Abnormalities in dopaminergic and serotonergic neurotransmission in the forebrain are believed to be involved in the underlying mechanism of schizophrenia; therefore, the direct blockade of the receptors associated with these systems is a central strategy for schizophrenia treatment, even though this strategy concurrently produces adverse effects like extrapyramidal effects. Kappa opioid receptors exist extensively in the brain and recent reports have suggested that these receptors are involved in modulating the release of several neurotransmitters including dopamine and serotonin. In the present study, we investigated the effect of TRK-820,(E)-N-[17-(cyclopropylmethyl)-4,5alpha-epoxy-3,14-dihydroxymorphinan-6beta-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride, a selective kappa opioid receptor agonist, on phencyclidine-induced rat behavioral changes and on biochemical changes in the prefrontal cortex. First, TRK-820 dose-dependently inhibited phencyclidine-induced rat hyperlocomotion, which is one of the abnormal behaviors recognized as a rodent schizophrenia model. The inhibitory effect was completely antagonized with nor-BNI (nor-binaltorphimine hydrochloride), a selective kappa opioid receptor antagonist. Second, TRK-820 dose-dependently inhibited phencyclidine-induced stereotyped behaviors including head-weaving, which is considered a behavioral syndrome based on the impairment of the serotonergic system. Third, in an in vivo microdialysis study, TRK-820 dose-dependently attenuated the biochemical changes of both dopamine and serotonin in the prefrontal cortex of rats treated with phencyclidine without affecting their basal levels in normal rats. The initial findings that TRK-820 potentially modulates such monoamine changes and ameliorates abnormal behaviors related to their changes may suggest its therapeutic potential against the symptoms of schizophrenia.

We studied the effect of opiates acting preferentially on mu receptors, like morphine, methadone and fentanyl (mu agonists) and on kappa receptors, like U50,488, bremazocine and tifluadom (kappa agonists) on the release of dopamine (DA) and of its metabolites, dihydroxyphenylacetic acid and homovanillic acid, from the nucleus accumbens and from the dorsal caudate of freely moving rats using brain dialysis coupled to high-performance liquid chromatography with electrochemical detection. Spontaneous behavior was videotaped and analyzed by estimating the percentage of time spent by the animals in performing certain specific behavioral items. Mu agonists stimulated DA-release and metabolism in the accumbens at lower doses than in the caudate. Maximal stimulation of DA release did not exceed 100% except after high doses of methadone (10 mg/kg) which stimulated DA release in the accumbens by more than 300%, possibly as a result of hypoxia. Stimulation of DA release was associated to stimulation of behavior at low doses and to a biphasic inhibitory-stimulatory syndrome after higher doses of the opiates. Pretreatment with low doses of naloxone (0.1 mg/kg s.c.) or with the irreversible mu antagonist beta-funaltrexamine (10 nmol i.c.v.) increased the ED50 for the stimulation of DA release by the three opiates. In contrast with mu agonists, agonists of kappa receptors like U50,488, bremazocine and tifluadom decreased DA release in the accumbens and in the caudate and reduced motor activity. These effects were antagonized only by rather high doses of naloxone (2.5 mg/kg s.c.) and were not affected by pretreatment with beta-funaltrexamine (10 nmol i.c.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

CONTEXT: Alcoholism affects approximately 10% of Americans at some time in their lives. Treatment consists of psychosocial interventions, pharmacological interventions, or both, but which drugs are most effective at enhancing abstinence and preventing relapse has not been systematically reviewed. OBJECTIVE: To evaluate the efficacy of 5 categories of drugs used to treat alcohol dependence--disulfiram, the opioid antagonists naltrexone and nalmefene, acamprosate, various serotonergic agents (including selective serotonergic reuptake inhibitors), and lithium. DATA SOURCES: Reports of randomized controlled trials, nonrandomized trials, and other study designs in English, French, and German identified from multiple searches of MEDLINE, EMBASE, and specialized databases; hand searching bibliographies of review articles; searches for unpublished literature; and discussions with investigators in the field. STUDY SELECTION: We included all studies on alcohol-dependent human subjects aged 18 years or older from all inpatient and outpatient settings between 1966 and December 1997 that met our inclusion criteria. DATA EXTRACTION: We abstracted the following information: study design and blinding, diagnostic instrument and severity assessment, drug interventions and cointerventions, demographic and comorbidity details about patients, compliance, and numerous outcome measures (eg, relapse, return to drinking, drinking or nondrinking days, time to first drink, alcohol consumed per unit of time, craving). We graded quality of the individual articles (scale, 0-100) independently from the strength of evidence for each drug class (A, strong and consistent evidence of efficacy in studies of large size and/or high quality; B, mixed evidence of efficacy; C, evidence of lack of efficacy; and I, insufficient evidence). DATA SYNTHESIS: Of 375 articles evaluated, we abstracted and analyzed data from 41 studies and 11 follow-up or subgroup studies. Naltrexone (grade A) reduces the risk of relapse to heavy drinking and the frequency of drinking compared with placebo but does not substantially enhance abstinence, ie, avoidance of any alcohol consumption. Acamprosate (grade A, from large-scale studies in Europe) reduces drinking frequency, although its effects on enhancing abstinence or reducing time to first drink are less clear. Controlled studies of disulfiram (grade B) reveal a mixed outcome pattern--some evidence that drinking frequency is reduced but minimal evidence to support improved continuous abstinence rates. The limited data on serotonergic agents were not very promising (grade I), although most studies were confounded by high rates of comorbid mood disorders. Lithium lacks efficacy (grade C) in the treatment of primary alcohol dependence. CONCLUSIONS: Recent reports documenting that naltrexone and acamprosate are more effective than placebo in the treatment of alcoholism justify clinical interest in use of these medications for alcohol-dependent patients. Use of disulfiram is widespread but less clearly supported by the clinical trial evidence; however, targeted studies on supervised administration of disulfiram may be warranted. Use of existing serotonergic agents or lithium for patients with primary alcohol dependence does not appear to be supported by the efficacy data available at this time; these medications may still have a positive effect in patients with coexisting psychiatric disorders.

