' supply of opioids was also lower for African Americans and older patients. Daily opioid doses were, on average, below recommended daily doses for the treatment of OA. Findings of this study suggest that opioids are frequently prescribed to individuals with OA and that these drugs may be gaining acceptability for the treatment of chronic musculoskeletal pain. Additional research is needed to examine reasons for racial differences in opioid prescribing, as well as the prescription of these medications at fairly low doses.

  18. Determination of substance overdose in two Iranian centers: comparison between opioids and non-opioids.

    PubMed

    Taghaddosinejad, Fakhreddin; Arefi, Mohammad; Fayaz, Amir Farshid; Tanhaeivash, Roozbeh

    2013-04-01

    Recently, new trend toward non-opioid substances is observed in Iran. This is, therefore, to compare overdose of opioids and non-opioids origin. We performed this investigation to provide more detailed information so that preventive actions are taken in future. Over 18 month, 1876 individuals with opioid (opium, heroin, compact-heroin, buprenorphine and opiates) or non-opioid (MDMA (ecstasy), LSD, hashish and cocaine) overdose were selected. They have been compared regarding sex, age, reason of overdose, method of substance use, occupation, marital status, history of addiction in parents/siblings, duration of hospital admission and educational level. There were 1782 and 94 persons with opioid and non-opioid, respectively. Inhalation was the method of choice and women were found to have more tendencies to hallucinogens rather opioids. Moreover, use of non-opioids was observed more in individuals with university education and moreover in whom none of whose parents/siblings was addict. Policies should be planned by the governments to prevent further addictions especially to non-opioids.

  19. Denial of urinalysis-confirmed opioid use in prescription opioid dependence

    PubMed Central

    Hilario, E. Yvette; Griffin, Margaret L.; McHugh, R. Kathryn; McDermott, Katherine A.; Connery, Hilary S.; Fitzmaurice, Garrett M.; Weiss, Roger D.

    2014-01-01

    Although research has generally supported the validity of substance use self-reports, some patients deny urine-verified substance use. We examined the prevalence and patterns of denying urinalysis-confirmed opioid use in a sample of prescription opioid dependent patients. We also identified characteristics associated with denial in this population of increasing public health concern. Opioid use self-reports were compared with weekly urinalysis results in a 12-week multi-site treatment study for prescription opioid dependence. Among those who used opioids during the trial (n=246/360), 44.3% (n=109) denied urinalysis-confirmed opioid use, although usually only once (78%). Overall, 22.9% of opioid-positive urine tests (149/650) were denied on self-report. Multivariable analysis found that initially using opioids to relieve pain was associated with denying opioid use. These findings support the use of both self-reports and urine testing in treating prescription opioid dependence. PMID:25115135

  20. Pharmacological Profiles of Oligomerized μ-Opioid Receptors

    PubMed Central

    Lee, Cynthia Wei-Sheng; Ho, Ing-Kang

    2013-01-01

    Opioids are widely prescribed pain relievers with multiple side effects and potential complications. They produce analgesia via G-protein-protein coupled receptors: μ-, δ-, κ-opioid and opioid receptor-like 1 receptors. Bivalent ligands targeted to the oligomerized opioid receptors might be the key to developing analgesics without undesired side effects and obtaining effective treatment for opioid addicts. In this review we will update the biological effects of μ-opioids on homo- or hetero-oligomerized μ-opioid receptor and discuss potential mechanisms through which bivalent ligands exert beneficial effects, including adenylate cyclase regulation and receptor-mediated signaling pathways. PMID:24709876

  1. Impact of a Standardized Treatment Guideline for Pediatric Iatrogenic Opioid Dependence: A Quality Improvement Initiative

    PubMed Central

    Reyburn-Orne, Teri; Youssef, Tarek H.; Haddad, Imad Y.; Gerkin, Richard D.

    2016-01-01

    OBJECTIVES: To determine whether utilization of a hospital-based clinical practice guideline for the care of pediatric iatrogenic opioid dependence (IOD) would promote a decrease in opioid exposure and improve management of opioid abstinence syndrome (AS). METHODS: This study is a retrospective chart review of critically ill patients from a tertiary care children's hospital. Inclusion criteria included mechanically ventilated patients up to 18 years of age who received continuous opioid infusions for at least 7 days and any length of methadone administration. Data on IOD patients from January 2005 to June 2010 was divided into 3 periods: baseline, phase 1, and phase 2. Primary outcome was decrease in opioid exposure, measured by methadone duration of use and any additional opioid bolus doses used in AS management. Documentation of additional opioid bolus doses was regarded as a surrogate measure of AS. Secondary outcomes included total cumulative fentanyl dose, continuous fentanyl infusion duration of use, and hospital and pediatric intensive care unit length of stay. RESULTS: There was a significant decrease in methadone duration of use in IOD patients from 15.3 ± 8.7 days at baseline to 9.5 ± 3.7 days during phase 1 (p = 0.002), to 8.1 ± 3.7 days on phase 2 (reduction not significant, p = 0.106) of this evaluation. Additional opioid bolus doses were significantly lower from baseline to phase 1 (5.5 ± 5.1 vs. 1.8 ± 2.3, p = 0.001) and from phase 1 to phase 2 (1.8 ± 2.3 vs. 0.2 ± 1.5, p = 0.003). For the remaining outcomes, differences were not observed among the evaluation periods, except for the total cumulative fentanyl dose, which was reduced from 2.8 ± 3.7 mg/kg at baseline to 1 ± 1 mg/kg only during phase 1 (p = 0.017). CONCLUSIONS: Introduction of a standardized, hospital-based clinical practice guideline for children with IOD reduced the length of exposure to opioids and improved opioid AS management. PMID:26997929

  2. Opioid modulation of ingestive behavior.

    PubMed

    Jalowiec, J E; Panksepp, J; Zolovick, A J; Najam, N; Herman, B H

    1981-09-01

    Supportive evidence for an important role of endogenous opioid systems in modulation of ingestive behaviors is presented. Low doses of morphine (1.0-5.0 mg/kg) increase and low doses of naloxone (0.5-2.5 mg/kg) decrease food and water intake during both acute and chronic testing in mildly-deprived rats. Chronic infusions of naloxone with implanted osmotic mini-pumps elicited sustained dose-related suppression of food, water, and saccharin solution intakes but did not reduce ingestion of 10.0% glucose solution or food following 12 hr deprivation. Finally, naloxone treatment did not antagonize nocturnal ingestion of food any more than it reduced day time feeding when the latter was enhanced by prior food deprivation. These results indicate that an opiate agonist and an opiate antagonist modify ingestive behaviors oppositely, affirming that endogenous opioid systems may be involved in control of feeding and drinking. However, their role may be restricted to only indirect participation in homeostatic regulation via neural systems modulating emotional tone or goal-directed behaviors in general.

  3. Novel diazabicycloalkane delta opioid agonists.

    PubMed

    Loriga, Giovanni; Lazzari, Paolo; Manca, Ilaria; Ruiu, Stefania; Falzoi, Matteo; Murineddu, Gabriele; Bottazzi, Mirko Emilio Heiner; Pinna, Giovanni; Pinna, Gérard Aimè

    2015-09-01

    Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80.

  4. Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice.

    PubMed

    Oberdick, John; Ling, Yonghua; Phelps, Mitch A; Yudovich, Max S; Schilling, Karl; Sadee, Wolfgang

    2016-07-01

    Prolonged fetal exposure to opioids results in neonatal abstinence syndrome (NAS), a major medical problem requiring intensive care and increased hospitalization times for newborns with NAS. Multiple strategies are currently available to alleviate withdrawal in infants with NAS. To prevent NAS caused by opioid maintenance programs in pregnant women, blocking fetal dependence without compromising the mother's opiate therapy is desirable. Here we tested in pregnant mice whether a peripherally selective opioid antagonist can preferentially enter the fetal brain and, thereby, in principle, selectively protect the fetus. We show using mass spectrometry that 6β-naltrexol, a neutral opioid antagonist with very limited ability to cross the blood-brain barrier (BBB), readily crosses the placental barrier and enters the fetal brain at high levels, although it is relatively excluded from the maternal brain. Furthermore, owing to the late development of the BBB in postnatal mice, we show that 6β-naltrexol can readily enter the juvenile mouse brain until at least postnatal day 14. Taking advantage of this observation, we show that long-term exposure to morphine starting in the second postnatal week causes robust and quantifiable dependence behaviors that are suppressed by concomitant administration of 6β-naltrexol with much greater potency (ID50 0.022-0.044 mg/kg, or 1/500 the applied dose of morphine) than previously demonstrated for either the suppression of central nervous system opioid effects or the induction of withdrawal in adults. These results indicate that peripherally selective opioid antagonists capable of penetrating the placenta may be beneficial for preventing or reducing neonatal dependence and NAS in a dose range that should not interfere with maternal opioid maintenance. PMID:27189967

