Showing papers on "Opiate published in 2008"
TL;DR: It is reported that males had a significantly higher expression of MOR in the ventrolateral PAG compared with cycling females, whereas the lowest level of expression was observed in proestrus females, and selective lesions of MOR-expressing neurons in the vents resulted in a significant reduction in the effects of systemic morphine in males only.
Abstract: Opioid-based narcotics are the most widely prescribed therapeutic agent for the alleviation of persistent pain; however, it is becoming increasingly clear that morphine is significantly less potent in women compared with men. Morphine primarily binds to μ-opioid receptors (MORs), and the periaqueductal gray (PAG) contains a dense population of MOR-expressing neurons. Via its descending projections to the rostral ventromedial medulla and the dorsal horn of the spinal cord, the PAG is considered an essential neural substrate for opioid-based analgesia. We hypothesized that MOR expression in the PAG was sexually dimorphic, and that these sex differences contribute to the observed sex differences in morphine potency. Using immunohistochemistry, we report that males had a significantly higher expression of MOR in the ventrolateral PAG compared with cycling females, whereas the lowest level of expression was observed in proestrus females. CFA-induced inflammatory pain produced thermal hyperalgesia in both males and females that was significantly reversed in males with a microinjection of morphine into the ventrolateral PAG; this effect was significantly greater than that observed in proestrus and estrus females. Selective lesions of MOR-expressing neurons in the ventrolateral PAG resulted in a significant reduction in the effects of systemic morphine in males only, and this reduction was positively correlated with the level of MOR expression in the ventrolateral PAG. Together, these results provide a mechanism for sex differences in morphine potency.
149 citations
TL;DR: A family history of alcoholism appears to predict response to an opiate antagonist in PG, and future research is needed to identify specific factors mediating favorable responses.
Abstract: Although opiate antagonists have shown promise in the treatment of pathological gambling (PG), individual responses vary. No studies have systematically examined predictors of medication treatment outcome in PG. Understanding clinical variables related to treatment outcome should help generate treatment algorithms for PG. We sought to identify clinical variables associated with treatment outcome in PG subjects receiving opiate antagonists. Two hundred eighty-four subjects [137 (48.2%) women] with DSM-IV PG were treated in one of two double-blind placebo-controlled trials (16 weeks of nalmefene or 18 weeks of naltrexone). Gambling severity was assessed with the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) with positive response defined as ≥35% reduction in PG-YBOCS score for at least 1 month by study endpoint. Depression, anxiety, and psychosocial functioning were included in stepwise logistic regression analyses designed to identify clinical factors independently associated with treatment response. The clinical variable most strongly associated with a positive response to an opiate antagonist was a positive family history of alcoholism (p = 0.006). Among individuals receiving higher doses of opiate antagonists (i.e., nalmefene 50 or 100 mg/day or naltrexone 100 or 150 mg/day), intensity of gambling urges (PG-YBOCS urge subscale) was associated with a positive response on a trend level (p = 0.036). Among individuals receiving placebo, younger age was associated, on a trend level, with positive treatment outcome (p = 0.012). A family history of alcoholism appears to predict response to an opiate antagonist in PG. Future research is needed to identify specific factors (e.g., genetic) mediating favorable responses.
147 citations
TL;DR: It is found that the rat's response to environmental cues previously paired with morphine progressively increases or incubates over the first 14 d of withdrawal from low but not high morphine doses, which is mediated by acute activation of central amygdala ERK pathway.