Intracellular recordings of membrane potassium current were made from rat locus coeruleus in vitro. The effects of agonists at mu-opioid receptors were studied on neurons from rats that had been chronically treated with morphine; these were compared with actions on neurons from control rats. Tolerance to the opioid-induced increase in potassium conductance was observed, and this was more pronounced for normorphine than for [Met5]enkephalin and [D-Ala2, Mephe4, Gly5-ol]enkephalin: experiments with the irreversible receptor blocker beta-chlornaltrexamine indicated that normorphine had lower intrinsic efficacy than [Met5]enkephalin and [D-Ala2 MePhe4, Gly5-ol]enkephalin. This adaptation was not due to any change of the properties of the potassium conductance activated by mu-receptors because both full and partial agonists at alpha 2-adrenoceptors, which couple to the same potassium conductance, were unchanged in their effectiveness; nor was it associated with any change in the affinity of mu-receptors for the antagonist naloxone. Naloxone had no effect on the neurons other than simple competitive reversal of the action of the mu-receptor agonists. These results demonstrate that 1) the mechanism responsible for tolerance in locus coeruleus neurons is specifically associated with mu-receptors and/or their coupling to potassium channels, 2) the intrinsic efficacy of an opioid determines the degree of tolerance observed, and 3) tolerance and physical dependence can be dissociated at the cellular level.

The role of the opioid system in controlling pain, reward and addiction is well established, but its role in regulating other emotional responses is poorly documented in pharmacology. The mu-, delta- and kappa- opioid receptors (encoded by Oprm, Oprd1 and Oprk1, respectively) mediate the biological activity of opioids. We have generated Oprd1-deficient mice and compared the behavioural responses of mice lacking Oprd1, Oprm (ref. 6) and Oprk1 (ref. 7) in several models of anxiety and depression. Our data show no detectable phenotype in Oprk1-/- mutants, suggesting that kappa-receptors do not have a role in this aspect of opioid function; opposing phenotypes in Oprm-/- and Oprd1-/- mutants which contrasts with the classical notion of similar activities of mu- and delta-receptors; and consistent anxiogenic- and depressive-like responses in Oprd1-/- mice, indicating that delta-receptor activity contributes to improvement of mood states. We conclude that the Oprd1-encoded receptor, which has been proposed to be a promising target for the clinical management of pain, should also be considered in the treatment of drug addiction and other mood-related disorders.

Mice were tested for antinociceptive activity after intrathecal injection of opioid or noradrenergic agonists by lumbar puncture. Opioid agonists with mu or delta activity and adrenergic agonists with alpha activity demonstrated dose-related, receptor-mediated analgesia in the tail-flick assay, s.c. hypertonic saline assay and the intrathecal substance P behavioral assay. Inhibition of substance P-induced biting and scratching by intrathecally administered antinociceptive agents is likely mediated by post-synaptic receptors. This action of opioids and norepinephrine was antagonized by their respective pharmacological antagonists. Subanalgesic doses of Leu-enkephalin or norepinephrine potentiated the antinociceptive activity of morphine in the substance P assay. Similarly, opioid agonists potentiated the action of norepinephrine. These results suggest that opioid and alpha adrenergic agonists act on separate receptors to produce a synergistic inhibition of the transmission of nociceptive information at the spinal level.

The role of central versus peripheral opioid receptors in mediating the aversive effects of opioids was examined by use of an unbiased place preference conditioning procedure in rats. The non-selective opioid antagonist naloxone (NLX) produced conditioned aversions for the drug-associated place after subcutaneous (SC) as well as intracerebroventricular (ICV) administration. Place aversions were also observed in response to the ICV administration of the selective mu-antagonist CTOP. In contrast, the selective delta-antagonist ICI 174,864 and the selective kappa-antagonist norbinaltorphimine (nor-BNI)(ICV) were without effect. Place aversions were also produced by central applications of the selective kappa-agonist U50,488H and the dynorphin derivative E-2078. For those opioid ligands tested, the doses required to produce place aversions were substantially lower following ICV as compared to SC administration. These data confirm that kappa-agonists and opioid antagonists produce aversive states in the drug-naive animal and demonstrate that this effect is centrally mediated. Furthermore, the ability of NLX and CTOP, in contrast to both ICI 174,864 and nor-BNI, to produce place aversions suggests that the aversive effects of opioid antagonists result from the blockade of mu-receptors.