  5. Use of preoperative gabapentin significantly reduces postoperative opioid consumption: a meta-analysis

    PubMed Central

    Arumugam, Sudha; Lau, Christine SM; Chamberlain, Ronald S

    2016-01-01

    Objectives Effective postoperative pain management is crucial in the care of surgical patients. Opioids, which are commonly used in managing postoperative pain, have a potential for tolerance and addiction, along with sedating side effects. Gabapentin’s use as a multimodal analgesic regimen to treat neuropathic pain has been documented as having favorable side effects. This meta-analysis examined the use of preoperative gabapentin and its impact on postoperative opioid consumption. Materials and methods A comprehensive literature search was conducted to identify randomized control trials that evaluated preoperative gabapentin on postoperative opioid consumption. The outcomes of interest were cumulative opioid consumption following the surgery and the incidence of vomiting, somnolence, and nausea. Results A total of 1,793 patients involved in 17 randomized control trials formed the final analysis for this study. Postoperative opioid consumption was reduced when using gabapentin within the initial 24 hours following surgery (standard mean difference −1.35, 95% confidence interval [CI]: −1.96 to −0.73; P<0.001). There was a significant reduction in morphine, fentanyl, and tramadol consumption (P<0.05). While a significant increase in postoperative somnolence incidence was observed (relative risk 1.30, 95% CI: 1.10–1.54, P<0.05), there were no significant effects on postoperative vomiting and nausea. Conclusion The administration of preoperative gabapentin reduced the consumption of opioids during the initial 24 hours following surgery. The reduction in postoperative opioids with preoperative gabapentin increased postoperative somnolence, but no significant differences were observed in nausea and vomiting incidences. The results from this study demonstrate that gabapentin is more beneficial in mastectomy and spinal, abdominal, and thyroid surgeries. Gabapentin is an effective analgesic adjunct, and clinicians should consider its use in multimodal treatment

  6. Predator-scent stress, ethanol consumption and the opioid system in an animal model of PTSD.

    PubMed

    Manjoch, Hadar; Vainer, Ella; Matar, Michael; Ifergane, Gal; Zohar, Joseph; Kaplan, Zeev; Cohen, Hagit

    2016-06-01

    Emerging literature points to stress exposure as a potential contributor to the development of alcohol abuse, but animal models have yielded inconsistent results. Converging experimental data indicate that the endogenous opioid system modulates alcohol consumption and stress regulation. The aim of the present study is to examine the interplay between stress exposure, behavioral stress responses, ethanol (EtOH) consumption and the endogenous opioid system in an animal model of posttraumatic stress disorder. Rats were exposed to stress and then tested in a two-bottle free choice (TBC) assay or in a conditioned place preference paradigm. In some experiments, the endogenous opioid system was pharmacologically manipulated prior to stress exposure. The behavioral outcomes of stress exposure were assessed in an elevated plus-maze, with the acoustic startle response, and by monitoring the freezing response to trauma reminder. Immunoreactivity of phosphorylated opioid receptors in hippocampal subregions was also measured. Stress significantly increased the consumption of EtOH in the TBC assay. The severity of the behavioral response to stress was associated with EtOH consumption, cue-triggered freezing response to a trauma reminder, and endogenous levels of phosphorylated opioid receptors in the hippocampus. Pharmacologically manipulating the endogenous opioid system prior to stress exposure attenuated trauma cue-triggered freezing responses and blocked predator scent stress-induced potentiation of EtOH consumption. These data demonstrate a stress-induced potentiation of EtOH self-administration and reveal a clear association between individual patterns of the behavioral response to stress and alcohol preference, while indicating a role for the endogenous opioid system in the neurobiological response to stress. PMID:26965572

  7. Antinociceptive action of isolated mitragynine from Mitragyna Speciosa through activation of opioid receptor system.

    PubMed

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

    2012-01-01

    Cannabinoids and opioids systems share numerous pharmacological properties and antinociception is one of them. Previous findings have shown that mitragynine (MG), a major indole alkaloid found in Mitragyna speciosa (MS) can exert its antinociceptive effects through the opioids system. In the present study, the action of MG was investigated as the antinociceptive agent acting on Cannabinoid receptor type 1 (CB1) and effects on the opioids receptor. The latency time was recorded until the mice showed pain responses such as shaking, licking or jumping and the duration of latency was measured for 2 h at every 15 min interval by hot plate analysis. To investigate the beneficial effects of MG as antinociceptive agent, it was administered intraperitoneally 15 min prior to pain induction with a single dosage (3, 10, 15, 30, and 35 mg/kg b.wt). In this investigation, 35 mg/kg of MG showed significant increase in the latency time and this dosage was used in the antagonist receptor study. The treated groups were administered with AM251 (cannabinoid receptor-1 antagonist), naloxone (non-selective opioid antagonist), naltrindole (δ-opioid antagonist) naloxonazine (μ(1)-receptor antagonist) and norbinaltorpimine (κ-opioid antagonist) respectively, prior to administration of MG (35 mg/kg). The results showed that the antinociceptive effect of MG was not antagonized by AM251; naloxone and naltrindole were effectively blocked; and norbinaltorpimine partially blocked the antinociceptive effect of MG. Naloxonazine did inhibit the effect of MG, but it was not statistically significant. These results demonstrate that CB1 does not directly have a role in the antinociceptive action of MG where the effect was observed with the activation of opioid receptor. PMID:23109863

  8. Antinociceptive Action of Isolated Mitragynine from Mitragyna Speciosa through Activation of Opioid Receptor System

    PubMed Central

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

    2012-01-01

    Cannabinoids and opioids systems share numerous pharmacological properties and antinociception is one of them. Previous findings have shown that mitragynine (MG), a major indole alkaloid found in Mitragyna speciosa (MS) can exert its antinociceptive effects through the opioids system. In the present study, the action of MG was investigated as the antinociceptive agent acting on Cannabinoid receptor type 1 (CB1) and effects on the opioids receptor. The latency time was recorded until the mice showed pain responses such as shaking, licking or jumping and the duration of latency was measured for 2 h at every 15 min interval by hot plate analysis. To investigate the beneficial effects of MG as antinociceptive agent, it was administered intraperitoneally 15 min prior to pain induction with a single dosage (3, 10, 15, 30, and 35 mg/kg b.wt). In this investigation, 35 mg/kg of MG showed significant increase in the latency time and this dosage was used in the antagonist receptor study. The treated groups were administered with AM251 (cannabinoid receptor-1 antagonist), naloxone (non-selective opioid antagonist), naltrindole (δ-opioid antagonist) naloxonazine (μ1-receptor antagonist) and norbinaltorpimine (κ-opioid antagonist) respectively, prior to administration of MG (35 mg/kg). The results showed that the antinociceptive effect of MG was not antagonized by AM251; naloxone and naltrindole were effectively blocked; and norbinaltorpimine partially blocked the antinociceptive effect of MG. Naloxonazine did inhibit the effect of MG, but it was not statistically significant. These results demonstrate that CB1 does not directly have a role in the antinociceptive action of MG where the effect was observed with the activation of opioid receptor. PMID:23109863

  9. Antinociceptive action of isolated mitragynine from Mitragyna Speciosa through activation of opioid receptor system.

    PubMed

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

    2012-01-01

    Cannabinoids and opioids systems share numerous pharmacological properties and antinociception is one of them. Previous findings have shown that mitragynine (MG), a major indole alkaloid found in Mitragyna speciosa (MS) can exert its antinociceptive effects through the opioids system. In the present study, the action of MG was investigated as the antinociceptive agent acting on Cannabinoid receptor type 1 (CB1) and effects on the opioids receptor. The latency time was recorded until the mice showed pain responses such as shaking, licking or jumping and the duration of latency was measured for 2 h at every 15 min interval by hot plate analysis. To investigate the beneficial effects of MG as antinociceptive agent, it was administered intraperitoneally 15 min prior to pain induction with a single dosage (3, 10, 15, 30, and 35 mg/kg b.wt). In this investigation, 35 mg/kg of MG showed significant increase in the latency time and this dosage was used in the antagonist receptor study. The treated groups were administered with AM251 (cannabinoid receptor-1 antagonist), naloxone (non-selective opioid antagonist), naltrindole (δ-opioid antagonist) naloxonazine (μ(1)-receptor antagonist) and norbinaltorpimine (κ-opioid antagonist) respectively, prior to administration of MG (35 mg/kg). The results showed that the antinociceptive effect of MG was not antagonized by AM251; naloxone and naltrindole were effectively blocked; and norbinaltorpimine partially blocked the antinociceptive effect of MG. Naloxonazine did inhibit the effect of MG, but it was not statistically significant. These results demonstrate that CB1 does not directly have a role in the antinociceptive action of MG where the effect was observed with the activation of opioid receptor.