Abstract: Cue-induced drug-seeking in rodents progressively increases after withdrawal from operant self-administration of cocaine, heroin, methamphetamine, and alcohol, a phenomenon termed "incubation of drug craving." Here, we used the opiate drug morphine and explored whether incubation of drug craving also occurs in a pavlovian conditioned place preference (CPP) procedure in which rats learn to associate drug effects with a distinct environmental context. We also explored the role of amygdala extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in this incubation. We found that the expression of morphine CPP progressively increases over the first 14 d after the last drug exposure in rats receiving four pairings of low-dose (1 or 3 mg/kg) but not high-dose (10 mg/kg) morphine with a distinct environment. The progressive increase in low-dose (3 mg/kg) morphine CPP was associated with increased ERK phosphorylation (a measure of ERK activity) and CREB (a downstream target of ERK) phosphorylation in central but not basolateral amygdala. Furthermore, inhibition of central but not basolateral amygdala ERK and CREB phosphorylation by U0126 [1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene] decreased the enhanced (incubated) drug CPP after 14 d of withdrawal from morphine. Finally, stimulation of central amygdala ERK and CREB phosphorylation by NMDA enhanced drug CPP after 1 d of withdrawal from morphine, an effect reversed by U0126. These findings indicate that the rat's response to environmental cues previously paired with morphine progressively increases or incubates over the first 14 d of withdrawal from low but not high morphine doses. Additionally, this "incubation of morphine craving" is mediated by acute activation of central amygdala ERK pathway.
146 citations
TL;DR: The data suggest that the abuse liability profile and relative potency of these three commonly used opioids do not differ substantially from one another and suggest that analgesic potencies may not accurately reflect relative differences in abuse liability of prescription opioids.
143 citations
TL;DR: Treatment strategies that increase D2Rs may, therefore, be an interesting approach to prevent relapse in opiate addiction.
98 citations
TL;DR: It is suggested that chronic opioid use induces long-lasting striatum dopamine neuron impairment, and prolonged withdrawal from opioids can benefit the recovery of impaired dopamine neurons in the brain.
92 citations
TL;DR: Together, these data are consistent with the view that the hypocretin system may be an important direct target for drugs of abuse, including opiates, that induce sedation and mental lethargy.
Abstract: Arousal and maintenance of a wake state is dependent on the hypothalamic hypocretin/orexin system. We found that hypocretin neurons are depressed by opiates, drugs of abuse that reduce cognitive alertness. Met-enkephalin (mENK), an endogenous opioid, and exogenous opiates such as morphine inhibited the hypocretin system by direct actions on the cell body that include reduced spike frequency, hyperpolarization, increased G-protein-coupled inwardly rectifying K(+) channel current, and attenuated calcium current, and indirectly through reducing excitatory synaptic tone by a presynaptic mechanism. CTAP (H-d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH(2)) and naloxone, antagonists of mu-opioid receptors, blocked mu agonist actions. In the absence of exogenous opioids, mu receptor antagonists enhanced activity of the hypocretin system, suggesting ongoing inhibition by endogenous receptors. Morphine pretreatment attenuated subsequent excitatory responses to hypocretin, suggesting a long-lasting depression caused by opiate exposure. Chronic exposure to morphine reduced subsequent responses to morphine and to mENK, but increased the response to opioid receptor antagonists. Together, these data are consistent with the view that the hypocretin system may be an important direct target for drugs of abuse, including opiates, that induce sedation and mental lethargy.
85 citations
TL;DR: Aims: To describe important non‐biological factors which influence the course of opiate addiction.
Abstract: Aims: To describe important non-biological factors wh ich infl uence the course of opiate addiction. Method: Studies were reviewed that present empirical results on the long-term course of opiate addiction, progress of opiate addicts during and after treatment, variables that predict remission and abstinence, comparisons of treated and untreated samples, and recovery from opiate addiction without formal help. Results: Opiate addiction is a chronic disorder with high mortality risk. The course of opiate addiction often consists of recurring sequences of addictive opiate use and abstinence. Treatment for opiate addiction, especially maintenance treatment, reduces opiate use; however, it is unclear how long after treatment the effects last. In treated samples, long-term opiate use can be moderately predicted from psychosocial factors, such as peer-group relationships, family problems, employment, and social support. Little is known about addicts who do not participate in treatment or who recover without treatment. Common factors that both treated and untreated addicts view as most important to their success are the social environment and their social life and daily activities. Conclusions: In view of the chronic course of opiate addiction and the phenomenon of spontaneous recovery without treatment, the role of drug-abuse treatment as an infl uencing factor would seem to require further clarifi cation. Current treatment programmes may leave unaddressed important factors that contribute to the recovery of drug addicts. Copyright © 2008 John Wiley & Sons, Ltd.