  10. Use of preoperative gabapentin significantly reduces postoperative opioid consumption: a meta-analysis

    PubMed Central

    Arumugam, Sudha; Lau, Christine SM; Chamberlain, Ronald S

    2016-01-01

    Objectives Effective postoperative pain management is crucial in the care of surgical patients. Opioids, which are commonly used in managing postoperative pain, have a potential for tolerance and addiction, along with sedating side effects. Gabapentin’s use as a multimodal analgesic regimen to treat neuropathic pain has been documented as having favorable side effects. This meta-analysis examined the use of preoperative gabapentin and its impact on postoperative opioid consumption. Materials and methods A comprehensive literature search was conducted to identify randomized control trials that evaluated preoperative gabapentin on postoperative opioid consumption. The outcomes of interest were cumulative opioid consumption following the surgery and the incidence of vomiting, somnolence, and nausea. Results A total of 1,793 patients involved in 17 randomized control trials formed the final analysis for this study. Postoperative opioid consumption was reduced when using gabapentin within the initial 24 hours following surgery (standard mean difference −1.35, 95% confidence interval [CI]: −1.96 to −0.73; P<0.001). There was a significant reduction in morphine, fentanyl, and tramadol consumption (P<0.05). While a significant increase in postoperative somnolence incidence was observed (relative risk 1.30, 95% CI: 1.10–1.54, P<0.05), there were no significant effects on postoperative vomiting and nausea. Conclusion The administration of preoperative gabapentin reduced the consumption of opioids during the initial 24 hours following surgery. The reduction in postoperative opioids with preoperative gabapentin increased postoperative somnolence, but no significant differences were observed in nausea and vomiting incidences. The results from this study demonstrate that gabapentin is more beneficial in mastectomy and spinal, abdominal, and thyroid surgeries. Gabapentin is an effective analgesic adjunct, and clinicians should consider its use in multimodal treatment

  11. Psychotherapeutic benefits of opioid agonist therapy.

    PubMed

    Tenore, Peter L

    2008-01-01

    Opioids have been used for centuries to treat a variety of psychiatric conditions with much success. The so-called "opium cure" lost popularity in the early 1950s with the development of non-addictive tricyclic antidepressants and monoamine oxidase inhibitors. Nonetheless, recent literature supports the potent role of methadone, buprenorphine, tramadol, morphine, and other opioids as effective, durable, and rapid therapeutic agents for anxiety and depression. This article reviews the medical literature on the treatment of psychiatric disorders with opioids (notably, methadone and buprenorphine) in both the non-opioid-dependent population and in the opioid-dependent methadone maintenance population. The most recent neurotransmitter theories on the origin of depression and anxiety will be reviewed, including current information on the role of serotonin, N-Methyl d-Aspartate, glutamate, cortisol, catecholamine, and dopamine in psychiatric disorders. The observation that methadone maintenance patients with co-existing psychiatric morbidity (so called dual diagnosis patients) require substantially higher methadone dosages by between 20% and 50% will be explored and qualified. The role of methadone and other opioids as beneficial psychiatric medications that are independent of their drug abuse mitigating properties will be discussed. The mechanisms by which methadone and other opioids can favorably modulate the neurotransmitter systems controlling mood will also be discussed.

  12. Involvement of kappa type opioids on ethanol drinking

    SciTech Connect

    Sandi, C.; Borrell, J.; Guaza, C.

    1988-01-01

    The effects of the administration of the kappa agonist dynorphin/sub 1/..sqrt../sub 17/ andor the kappa antagonist MR-2266-BS on ethanol preference was investigated using a paradigm by which rats develop alcohol preference. Administration of dynorphin shortly before or after the conditioning session (forced ethanol exposure) failed to affect later ethanol preference. However, dynorphin treatment prior to the first choice session reduced ethanol preference during the three consecutive testing days. This effect was reversed by the simultaneous administration of the kappa antagonist MR-2266-BS. The results of the present study provide further support for evidence of the involvement of dynorphinergic systems on drinking behavior and suggest that kappa-type opioid mechanisms may be involved in the consumption and development of preference to ethanol in rats. 32 references, 3 figures, 2 tables

  13. Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain - new perspective of opioid-induced hyperalgesia.

    PubMed

    Ram, Kerstin Carlin; Eisenberg, Elon; Haddad, May; Pud, Dorit

    2008-10-15

    Opioids can elicit unexpected changes in pain sensitivity, known as opioid-induced hyperalgesia (OIH). The aim of this study was to explore whether OIH exists in patients with chronic pain treated with oral opioids (OP) versus non-opioid (NOP) analgesics. The sensitivity to cold pain and the magnitude of diffuse noxious inhibitory control (DNIC) were evaluated in 73 OP and 37 NOP treated patients. Pain threshold, intensity and tolerance in response to the cold pressor (1 degrees C) were measured. DNIC was tested by co-administrating conditioned heat stimulation (47 degrees C) to the left forearm and a conditioning stimulation of 12 degrees C for 30s to the right hand. The results showed no differences between the two groups in any of the cold pain measures. In contrast, the magnitude of DNIC was significantly larger in the NOP than in the OP treated patients (p=0.003). A gender based analysis showed a significant difference in DNIC between OP and NOP treated men only. However, a mixed model ANOVA demonstrated a significant effect of treatment (OP versus NOP) (F=5.928, p=0.017) rather than gender on DNIC. A regression analysis showed that opioid dosage and treatment duration had a significant negative effect on the magnitude of DNIC in OP treated men (beta=-2.175, p=0.036 and beta=-2.061, p=0.047, respectively). In conclusion, oral opioids usage for the treatment of chronic pain does not result in abnormal sensitivity to cold pain, but seems to alter pain modulation. The use of 'advanced' psychophysics tests such as evaluation of DNIC can help understanding the phenomenon of OIH. PMID:18583047

  14. Genetics of Opioid Dependence: A Review of the Genetic Contribution to Opioid Dependence

    PubMed Central

    Mistry, Chetna J; Bawor, Monica; Desai, Dipika; Marsh, David C; Samaan, Zainab

    2014-01-01

    This narrative review aims to provide an overview of the impact of opioid dependence and the contribution of genetics to opioid dependence. Epidemiological data demonstrate that opioid dependence is a global trend with far-reaching effects on the social, economic, and health care systems. A review of classical genetic studies of opioid use suggests significant heritability of drug use behavior, however the evidence from molecular genetic studies is inconclusive. Nonetheless, certain genetic variants are important to consider given their role in the pathophysiology of addictive behavior. We undertook a literature review to identify the current state of knowledge regarding the role of genes in opioid dependence. Determining the association of genetic markers could change the current understanding of the various factors contributing to opioid dependence and therefore may improve recognition of individuals at risk for the disorder and prevention and treatment strategies. PMID:25242908

  15. Dmt and opioid peptides: a potent alliance.

    PubMed

    Bryant, Sharon D; Jinsmaa, Yunden; Salvadori, Severo; Okada, Yoshio; Lazarus, Lawrence H

    2003-01-01

    The introduction of the Dmt (2',6'-dimethyl-L-tyrosine)-Tic pharmacophore into the design of opioid ligands produced an extraordinary family of potent delta-opioid receptor antagonists and heralded a new phase in opioid research. First reviewed extensively in 1998, the incorporation of Dmt into a diverse group of opioid molecules stimulated the opioid field leading to the development of unique analogues with remarkable properties. This overview will document the crucial role played by this residue in the proliferation of opioid peptides with high receptor affinity (K(i) equal to or less than 1 nM) and potent bioactivity. The discussion will include the metamorphosis between delta-opioid receptor antagonists to delta-agonists based solely on subtle structural changes at the C-terminal region of the Dmt-Tic pharmacophore as well as their behavior in vivo. Dmt may be considered promiscuous due to the acquisition of potent mu-agonism by dermorphin and endomorphin derivatives as well as by a unique class of opioidmimetics containing two Dmt residues separated by alkyl or pyrazinone linkers. Structural studies on the Dmt-Tic compounds were enhanced tremendously by x-ray diffraction data for three potent and biologically diverse Dmt-Tic opioidmimetics that led to the development of pharmacophores for both delta-opioid receptor agonists and antagonists. Molecular modeling studies of other unique Dmt opioid analogues illuminated structural differences between delta- and mu-receptor ligand interactions. The future of these compounds as therapeutic applications for various medical syndromes including the control of cancer-associated pain is only a matter of time and perseverance.

  16. Long-term course of opioid addiction.

    PubMed

    Hser, Yih-Ing; Evans, Elizabeth; Grella, Christine; Ling, Walter; Anglin, Douglas

    2015-01-01

    Opioid addiction is associated with excess mortality, morbidities, and other adverse conditions. Guided by a life-course framework, we review the literature on the long-term course of opioid addiction in terms of use trajectories, transitions, and turning points, as well as other factors that facilitate recovery from addiction. Most long-term follow-up studies are based on heroin addicts recruited from treatment settings (mostly methadone maintenance treatment), many of whom are referred by the criminal justice system. Cumulative evidence indicates that opioid addiction is a chronic disorder with frequent relapses. Longer treatment retention is associated with a greater likelihood of abstinence, whereas incarceration is negatively related to subsequent abstinence. Over the long term, the mortality rate of opioid addicts (overdose being the most common cause) is about 6 to 20 times greater than that of the general population; among those who remain alive, the prevalence of stable abstinence from opioid use is low (less than 30% after 10-30 years of observation), and many continue to use alcohol and other drugs after ceasing to use opioids. Histories of sexual or physical abuse and comorbid mental disorders are associated with the persistence of opioid use, whereas family and social support, as well as employment, facilitates recovery. Maintaining opioid abstinence for at least five years substantially increases the likelihood of future stable abstinence. Recent advances in pharmacological treatment options (buprenorphine and naltrexone) include depot formulations offering longer duration of medication; their impact on the long-term course of opioid addiction remains to be assessed.