75 citations
TL;DR: The intention of this paper is to review the literature that has established a role for the opioid system in neurogenesis in vivo in fetal, postnatal, and adult animals and to examine the links of opioids to modulation of astrocytic proliferation.
Abstract: Opiate drugs, such as codeine, morphine, and heroin, are powerful analgesics, but also are used as drugs of abuse because of their psychogenic properties. Many studies have shown that opiates impact on cellular proliferation in the adult and developing brain, although anatomical pathologies are lacking in in utero exposed infants and opioid knockout mice. Recent research has defined a context-dependent role for the opioid system in neurogenesis in the adult hippocampus with exercise. Opioids have been shown to interact with proliferating cells of the postnatal subventricular zone of the lateral ventricles. The subventricular zone is also a region of adult neurogenesis, a fact that was not well established at the time this earlier research was conducted. Although a relationship between opioids and fetal neurogenesis has yet to be firmly established, many studies have implicated the opioid system in this process. One common factor that links neurogenesis in adult, postnatal, and fetal structures is the involvement of neuronal progenitor cells of the astrocytic lineage. It is therefore of interest that opioids have been consistently shown to impact upon astrocytic proliferation. It is the intention of this paper to review the literature that has established a role for the opioid system in neurogenesis in vivo in fetal, postnatal, and adult animals and to examine the links of opioids to modulation of astrocytic proliferation.
74 citations
TL;DR: A critical role for glutamate receptors in the VTA in opiate reward is suggested, as well as behavioral and anatomical dissociation between the rewarding and psychomotor effects of opiates.
Abstract: The rewarding effects of drugs of abuse are thought to be dependent on the mesocorticolimbic dopamine system, which originates in the ventral tegmental area (VTA) and projects into the nucleus accumbens (NAC) and other forebrain regions. Heroin, by inhibiting GABAergic interneurons in the VTA, induces local dopaminergic activation and release in the NAC terminals. The role of other basic neurotransmitter systems, such as glutamate in the VTA, in mediating the rewarding effect of addictive drugs, is less established. We explored whether blockade of glutamate receptors in subregions of the VTA modulate the rewarding properties and/or the development of psychomotor changes induced by opiates. Administration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; an AMPA/kainate receptor antagonist) into the anterior VTA blocked the rewarding effects of opiates in both the conditioned place preference and the self-administration paradigms without affecting the gradual increase of the psychomotor response to opiates. In contrast, administration of CNQX into the posterior VTA did not affect the rewarding properties of opiates, but blocked the initial sedative effect of opiates and the gradual increase of the psychomotor response to the drug. These findings suggest a critical role for glutamate receptors in the VTA in opiate reward, as well as behavioral and anatomical dissociation between the rewarding and psychomotor effects of opiates.
69 citations
TL;DR: Data indicate that adult male rats exposed to the cannabinoid in adolescence self-administer more morphine than females, but only when the demands required by the schedule of reinforcement are low, which might be related to the decrease in mu-opioid receptor functionality in the NAcc-shell observed in these animals.
TL;DR: The results support the potential use of l-THP for the treatment of heroin addiction, especially reducing drug craving and increasing the abstinence rate among heroin-dependent patients.
Abstract: Medication of l -tetrahydropalmatine significantly ameliorates opiate craving and increases the abstinence rate in heroin users: a pilot study
TL;DR: The results suggest that NMDA receptors are broadly involved in opiate-induced plasticity, including the development of opiate tolerance and sensitization.
Abstract: N-Methyl-d-aspartate (NMDA) receptors have an important role in different forms of behavioral and neural plasticity. Evidence suggests that these receptors may also be involved in plasticity arising from long-term treatment with different drugs of abuse, including tolerance, sensitization, and physical dependence. There is abundant evidence demonstrating that NMDA receptors are involved in tolerance to opiate-induced antinociception; however, the role of these receptors in sensitization to the locomotor effects of opiates is more controversial. The ability of NMDA receptor antagonists to modify the development of sensitization to the locomotor stimulant effect of three different opiates was examined. In selected studies, the ability of the antagonists to modify tolerance to the antinociceptive effects of the opiates was also examined. Adult male Sprague–Dawley rats were used to assess the effects of NMDA receptor antagonists (MK-801, memantine or LY235959) on tolerance and sensitization to three opiates: morphine, methadone, or buprenorphine. It was predicted that low, selective doses of the antagonists would inhibit the development of opiate tolerance and sensitization. Consistent with our predictions, the noncompetitive NMDA receptor antagonists MK-801 and memantine and the competitive NMDA receptor antagonist LY235959 inhibited the development of sensitization to the locomotor stimulant effect of morphine. Additionally, MK-801 inhibited the development of tolerance and sensitization to methadone and buprenorphine in a similar manner. The results, together with previous research, suggest that NMDA receptors are broadly involved in opiate-induced plasticity, including the development of opiate tolerance and sensitization.
TL;DR: The data suggest that prenatal opiate exposure and/or postnatal withdrawal compromise expression of proteins involved in the neural plasticity underlying learning in male rats prenatally exposed to the opiates.
TL;DR: VTA MORs, but not DORs, are critical for morphine reward and the role of VTA-thalamic projections in opiate reward deserves to be further explored.
TL;DR: Galanin agonists decrease opiate reward, measured by conditioned place preference, and opiate withdrawal signs, whereas opiates reward and withdrawal are increased in knock-out mice lacking galanin, suggesting that polymorphisms in genes encoding Galanin or galan in receptors might be associated with susceptibility to opiate abuse.
Abstract: There has been increasing interest in the ability of neuropeptides involved in feeding to modulate circuits important for responses to drugs of abuse A number of peptides with effects on hypothalamic function also modulate the mesolimbic dopamine system (ventral tegmental area and nucleus accumbens) Similarly, common stress-related pathways can modulate food intake, drug reward and symptoms of drug withdrawal Galanin promotes food intake and the analgesic properties of opiates; thus it initially seemed possible that galanin might potentiate opiate reinforcement Instead, galanin agonists decrease opiate reward, measured by conditioned place preference, and opiate withdrawal signs, whereas opiate reward and withdrawal are increased in knock-out mice lacking galanin This is consistent with studies showing that galanin decreases activity-evoked dopamine release in striatal slices and decreases the firing rate of noradrenergic neurons in locus coeruleus, areas involved in drug reward and withdrawal, respectively These data suggest that polymorphisms in genes encoding galanin or galanin receptors might be associated with susceptibility to opiate abuse Further, galanin receptors might be potential targets for development of novel treatments for addiction (Part of a Multi-author Review)
Journal Article•
TL;DR: With this proof of concept, several phase III studies are under way to define optimal dosage, dosing regimen as well as long-term efficacy and safety of methylnaltrexone and alvimopan, and preliminary evidence that these peripherally restricted opioid receptor antagonists may act as prokinetic drugs in their own right.
Abstract: Opiates are indispensable for the treatment of moderate to severe pain. The gastrointestinal tract is one of the major victims of the undesired effects of opiates, because the enteric nervous system expresses all major subtypes of opioid receptors. As a result, propulsive motility and secretory processes in the gut are inhibited by opioid analgesics, and the ensuing constipation is one of the most frequent and troublesome adverse reactions. Many treatments involving laxatives, prokinetic drugs and opioid-sparing regimens have been explored to circumvent opioid-induced bowel dysfunction, but the outcome has in general been unsatisfactory. Specific antagonism of peripheral opioid receptors offers a more rational approach to the management of the adverse actions of opioid analgesics in the gut. This goal is currently addressed by the use of opioid receptor antagonists with limited absorption such as oral naloxone and by the development of peripherally restricted opioid receptor antagonists such as methylnaltrexone and alvimopan. These investigational drugs hold considerable promise in preventing constipation due to opiate treatment, whereas the analgesic action of opiates remains unabated. Postoperative ileus associated with opioid-induced postsurgical pain control is likewise ameliorated by the compounds. With this proof of concept, several phase III studies are under way to define optimal dosage, dosing regimen as well as long-term efficacy and safety of methylnaltrexone and alvimopan. In addition, there is preliminary evidence that these peripherally restricted opioid receptor antagonists may act as prokinetic drugs in their own right.