  17. Recent advances in abuse-deterrent technologies for the delivery of opioids.

    PubMed

    Maincent, Julien; Zhang, Feng

    2016-08-20

    Over the past decade, the abuse of prescription opioid drugs has become a national health crisis in the United States. Pharmaceutical companies, the Food and Drug Administration, and other government agencies are confronting opioid abuse by developing and commercializing various abuse-deterrent drug delivery technologies. To deter opioid abuse, various strategies including physical barriers, chemical barriers, antagonists, aversive agents, and prodrugs have been investigated. A number of drug products with abuse-deterrent properties have been approved by the FDA over the last six years, while many products and technologies with progressively-improved abuse-deterrence properties are currently being evaluated. This article provides a comprehensive review of the material sciences principles that govern the formulation and processing of a wide range of abuse-deterrent products and technologies. PMID:27291971

  18. Evaluation of US Federal Legislation for Opioid Abuse: 1973-2016.

    PubMed

    Ruble, James H

    2016-09-01

    The 114th Congress (2014-2016) has received recent attention for the high number of legislative bills directed to the public health crisis in prescription opioid abuse. The US government does not have a single source for determining public policy; however, the people expect that there will be some level of efficiency and coordination between federal and state leaders to improve the nation's health. A search of the National Library of Congress database to analyze legislative bills introduced between 1973 and 2016 and which contain the term "opioid" identified 127 bills that characterize consistency and coordination with other governmental efforts in prescription opioid abuse. Despite the recent number of introduced bills, there does not appear to be a close coordination between Congress and Federal Administrative agencies regarding this crisis. PMID:27585641

  19. Evaluation of US Federal Legislation for Opioid Abuse: 1973-2016.

    PubMed

    Ruble, James H

    2016-09-01

    The 114th Congress (2014-2016) has received recent attention for the high number of legislative bills directed to the public health crisis in prescription opioid abuse. The US government does not have a single source for determining public policy; however, the people expect that there will be some level of efficiency and coordination between federal and state leaders to improve the nation's health. A search of the National Library of Congress database to analyze legislative bills introduced between 1973 and 2016 and which contain the term "opioid" identified 127 bills that characterize consistency and coordination with other governmental efforts in prescription opioid abuse. Despite the recent number of introduced bills, there does not appear to be a close coordination between Congress and Federal Administrative agencies regarding this crisis.

  20. Gaps in the evidence base of opioids for refractory breathlessness. A future work plan?

    PubMed

    Johnson, Miriam J; Abernethy, Amy P; Currow, David C

    2012-03-01

    Breathlessness or "shortness of breath," medically termed dyspnea, remains a devastating problem for many people and those who care for them. As a treatment intervention, administration of opioids to relieve breathlessness is an area where progress has been made with the development of an evidence base. As evidence in support of opioids has accumulated, so has our collective understanding about trial methodology, research collaboration, and infrastructure that is crucial to generate reliable research results for palliative care clinical settings. Analysis of achievements to date and what it takes to accomplish these studies provides important insights into knowledge gaps needing further research and practical insight into design of pharmacological and nonpharmacological intervention trials in breathlessness and palliative care. This article presents the current understanding of opioids for treating breathlessness, what is still unknown as priorities for future research, and highlights methodological issues for consideration in planned studies.

  1. Pharmacological and genetic manipulation of kappa opioid receptors: effects on cocaine- and pentylenetetrazol-induced convulsions and seizure kindling.

    PubMed

    Kaminski, Rafal M; Witkin, Jeffrey M; Shippenberg, Toni S

    2007-03-01

    The present study used pharmacological and gene ablation techniques to examine the involvement of kappa opioid receptors (KOPr) in modulating the convulsant effects of two mechanistically different drugs: cocaine and pentylenetetrazol (PTZ; GABA-A receptor antagonist) in mice. Systemic administration of the selective KOPr-1 agonist, U69593 (0.16-0.6mg/kg; s.c.), failed to modify cocaine-evoked convulsions or cocaine kindling. Similarly, no alteration in responsiveness to cocaine was observed in wild-type mice that received the selective KOPr-1 antagonist, nor-binaltorphimine (nor-BNI; 5mg/kg) or in mice lacking the gene encoding KOPr-1. In contrast to cocaine, U69593 attenuated the seizures induced by acute or repeated PTZ administration. Nor-BNI decreased the threshold for PTZ-evoked seizures and increased seizure incidence during the initial induction of kindling relative to controls. Decreased thresholds for PTZ-induced seizures were also observed in KOPr-1 knock out mice. Together, these data demonstrate an involvement of endogenous KOPr systems in modulating vulnerability to the convulsant effects of PTZ but not cocaine. Furthermore, they demonstrate that KOPr-1 activation protects against acute and kindled seizures induced by this convulsant. Finally, the results of our study suggest that KOPr-1 antagonists will not have therapeutic utility against cocaine-induced seizures, while they may prove beneficial in attenuating several actions of cocaine that have been linked to its abuse.

  2. Effects of the δ opioid agonist AZD2327 upon operant behaviors and assessment of its potential for abuse.

    PubMed

    Hudzik, T J; Pietras, M R; Caccese, R; Bui, K H; Yocca, F; Paronis, C A; Swedberg, M D B

    2014-09-01

    AZD2327 is a brain-penetrant agonist at δ opioid receptors which has antidepressant and anxiolytic properties in a wide array of animal models. As part of the preclinical safety pharmacology assessment, a number of studies were conducted in order to characterize its behavioral effects and its potential for abuse, in order to enable testing in humans. AZD2327 produced only modest effects when tested in a multiple fixed-ratio differential reinforcement of low rate schedule in rats, and did not enhance the rate-suppressing effects of ethanol in the procedure. In a suppressed responding test, AZD2327 only reduced rates of unpunished responding. In drug discrimination studies, AZD2327 produced partial or no generalization from known drugs of abuse. In primates trained to self-administer cocaine, substitution with AZD2327 did not result in appreciable self-administration of AZD2327, indicating that it does not behave as a positive reinforcer under the present conditions. Following termination of repeated administration of AZD2327, no signs of physical dependence (withdrawal) were noted. Overall, the data suggest that AZD2327 does not possess a high potential for abuse, and appears to have only subtle behavioral effects as measured by operant behaviors. PMID:24857840

  3. The Opioid Epidemic in the United States.

    PubMed

    Wilkerson, Richard Gentry; Kim, Hong K; Windsor, Thomas Andrew; Mareiniss, Darren P

    2016-05-01

    There is an epidemic of opioid abuse. This article discusses the history of opioid use. Abusers of opioids are at great risk of harm. There have been increasing legislative efforts to curb this abuse and we present a review of the current state of these laws. Naloxone has made a profound impact in the care of these patients if they present for medical care early enough. This paper discusses naloxone pharmacodynamics, its use in the medical setting, and how its use is now being expanded to include nontraditional providers with take home naloxone programs. PMID:27133253

  4. Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa korth)

    PubMed Central

    Boyer, Edward W.; Babu, Kavita M.; Adkins, Jessica E.; McCurdy, Christopher R.; Halpern, John H.