TL;DR: It is shown that GKO mice demonstrate increased locomotor activation following morphine administration, which is inhibited by acute administration of galnon, and galanin agonists may represent a new class of therapeutic targets for opiate addiction.
TL;DR: The chronic modulation of some of their components (downregulation of FADD and cytochrome c; upregulation of FLIP(L) and Bcl-2) suggests the induction of non-apoptotic actions by opiate drugs related to phenomena of synaptic plasticity in the brain.
TL;DR: Maintenance treatment with SROM appears to be a clinically useful alternative treatment in subjects not tolerating methadone or with inadequate withdrawal suppression, and signs and symptoms of opioid withdrawal as well as craving for opiates were improved significantly in patients with inadequate response to Methadone.
Abstract: Aims Evaluation of the efficacy, safety and acceptability of slow-release oral morphine (SROM) in opioid addicts intolerant to methadone or with inadequate withdrawal suppression.
Design Prospective, open, non-comparative multi-centre study.
Setting Twelve out-patient Centres for Prevention and Treatment of Drug Addiction in Slovenia.
Participants Male and female opioid addicts (age >18 years) under methadone maintenance therapy requiring a change of treatment in order to continue more effectively with maintenance.
Interventions Maintenance therapy with methadone was switched to once-daily SROM.
Measurements Efficacy evaluations were based on the reduction of side effects and on the degree of suppression of opiate craving, signs and symptoms of withdrawal. In addition, self-reported somatic and psychic symptoms (SCL-27) as well as World Health Organization quality of life-related (WHO QOL) parameters were monitored.
Findings Thirty-nine subjects intolerant to methadone and 28 subjects showing inadequate withdrawal suppression under methadone ≥90 mg/day were included as two separate groups in the efficacy analyses. Treatment was switched easily from methadone to SROM on a 1 : 8 ratio. Four-week SROM treatment resulted in significant reduction of side effects reported under methadone. Signs and symptoms of opioid withdrawal as well as craving for opiates were improved significantly in patients with inadequate response to methadone. Physical and psychological wellbeing improved significantly under SROM treatment. SROM was tolerated very well.
Conclusions Maintenance treatment with SROM appears to be a clinically useful alternative treatment in subjects not tolerating methadone or with inadequate withdrawal suppression.
TL;DR: It is suggested that alternating opioid and cannabinoid treatment could be therapeutically advantageous by preventing the development of tolerance and enhancing morphine antinociception.
TL;DR: It is demonstrated that morphine withdrawal ultimately enhances the reinforcing effects of remifentanil, and the increased responding observed in the MW group compared with the control and MD groups resulted in an upward shift in the remifENTanil dose-response curve.
Abstract: Opiate dependence and withdrawal have long been hypothesized to enhance the reinforcing effects of opiates; however, opiate agonist self-administration in these states has yet to be systematically assessed. To address this issue, the reinforcing property of the short-acting μ-opioid agonist, remifentanil, was assessed in morphine-dependent (MD), morphine-dependent and -withdrawn (MW), and nondependent, control (C) rats. Dependence was established by twice daily administration of increasing doses of morphine for 4 days (10, 20, 30, and 40 mg/kg s.c.) and then maintained with a daily injection of the large dose. Morphine deprivation-induced withdrawal (defined by weight loss and hyperalgesia) was apparent 24, but not 12, h after morphine treatment. Remifentanil self-administration (0.4, 0.8, 1.6, 3.2, or 6.4 μg/kg/infusion) was assessed over 20 successive, daily, 1-h sessions, either 12 or 24 h after the maintenance dose of morphine. Compared with the control group, the MD group demonstrated suppressed remifentanil self-administration, whereas the MW group exhibited enhanced responding for every dose of remifentanil. The increased responding observed in the MW group compared with the control and MD groups resulted in an upward shift in the remifentanil dose-response curve, an effect that was expressed only after repeated exposure to the contingency, demonstrating that morphine withdrawal ultimately enhances the reinforcing effects of remifentanil.
TL;DR: This paper re‐evaluates recent data on the effectiveness of naltrexone in subjects differentiated according to Cloninger Type I and II and combines and cross‐validates results of two recent European studies that found nalt Rexone treatment more beneficial in alcohol‐dependent patients with early age at onset of drinking problems.
Abstract: Naltrexone is an opiate receptor antagonist mainly at the micro-receptor that is thought to reduce the positively reinforcing, pleasurable effects of alcohol and to reduce craving. An increase in time to first relapse to heavy drinking has been the most consistent finding obtained with naltrexone, although not all trials including two of the largest have been positive. Inconsistent outcome data suggest that effectiveness varies among different subgroups of patients. This paper re-evaluates recent data on the effectiveness of naltrexone in subjects differentiated according to Cloninger Type I and II. Moreover, it combines and cross-validates results of two recent European studies that found naltrexone treatment more beneficial in alcohol-dependent patients with early age at onset of drinking problems (Cloninger Type II). It is discussed whether especially these subjects should be targeted for pharmacological relapse prevention treatment with naltrexone.
TL;DR: Specific c-fos and arc patterns of reactivity in amygdala nuclei during withdrawal conditioning improve the understanding of the involvement of the amygdala network in the formation and retrieval of withdrawal memories.
TL;DR: In a free-choice administration of methadone or buprenorphine, there seems to be no difference in cognitive functioning.
Abstract: Objectives: In the present study, we investigated whether buprenorphine as a partial µ-opioid receptor agonist is associated with less cognitive impairment than methadone. Methods: Neuropsychological functioning of opioid-dependent patients, previously assigned to methadone (MMP, n = 30) or buprenorphine (BMP, n = 26) maintenance treatment according to their own preference, was compared and dose effects were investigated. Results: MMP and BMP performed equally well on all mea- sures of neuropsychological functioning including the trail making test, the continuous performance test, and a vigilance task. However, patients receiving a higher dose of methadone were impaired in a vigilance task. Conclusions: In a free-choice adminis- tration of methadone or buprenorphine, there seems to be no difference in cognitive functioning. Possible explanations are discussed.
TL;DR: Analysis of NE and addiction in psychostimulant abuse and the elegant, recently developed dopamine-beta-hydroxylase knock-out mouse shows that central NE is necessary for such cocaine-induced anxiety, indicating that anxiogenic effects of cocaine are due, at least in part, to NE acting at beta adrenoceptors.
TL;DR: The results unravel a novel role for the CRF2 receptor pathway in opiate withdrawal, which might be a critical target of therapies aimed at alleviating opiates withdrawal symptoms and reducing relapse to drug intake.
Journal Article•
TL;DR: Non opioid drug Nigella sativa is effective in long-term treatment of opioid dependence and not merely cures the opioid dependence but also cures the infections and weakness from which majority of addicts suffer.
Abstract: Background Opioid dependence is one of the major social and psychiatric problem of society. Unfortunately there is no non opiate treatment available. For centuries man has used plants for their healing proprieties. These plants play a fundamental part in all treatment modalities, both ancient and modern. Methods This study was conducted to find non opiate treatment for opiate withdrawal. Total 35 known addicts of opiates were included in the study. This study was based on DSM IV criteria for opioid dependence. Result This study demonstrates that non opioid treatment for opioid addiction decreases the withdrawal effects significantly. It further demonstrates that there are no changes in physiological parameters of subjects during treatment (BP, Pulse rate etc.). There is increased appetite but no significant weight gain in the subjects. Conclusion Non opioid drug Nigella sativa is effective in long-term treatment of opioid dependence. It not merely cures the opioid dependence but also cures the infections and weakness from which majority of addicts suffer.
TL;DR: Buprenorphine maintenance showed a dampened HPA axis response to metyrapone, with OPRM1 118G carriers showing a significantly attenuated response compared with 118A carriers, implying a dissociation of HPAaxis responsiveness and affect in heroin dependence.