    2013-01-01

    Background Kratom (Mitragynia speciosa korth) is recognized increasingly as a remedy for opioid withdrawal by individuals who self-treat chronic pain. Case description A patient who had abruptly ceased injection hydromorphone abuse self-managed opioid withdrawal and chronic pain using kratom. After co-administering the herb with modafinil he experienced a tonic-clonic seizure, but he reported only modest abstinence once kratom administration stopped. We confirmed the identity of the plant matter he ingested as kratom and identified no contaminants or adulterants. We also conducted high-throughput molecular screening and the binding affinity at mu, delta and kappa receptors of mitragynine. Conclusion We report the self-treatment of chronic pain and opioid withdrawal with kratom. The predominant alkaloid of kratom, mitragynine, binds mu- and kappa-opioid receptors, but has additional receptor affinities that might augment its effectiveness at mitigating opioid withdrawal. The natural history of kratom use, including its clinical pharmacology and toxicology, are poorly understood. PMID:18482427

  5. Opiate-induced constipation related to activation of small intestine opioid μ2-receptors

    PubMed Central

    Chen, Wency; Chung, Hsien-Hui; Cheng, Juei-Tang

    2012-01-01

    AIM: To investigate the role of opioid μ-receptor subtype in opiate-induced constipation (OIC). METHODS: The effect of loperamide on intestinal transit was investigated in mice. Ileum strips were isolated from 12-wk-old male BALB/c mice for identification of isometric tension. The ileum strips were precontracted with 1 μmol/L acetylcholine (ACh). Then, decrease in muscle tone (relaxation) was characterized after cumulative administration of 0.1-10 μmol/L loperamide into the organ bath, for a concentration-dependent study. Specific blockers or antagonists were used for pretreatment to compare the changes in loperamide-induced relaxation. RESULTS: In addition to the delay in intestinal transit, loperamide produced a marked relaxation in isolated ileum precontracted with ACh, in a dose-dependent manner. This relaxation was abolished by cyprodime, a selective opioid μ-receptor antagonist, but not modified by naloxonazine at a dose sufficient to block opioid μ-1 receptors. Also, treatment with opioid μ-1 receptor agonist failed to modify the muscle tone. Moreover, the relaxation by loperamide was attenuated by glibenclamide at a dose sufficient to block ATP-sensitive K+ (KATP) channels, and by protein kinase A (PKA) inhibitor, but was enhanced by an inhibitor of phosphodiesterase for cyclic adenosine monophosphate (cAMP). CONCLUSION: Loperamide induces intestinal relaxation by activation of opioid μ-2 receptors via the cAMP-PKA pathway to open KATP channels, relates to OIC. PMID:22493554

  6. National and State Treatment Need and Capacity for Opioid Agonist Medication-Assisted Treatment

    PubMed Central

    Campopiano, Melinda; Baldwin, Grant; McCance-Katz, Elinore

    2015-01-01

    Objectives. We estimated national and state trends in opioid agonist medication-assisted treatment (OA-MAT) need and capacity to identify gaps and inform policy decisions. Methods. We generated national and state rates of past-year opioid abuse or dependence, maximum potential buprenorphine treatment capacity, number of patients receiving methadone from opioid treatment programs (OTPs), and the percentage of OTPs operating at 80% capacity or more using Substance Abuse and Mental Health Services Administration data. Results. Nationally, in 2012, the rate of opioid abuse or dependence was 891.8 per 100 000 people aged 12 years or older compared with national rates of maximum potential buprenorphine treatment capacity and patients receiving methadone in OTPs of, respectively, 420.3 and 119.9. Among states and the District of Columbia, 96% had opioid abuse or dependence rates higher than their buprenorphine treatment capacity rates; 37% had a gap of at least 5 per 1000 people. Thirty-eight states (77.6%) reported at least 75% of their OTPs were operating at 80% capacity or more. Conclusions. Significant gaps between treatment need and capacity exist at the state and national levels. Strategies to increase the number of OA-MAT providers are needed. PMID:26066931

  7. Effects of naltrexone on pain sensitivity and mood in fibromyalgia: no evidence for endogenous opioid pathophysiology.

    PubMed

    Younger, Jarred W; Zautra, Alex J; Cummins, Eric T

    2009-01-01

    The pathophysiological mechanisms underlying fibromyalgia are still unknown, although some evidence points to endogenous opioid dysfunction. We examined how endogenous opioid antagonism affects pain and mood for women with and without fibromyalgia. Ten women with fibromyalgia and ten age- and gender-matched, healthy controls each attended two laboratory sessions. Each participant received naltrexone (50mg) at one session, and placebo at the other session, in a randomized and double-blind fashion. Participants were tested for changes in sensitivity to heat, cold, and mechanical pain. Additionally, we collected measures of mood and opioid withdrawal symptoms during the laboratory sessions and at home the night following each session. At baseline, the fibromyalgia group exhibited more somatic complaints, greater sensory sensitivity, more opioid withdrawal somatic symptoms, and lower mechanical and cold pain-tolerance than did the healthy control group. Neither group experienced changes in pain sensitivity due to naltrexone administration. Naltrexone did not differentially affect self-reported withdrawal symptoms, or mood, in the fibromyalgia and control groups. Consistent with prior research, there was no evidence found for abnormal endogenous opioid activity in women with fibromyalgia.

  8. Interactions of Opioids and HIV Infection in the Pathogenesis of Chronic Pain

    PubMed Central

    Liu, Bolong; Liu, Xin; Tang, Shao-Jun

    2016-01-01

    Over 50% of HIV-1/AIDS patients suffer chronic pain. Currently, opioids are the cornerstone medications for treating severe pain in these patients. Ironically, emerging clinical data indicates that repeated use of opiate pain medicines might in fact heighten the chronic pain states in HIV patients. Both laboratory-based and clinical studies strongly suggest that opioids exacerbate the detrimental effects of HIV-1 infection on the nervous system, both on neurons and glia. The combination of opioids and HIV-1infection may promote the damage of neurons, including those in the pain sensory and transmission pathway, by activating both caspase-dependent and caspase-independent pro-apoptotic pathways. In addition, the opiate-HIV-1 interaction may also cause widespread disturbance of glial function and elicit glial-derived pro-inflammatory responses that dysregulate neuronal function. The deregulation of neuron-glia cross-talk that occurs with the combination of HIV-1 and opioids appears to play an important role in the development of the pathological pain state. In this article, we wish to provide an overview of the potential molecular and cellular mechanisms by which opioids may interact with HIV-1 to cause neurological problems, especially in the context of HIV-associated pathological pain. Elucidating the underlying mechanisms will help researchers and clinicians to understand how chronic use of opioids for analgesia enhances HIV-associated pain. It will also assist in optimizing therapeutic approaches to prevent or minimize this significant side effect of opiate analgesics in pain management for HIV patients. PMID:26903982

  9. Opioid and non-opioid mechanisms of stress analgesia: lack of cross-tolerance between stressors.

    PubMed

    Terman, G W; Lewis, J W; Liebeskind, J C

    1983-01-31

    Qualitatively different analgesic responses can be evoked in rats by exposure to prolonged, intermittent or brief, continuous footshock stress. These two forms of stress analgesia appear to be mediated by opioid and nonopioid pain-inhibitory substrates, respectively. The present study confirms our previous observation that tolerance develops to only the opioid form of stress analgesia and shows that cross-tolerance does not occur between the opioid and nonopioid forms. These data provide further evidence that independent mechanisms underlie opioid and nonopioid stress analgesia.

  10. Leukocyte opioid receptors mediate analgesia via Ca(2+)-regulated release of opioid peptides.

    PubMed

    Celik, Melih Ö; Labuz, Dominika; Henning, Karen; Busch-Dienstfertig, Melanie; Gaveriaux-Ruff, Claire; Kieffer, Brigitte L; Zimmer, Andreas; Machelska, Halina

    2016-10-01

    Opioids are the most powerful analgesics. As pain is driven by sensory transmission and opioid receptors couple to inhibitory G proteins, according to the classical concept, opioids alleviate pain by activating receptors on neurons and blocking the release of excitatory mediators (e.g., substance P). Here we show that analgesia can be mediated by opioid receptors in immune cells. We propose that activation of leukocyte opioid receptors leads to the secretion of opioid peptides Met-enkephalin, β-endorphin and dynorphin A (1-17), which subsequently act at local neuronal receptors, to relieve pain. In a mouse model of neuropathic pain induced by a chronic constriction injury of the sciatic nerve, exogenous agonists of δ-, μ- and κ-opioid receptors injected at the damaged nerve infiltrated by opioid peptide- and receptor-expressing leukocytes, produced analgesia, as assessed with von Frey filaments. The analgesia was attenuated by pharmacological or genetic inactivation of opioid peptides, and by leukocyte depletion. This decrease in analgesia was restored by the transfer of wild-type, but not opioid receptor-lacking leukocytes. Ex vivo, exogenous opioids triggered secretion of opioid peptides from wild-type immune cells isolated from damaged nerves, which was diminished by blockade of Gαi/o or Gβγ (but not Gαs) proteins, by chelator of intracellular (but not extracellular) Ca(2+), by blockers of phospholipase C (PLC) and inositol 1,4,5-trisphosphate (IP3) receptors, and was partially attenuated by protein kinase C inhibitor. Similarly, the leukocyte depletion-induced decrease in exogenous opioid analgesia was re-established by transfer of immune cells ex vivo pretreated with extracellular Ca(2+) chelator, but was unaltered by leukocytes pretreated with intracellular Ca(2+) chelator or blockers of Gαi/o and Gβγ proteins. Thus, both ex vivo opioid peptide release and in vivo analgesia were mediated by leukocyte opioid receptors coupled to the G

  11. Leukocyte opioid receptors mediate analgesia via Ca(2+)-regulated release of opioid peptides.

    PubMed

    Celik, Melih Ö; Labuz, Dominika; Henning, Karen; Busch-Dienstfertig, Melanie; Gaveriaux-Ruff, Claire; Kieffer, Brigitte L; Zimmer, Andreas; Machelska, Halina

    2016-10-01

    Opioids are the most powerful analgesics. As pain is driven by sensory transmission and opioid receptors couple to inhibitory G proteins, according to the classical concept, opioids alleviate pain by activating receptors on neurons and blocking the release of excitatory mediators (e.g., substance P). Here we show that analgesia can be mediated by opioid receptors in immune cells. We propose that activation of leukocyte opioid receptors leads to the secretion of opioid peptides Met-enkephalin, β-endorphin and dynorphin A (1-17), which subsequently act at local neuronal receptors, to relieve pain. In a mouse model of neuropathic pain induced by a chronic constriction injury of the sciatic nerve, exogenous agonists of δ-, μ- and κ-opioid receptors injected at the damaged nerve infiltrated by opioid peptide- and receptor-expressing leukocytes, produced analgesia, as assessed with von Frey filaments. The analgesia was attenuated by pharmacological or genetic inactivation of opioid peptides, and by leukocyte depletion. This decrease in analgesia was restored by the transfer of wild-type, but not opioid receptor-lacking leukocytes. Ex vivo, exogenous opioids triggered secretion of opioid peptides from wild-type immune cells isolated from damaged nerves, which was diminished by blockade of Gαi/o or Gβγ (but not Gαs) proteins, by chelator of intracellular (but not extracellular) Ca(2+), by blockers of phospholipase C (PLC) and inositol 1,4,5-trisphosphate (IP3) receptors, and was partially attenuated by protein kinase C inhibitor. Similarly, the leukocyte depletion-induced decrease in exogenous opioid analgesia was re-established by transfer of immune cells ex vivo pretreated with extracellular Ca(2+) chelator, but was unaltered by leukocytes pretreated with intracellular Ca(2+) chelator or blockers of Gαi/o and Gβγ proteins. Thus, both ex vivo opioid peptide release and in vivo analgesia were mediated by leukocyte opioid receptors coupled to the G

  12. Pressure Pain Sensitivity in Patients With Suspected Opioid-Induced Hyperalgesia

    PubMed Central

    Wasserman, Ronald A.; Hassett, Afton L.; Harte, Steven E.; Goesling, Jenna; Malinoff, Herbert L.; Berland, Daniel W.; Zollars, Jennifer; Moser, Stephanie E.; Brummett, Chad M.

    2015-01-01

    Background and Objectives This study was designed to test whether a brief quantitative sensory testing (QST) assessment could be used to detect hyperalgesia in patients with suspected opioid-induced hyperalgesia. Methods Twenty patients on long-term opioid therapy with suspected opioid-induced hyperalgesia were recruited along with and 20 healthy controls. Pressure pain threshold, Pain50, a measure of intermediate suprathreshold pressure pain sensitivity, and tolerance levels, were evaluated. As a secondary outcome, changes in pressure pain sensitivity following intravenous administration of placebo (saline) and fentanyl (1.5 μg/kg) were assessed. Results There were no significant differences in pain measures between healthy controls and patients. However, there was an association between higher doses of opioids and having a lower pain tolerance (r= -0.46, P=0.041) and lower Pain50 (r=-0.46, P = 0.044), which was consistent with the hypothesis. Patients on >100 mg oral morphine equivalents (OME) displayed decreased pressure pain tolerance compared to patients taking <100 mg OME (P = 0.042). In addition, male patients showed a hyperalgesic response to fentanyl administration, which was significant for the Pain50 measure (P=0.002). Conclusions Whereas there were no differences between patients suspected of having opioid-induced hyperalgesia and the healthy controls, the finding that higher doses of opioids were associated with more sensitivity suggests that dose might be an important factor in the development of hyperalgesia. In addition, male patients demonstrated a hyperalgesic response after a bolus of fentanyl. Future studies are needed to develop better diagnostics for detecting hyperalgesia in the clinical setting. PMID:26469365

  13. Morphine withdrawal precipitated by specific mu, delta or kappa opioid receptor antagonists: a c-Fos protein study in the rat central nervous system.

    PubMed

    Le Guen, Stéphanie; Gestreau, Christian; Besson, Jean-Marie

    2003-06-01

    We have recently shown concurrent changes in behavioural responses and c-Fos protein expression in the central nervous system in both naive and morphine-dependent rats after systemic administration of the opioid antagonist naloxone. However, because naloxone acts on the three major types of opioid receptors, the present study aimed at determining, in the same animals, both changes in behaviour and c-Fos-like immunoreactivity after intravenous injection of selective opioid antagonists, such as mu (beta-funaltrexamine, 10 mg/kg), delta (naltrindole, 4 mg/kg) or kappa (nor-binaltorphimine, 5 mg/kg) opioid receptor antagonists, in naive or morphine-dependent rats. In a first experimental series, only beta-funaltrexamine increased c-Fos expression in the eight central nervous system structures examined, whereas no effect was seen after naltrindole or nor-binaltorphimine administration in naive rats. These results suggest a tonic activity in the endogenous opioid peptides acting on mu opioid receptors in normal rats. A second experimental series in morphine-dependent rats showed that beta-funaltrexamine had the highest potency in the induction of classical signs of morphine withdrawal syndrome, as well as the increase in c-Fos expression in the 22 central nervous system structures studied, suggesting a major role of mu opioid receptors in opioid dependence. However, our results also demonstrated that naltrindole and, to a lesser extent, nor-binaltorphimine were able to induce moderate signs of morphine withdrawal and relatively weak c-Fos protein expression in restricted central nervous system structures. Therefore, delta and kappa opioid receptors may also contribute slightly to opioid dependence.

  14. Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

    PubMed Central

    Marrone, Gina F.; Grinnell, Steven G.; Lu, Zhigang; Rossi, Grace C.; Le Rouzic, Valerie; Xu, Jin; Majumdar, Susruta; Pan, Ying-Xian; Pasternak, Gavril W.

    2016-01-01

    The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3′-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α2-adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50,488H, or α2-mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa1, and α2 actions from analgesia. PMID:26976581

  15. Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS.

    PubMed

    Marrone, Gina F; Grinnell, Steven G; Lu, Zhigang; Rossi, Grace C; Le Rouzic, Valerie; Xu, Jin; Majumdar, Susruta; Pan, Ying-Xian; Pasternak, Gavril W

    2016-03-29

    The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3'-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α2-adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50, 488H, or α2-mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa1, and α2 actions from analgesia. PMID:26976581

  16. College Students Using More Pot, Fewer Opioids

    MedlinePlus

    ... More Pot, Fewer Opioids Nearly 5 percent use marijuana daily, survey finds To use the sharing features ... 2016 (HealthDay News) -- American college students' use of marijuana continues to increase, but the appeal of other ...

  17. Opioid induced hyperalgesia in anesthetic settings.

    PubMed

    Lee, Hyeon Jeong; Yeomans, David C

    2014-11-01

    Pain is difficult to investigate and difficult to treat, in part, because of problems in quantification and assessment. The use of opioids, combined with classic anesthetics to maintain hemodynamic stability by controlling responses to intraoperative painful events has gained significant popularity in the anesthetic field. However, several side effects profiles concerning perioperative use of opioid have been published. Over the past two decades, many concerns have arisen with respect to opioid-induced hyperalgesia (OIH), which is the paradoxical effect wherein opioid usage may decrease pain thresholds and increase atypical pain unrelated to the original, preexisting pain. This brief review focuses on the evidence, mechanisms, and modulatory and pharmacologic management of OIH in order to elaborate on the clinical implication of OIH.

  18. Guideline for Prescribing Opioids for Chronic Pain.

    PubMed

    Centers For Disease Control And Prevention Public Health Service U S Department Of Health And Human Services

    2016-06-01

    Improving the way opioids are prescribed through clinical practice guidelines can ensure patients have access to safer, more effective chronic pain treatment while reducing the number of people who misuse, abuse, or overdose from these drugs. The Centers for Disease Control and Prevention (CDC) developed and published the Guideline for Prescribing Opioids for Chronic Pain to provide recommendations for the prescribing of opioid pain medication for patients 18 and older in primary care settings. Recommendations focus on the use of opioids in treating chronic pain (pain lasting longer than 3 months or past the time of normal tissue healing) outside of active cancer treatment, palliative care, and end-of-life care. PMID:27301691

  19. Pharmacology of Nonsteroidal Antiinflammatory Drugs and Opioids

    PubMed Central

    Slater, Dick; Kunnathil, Sushama; McBride, Joseph; Koppala, Rajah

    2010-01-01

    Chronic pain affects up to 50 million Americans every day. Traditional treatment has included acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), or opioids. The combination of NSAIDs and opioids can provide effective treatment for up to 90% of patients with chronic pain, but the NSAIDs have the potential for significant, even life-threatening side effects. Additionally, the nonselective cyclooxygenase inhibitors with 16,000 deaths per year in the United States might not be any safer. The opioids are great for short-term pain, but may need to be adjusted or changed frequently due to the development of tolerance. Understanding of the mechanism of opioids and NSAIDs has improved greatly over the past decade, but is still incomplete. PMID:22550382

  20. Opioid-induced constipation: advances and clinical guidance

    PubMed Central

    Nelson, Alfred D.; Camilleri, Michael

    2016-01-01

    Currently opioids are the most frequently used medications for chronic noncancer pain. Opioid-induced constipation is the most common adverse effect associated with prolonged use of opioids, having a major impact on quality of life. There is an increasing need to treat opioid-induced constipation. With the recent approval of medications for the treatment of opioid-induced constipation, there are several therapeutic approaches. This review addresses the clinical presentation and diagnosis of opioid-induced constipation, barriers to its diagnosis, effects of opioids in the gastrointestinal tract, differential tolerance to opiates in different gastrointestinal organs, medications approved and in development for the treatment of opioid-induced constipation, and a proposed clinical management algorithm for treating opioid-induced constipation in patients with noncancer pain. PMID:26977281

  1. Opioid-induced androgen deficiency (OPIAD).

    PubMed

    Smith, Howard S; Elliott, Jennifer A

    2012-07-01

    Opioid therapy is one of the most effective forms of analgesia currently in use. In the past few decades, the use of opioids as a long-term treatment for chronic pain has increased dramatically. Accompanying this upsurge in the use of long-term opioid therapy has been an increase in the occurrence of opioid associated endocrinopathy, most commonly manifested as an androgen deficiency and therefore referred to as opioid associated androgen deficiency (OPIAD). This syndrome is characterized by the presence of inappropriately low levels of gonadotropins (follicle stimulating hormone and luteinizing hormone) leading to inadequate production of sex hormones, particularly testosterone. Symptoms that may manifest in patients with OPIAD include reduced libido, erectile dysfunction, fatigue, hot flashes, and depression. Physical findings may include reduced facial and body hair, anemia, decreased muscle mass, weight gain, and osteopenia or osteoporosis. Additionally, both men and women with OPIAD may suffer from infertility. While the literature regarding OPIAD remains limited, it is apparent that OPIAD is becoming increasingly prevalent among chronic opioid consumers but often goes unrecognized. OPIAD can have a significant negative impact on the the quality of life of opioid users, and clinicians should anticipate the potential for its occurrence whenever long-term opioid prescribing is undertaken. Once diagnosed, treatment for OPIAD may be offered utilizing a number of androgen replacement therapy options including a variety of testosterone preparations and, for female patients with OPIAD, dehydroepiandrosterone (DHEA) supplementation. Follow-up evaluation of patients receiving androgen replacement therapy should include a review of any unresolved symptoms of hypogonadism, laboratory evaluation, and surveillance for potential adverse effects of androgen replacement therapy including prostate disease in males.: PMID:22786453

  2. Comparison of the effects of two opioid antitussives, vadocaine hydrochloride, clobutinol and lidocaine on lung mechanics in guinea-pigs.

    PubMed

    Salonen, R O

    1988-04-01

    Intravenous administration of opioids, e.g. morphine and codeine, causes bronchoconstriction in animals and susceptible patients such as asthmatics. Therefore, the effects of two opioid antitussives (codeine and dextromethorphan), two non-opioid antitussives (vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl) propionanilide hydrochloride, OR K-242-HCl; INN: vadocaine) and clobutinol), and lidocaine on basal lung mechanics and methacholine (MeCh, 6 micrograms/kg i.v.)-induced airway obstruction were investigated in anaesthetized guinea-pigs. Intravenous administration of codeine (10-20 mg/kg) produced a dual response in the airways; initial bronchoconstriction was followed by attenuation of the MeCh-response. Dextromethorphan (10 and 15 mg/kg) caused bronchoconstriction only. Both the opioids affected dynamic lung compliance (CDyn) more than lung resistance (RL). At doses between 1 and 20 mg/kg i.v., vadocaine, clobutinol, and lidocaine had no obvious effect on the airways. Dextromethorphan and vadocaine, both at doses of 10 and 15 mg/kg, and clobutinol (15 and 20 mg/kg) caused irreversible bradycardia and hypotension, whereas codeine (5-20 mg/kg) increased blood pressure, and to a lesser extent heart rate. These results suggest that intravenous administration of an opioid antitussive influences the small peripheral airways more than the large airways, whether the opioid has euphoric analgesic properties or not. In contrast to this, non-opioid antitussives such as vadocaine and clobutinol are without effect. At large doses, all antitussives influence the cardiovascular system considerably.

  3. Comparison of the effects of two opioid antitussives, vadocaine hydrochloride, clobutinol and lidocaine on lung mechanics in guinea-pigs.

    PubMed

    Salonen, R O

    1988-04-01

    Intravenous administration of opioids, e.g. morphine and codeine, causes bronchoconstriction in animals and susceptible patients such as asthmatics. Therefore, the effects of two opioid antitussives (codeine and dextromethorphan), two non-opioid antitussives (vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl) propionanilide hydrochloride, OR K-242-HCl; INN: vadocaine) and clobutinol), and lidocaine on basal lung mechanics and methacholine (MeCh, 6 micrograms/kg i.v.)-induced airway obstruction were investigated in anaesthetized guinea-pigs. Intravenous administration of codeine (10-20 mg/kg) produced a dual response in the airways; initial bronchoconstriction was followed by attenuation of the MeCh-response. Dextromethorphan (10 and 15 mg/kg) caused bronchoconstriction only. Both the opioids affected dynamic lung compliance (CDyn) more than lung resistance (RL). At doses between 1 and 20 mg/kg i.v., vadocaine, clobutinol, and lidocaine had no obvious effect on the airways. Dextromethorphan and vadocaine, both at doses of 10 and 15 mg/kg, and clobutinol (15 and 20 mg/kg) caused irreversible bradycardia and hypotension, whereas codeine (5-20 mg/kg) increased blood pressure, and to a lesser extent heart rate. These results suggest that intravenous administration of an opioid antitussive influences the small peripheral airways more than the large airways, whether the opioid has euphoric analgesic properties or not. In contrast to this, non-opioid antitussives such as vadocaine and clobutinol are without effect. At large doses, all antitussives influence the cardiovascular system considerably. PMID:3395396

  4. Peripherally acting opioids and clinical implications for pain control.

    PubMed

    Sehgal, Nalini; Smith, Howard S; Manchikanti, Laxmaiah

    2011-01-01

    Opioid receptors are widely expressed in the central and peripheral nervous system and in the non-neuronal tissues. Data from animal and human clinical studies support the involvement of peripheral opioid receptors in analgesia, especially in the presence of inflammation. Inflammation has been shown to increase the synthesis of opioid receptors in the dorsal root ganglion neurons and enhance transport and accumulation of opioid receptors in the peripheral terminals of sensory neurons. Under the influence of chemokines and adhesion molecules, opioid peptide-containing immune cells extravasate and accumulate in the injured tissues. Stress, chemokines, cytokines, and other releasing factors in inflamed tissues stimulate these granulocytes to release opioid peptides. Once secreted, opioid peptides bind to and activate peripheral opioid receptors on sensory nerve fibers and produce analgesia by decreasing the excitability of sensory nerves and/or inhibiting release of pro-inflammatory neuropeptides. Research has revealed that local application of exogenous opioid agonists produces a potent analgesic effect by activating peripheral opioid receptors in inflamed tissues. The analgesic activity occurs without activation of opioid receptors in the central nervous system (CNS), and therefore centrally mediated side effects, such as respiratory depression, mental clouding, altered consciousness, or addiction, are not associated with peripheral opioid activity. This discovery has stimulated research on developing peripherally restricted opioid agonists that lack CNS effects. In addition, it has been recognized that opioid receptors modulate inflammation, and that opioids have anti-inflammatory effects. The anti-inflammatory actions of opioids are not well known or understood. Conflicting reports on mu-opioids suggest both anti-inflammatory and pro-inflammatory effects. This article will present the basis for peripheral opioid analgesia and describe current research directed at

  5. X Chromosome Inactivation in Opioid Addicted Women

    PubMed Central

    Vousooghi, Nasim; Shirazi, Mitra-Sadat Sadat; Goodarzi, Ali; Abharian, Peyman Hassani; Zarrindast, Mohammad-Reza

    2015-01-01

    Introduction: X chromosome inactivation (XCI) is a process during which one of the two X chromosomes in female human is silenced leading to equal gene expression with males who have only one X chromosome. Here we have investigated XCI ratio in females with opioid addiction to see whether XCI skewness in women could be a risk factor for opioid addiction. Methods: 30 adult females meeting DSM IV criteria for opioid addiction and 30 control females with no known history of addiction were included in the study. Digested and undigested DNA samples which were extracted from blood were analyzed after amplification of the polymorphic androgen receptor (AR) gene located on the X chromosome. XCI skewness was studied in 3 ranges: 50:50–64:36 (random inactivation), 65:35–80:20 (moderately skewed) and >80:20 (highly skewed). Results: XCI from informative females in control group was 63% (N=19) random, 27% (N=8) moderately skewed and 10% (N=3) highly skewed. Addicted women showed 57%, 23% and 20%, respectively. The distribution and frequency of XCI status in women with opioid addiction was not significantly different from control group (P=0.55). Discussion: Our data did not approve our hypothesis of increased XCI skewness among women with opioid addiction or unbalanced (non-random) expression of genes associated with X chromosome in female opioid addicted subjects. PMID:26904175

  6. Effects of the kappa opioid receptor antagonist MR-2266-BS on the acquisition of ethanol preference

    SciTech Connect

    Sandi, C.; Borrell, J.; Guaza, C. )

    1990-01-01

    Using a paradigm by which rats forced to drink a weak ethanol solution develop ethanol preference in consecutive retention testing days, the effects of the administration of the kappa opioid antagonist MR-2266-BS, prior to or after the forced ethanol session, were studied. Pre-conditioning subcutaneous (s.c.) administration of 1 mg/kg of MR-2266-BS induced a decrease in subsequent ethanol consumption without significantly modifying the acquisition of ethanol preference. Post-conditioning administration of MR-2266-BS induced both a dose-dependent reduction in ethanol consumption and in preference throughout the three following days. The results of the present study provide further support of the involvement of kappa-type opioids on drinking behavior, and suggest that kappa receptors may be involved in the consumption and development of preference to ethanol.

  7. Alcohol Screening among Opioid Agonist Patients in a Primary Care Clinic and an Opioid Treatment Program

    PubMed Central

    Klimas, Jan; Muench, John; Wiest, Katharina; Croff, Raina; Rieckmann, Traci; McCarty, Dennis

    2016-01-01

    Problem alcohol use is associated with adverse health and economic outcomes, especially among people in opioid agonist treatment. Screening, brief intervention and referral to treatment (SBIRT) are effective in reducing alcohol use; however, issues involved in SBIRT implementation among opioid agonist patients are unknown. To assess identification and treatment of alcohol use disorders, we reviewed clinical records of opioid agonist patients screened for an alcohol use disorder in a primary care clinic (n =208) and in an opioid treatment program (n = 204) over a two year period. In the primary care clinic, 193 (93%) buprenorphine patients completed an annual alcohol screening and six (3%) had elevated AUDIT scores. Among the patients treated in the opioid treatment program, an alcohol abuse or dependence diagnosis was recorded for 54 (27%) methadone patients. Practitioner focus groups were completed in the primary care (n = 4 physicians) and the opioid treatment program (n = 11 counsellors) to assess experience with and attitudes towards screening opioid agonist patients for alcohol use disorders. Focus groups suggested organizational, structural, provider, patient and community variables hindered or fostered alcohol screening. Alcohol screening is feasible among opioid agonist patients. Effective implementation, however, requires physician training and systematic changes in workflow. PMID:25715074

  8. Innovative Program Targets Five Common Pain Syndromes With Non-opioid Alternatives.

    PubMed

    2016-06-01

    To combat the prescription opioid problem, St. Joseph's Healthcare System in Paterson, NJ, has developed a new program that gives providers options they can use to effectively alleviate pain without resorting to highly addictive medication. Launched in January 2016 in the ED at St. Joseph's Regional Medical Center (SJRMC), the Alternatives to Opioids (ALTO) program utilizes protocols that primarily target five common conditions: renal colic, sciatica, headaches, musculoskeletal pain, and extremity fractures. Administrators say they have successfully treated more than 300 patients under the new program, and they see ALTO as a model other hospitals can duplicate. Among the alternative therapies called for in the ALTO program are trigger point injections, nitrous oxide, and ultrasound-guided nerve blocks. ALTO medications are specifically chosen because of how they affect the pain receptor sites for each different pain syndrome. While the primary goal of the program is to use alternatives to opioids when-ever possible, another important underlying goal is to stop acute pain from becoming chronic. While ALTO therapies typically take a bit longer to deliver than prescribing opioids, administrators note that this has not adversely affected patient flow in the ED. PMID:27295817

  9. Innovative Program Targets Five Common Pain Syndromes With Non-opioid Alternatives.

    PubMed

    2016-06-01

    To combat the prescription opioid problem, St. Joseph's Healthcare System in Paterson, NJ, has developed a new program that gives providers options they can use to effectively alleviate pain without resorting to highly addictive medication. Launched in January 2016 in the ED at St. Joseph's Regional Medical Center (SJRMC), the Alternatives to Opioids (ALTO) program utilizes protocols that primarily target five common conditions: renal colic, sciatica, headaches, musculoskeletal pain, and extremity fractures. Administrators say they have successfully treated more than 300 patients under the new program, and they see ALTO as a model other hospitals can duplicate. Among the alternative therapies called for in the ALTO program are trigger point injections, nitrous oxide, and ultrasound-guided nerve blocks. ALTO medications are specifically chosen because of how they affect the pain receptor sites for each different pain syndrome. While the primary goal of the program is to use alternatives to opioids when-ever possible, another important underlying goal is to stop acute pain from becoming chronic. While ALTO therapies typically take a bit longer to deliver than prescribing opioids, administrators note that this has not adversely affected patient flow in the ED.

  10. Recent developments toward the safer use of opioids, with a focus on hydrocodone.

    PubMed

    Covvey, Jordan R

    2015-01-01

    Opioids have become a mainstay of treatment for pain in the United States, with over 250 million prescription issued in 2012 alone. The increased prescribing of these medications has also contributed to the unintended consequence of a widening prevalence of abuse and misuse, and therefore safety has become a top agenda item for both government and health care providers alike. The move toward new abuse-deterrent formulation technologies, enhanced regulatory requirements from the Food and Drug Administration (FDA) and Drug Enforcement Administration (DEA), and developments in national/state policies have worked together to target a goal of promoting safer clinician prescribing, pharmacy dispensing and patient use of opioids. Hydrocodone in particular, as the most widely prescribed opioid product, has recently been subject to a myriad of changes, both through the federal rescheduling of hydrocodone-combination products (HCPs) to Schedule II, as well as the introduction of two new extended-release formulations to the USA market. These efforts represent a first step toward tackling the opioid harms epidemic, although continuing follow-up through research and policy implementation is needed to see any measureable impact on safety in the future. PMID:25769501

  11. New Federal Regulations for Improving Quality in Opioid Treatment Programs

    PubMed Central

    Pelletier, Luc R.; Hoffman, Jeffrey A.

    2006-01-01

    The U.S. Food and Drug Administration (FDA) has enforced federal requirements related to the use of methadone since 1972; regulations essentially have not changed for nearly 30 years. With Congress’ recently released federal regulations for opioid treatment programs (OTPs), however, oversight of OTPs has shifted from the FDA to the Substance Abuse and Mental Health Services Administration (SAMHSA). SAMHSA’s Center for Substance Abuse Treatment developed guidelines for accreditation agencies such as the Joint Commission on Accreditation of Healthcare Organizations and The Rehabilitation Accreditation Commission…CARF to develop standards for OTPs. Preliminary findings show that OTPs are indeed able to meet these accreditation standards. This article reviews the need for the changes, the history of methadone treatment oversight, the development of accreditation requirements, stakeholders’ initial response to the proposed regulations, and performance domains of importance to OTPs. PMID:16758002

  12. An overview of prodrug technology and its application for developing abuse-deterrent opioids.

    PubMed

    Gudin, Jeffrey A; Nalamachu, Srinivas R

    2016-01-01

    The Centers for Disease Control and Prevention has classified prescription drug abuse and overdose deaths as an epidemic. Prescription drug overdose is now the leading cause of injury death, with rates that have more than doubled since 1999. This crisis has developed concurrently with the increased prescribing and availability analgesic drugs, especially opioids, resulting from an effort on the part of clinicians to address a critical need for improved pain assessment and treatment. Clinicians have recognized that oftentimes, opioid analgesics are one of the few remaining options for patients who suffer with severe pain. A 2015 fact sheet issued by the Office of National Drug Policy stated: "While we must ensure better access to prescription medications to alleviate suffering, it is also vital that we do all we can to reduce the diversion and abuse of pharmaceuticals." The US Food and Drug Administration has issued guidance that encourages the research and development of abuse-deterrent formulation of opioids which have the potential to curtail abuse. Included among the recommended formulations for development of abuse-deterrent opioids are prodrugs. Prodrugs are chemically modified versions of pharmacological agents that must undergo a biochemical conversion following administration, often by enzymatic cleavage, to free the active drug. Prodrugs may be inherently abuse-deterrent because they are inactive or significantly less active until conversion to the active drug. This requirement for conversion in the GI tract can modify the pharmacokinetic profile and eliminate or reduce the euphoria when abusers change the route of administration. Abusers often attempt to extract the active drug for injection or insufflation. Prodrugs can be designed to be resistant to crushing or dissolving. In this article, we review the concept of prodrugs and introduce and examine the potential of abuse-deterrent opioid prodrugs.

  13. Non-Medical Prescription Opioid Use and Prescription Opioid Use Disorder: A Review

    PubMed Central

    Tetrault, Jeanette M.; Butner, Jenna L.

    2015-01-01

    Over the past few decades, there has been a rise in the non-medical use of prescription opioids, which has now reached epidemic proportions in the United States.