In this study naltrindole (NTI) and its benzofuran derivative (NTB) were studied for their antagonist activity against various delta opioid receptor agonists in the tail-flick antinociceptive assay in mice. The antinociceptive ED50 of i.c.v. administered DSLET [(D-Ser2, Leu5, Thr6)enkephalin] was shifted about 4-fold by either s.c. NTB or i.c.v. NTI injection. On the other hand, the antinociceptive ED50 of i.c.v. administered DPDPE [(D-Pen2,D-Pen5)enkephalin] was shifted 1.4- and 1.8-fold with s.c. NTB and i.c.v. NTI administration, respectively, which were significantly lower than the shifts observed with DSLET. NTB did not alter the antinociceptive action of i.c.v. administered [(D-Ala2,D-Leu5)enkephalin], morphine sulfate,[(D-Ala2,MePhe4,Gly-ol5)enkephalin] or U-50,488H (trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide). At spinal sites, the antinociceptive ED50 of intrathecal (i.t.) administered DSLET was increased by 12.5-fold by s.c. NTB injection, whereas that of DPDPE was unaffected. NTB injection at this site also did not alter the antinociceptive action of i.t. administered [D-Ala2, D-Leu5]enkephalin,[(D-Ala2,MePhe4,Gly-ol5)enkephalin] or morphine sulfate. Pretreatment of animals with beta-funaltrexamine caused a large increase in the capacity of NTB to antagonize the antinociceptive activity of i.t. administered DSLET with little change in that of i.t. administered DPDPE. When cross-tolerance between DSLET and DPDPE was studied by i.c.v. injection of a single large dose of either DSLET or DPDPE 24 hr before the antinociceptive assay, there was no development of cross-tolerance between the two peptides. Based on these results, it was concluded that the antinociceptive action of DSLET and DPDPE may be mediated by different receptors, possibly delta opioid subtypes.

The cAMP response element-binding protein (CREB) is a critical integrator of neural plasticity that is responsive in a brain region-specific manner to a variety of environmental and pharmacological stimuli, including widely prescribed antidepressant medications. We developed inducible transgenic lines of mice that express either CREB or a dominant-negative mutant of CREB (mCREB) in forebrain regions and used these mice to determine the functional significance of this transcription factor in the learned helplessness paradigm, a behavioral model of depression. We also use a complementary viral-mediated gene transfer approach to directly test the effect of mCREB in the nucleus accumbens, a brain region important for motivation and reward. The results demonstrate that blockade of CREB by overexpression of mCREB in transgenic mice or by viral expression of mCREB in the nucleus accumbens produces an antidepressant-like effect, whereas overexpression of CREB in transgenic mice results in the opposite phenotype. In addition, mCREB expression was colocalized with and decreased the expression of prodynorphin in nucleus accumbens medium spiny neurons, and antagonism of dynorphin in the nucleus accumbens was sufficient to produce an antidepressant-like effect similar to that observed after blockade of CREB. Together, the results demonstrate that nucleus accumbens CREB-dynorphin influence behavior in the learned helplessness model and suggest that this signaling cascade may contribute to symptoms of depression.

BACKGROUND: The benefits of selective serotonin reuptake inhibitors, disulfiram, and lithium have not been clear for people with alcohol dependence. While the results of many studies have suggested that opioid agonists increase alcohol consumption, others have shown that mu-opioid antagonists and partial agonists reduce alcohol consumption. The results from animal studies suggest that these agents may prevent the reinforcing effects of alcohol consumption. Based on the results of those animal studies, some opioid antagonists, such as, naltrexone, nalmefene, have been studied for their benefits in treating alcohol dependence. OBJECTIVES: To determine the effectiveness of opioid antagonists in attenuating or preventing the recommencement of alcohol consumption in patients with alcohol dependence in comparison to placebo, other medications and psychosocial treatments. In addition, discontinuation rate, death, patient satisfaction, functioning, health-related quality of life and economic outcomes were also evaluated. SEARCH STRATEGY: Electronic searches of MEDLINE, EMBASE, CINAHL and Cochrane Controlled Trials Register were undertaken. Du Pont Pharmaceutical and Ivax Corporation were contacted for information regarding unpublished trials. The reference lists of the obtained papers were also examined. SELECTION CRITERIA: All relevant randomised controlled trials (RCTs) and clinical control trials (CCTs) were included. Participants were people with alcohol dependence, diagnosed by any set of criteria, except alcohol dependence who were currently abstinent. Naltrexone (NTX), nalmefene (NMF) and other opioid antagonists with/without other biological or psychosocial treatments were examined. A variety of clinical outcomes, for example alcohol consumption, duration of abstinence, were considered. DATA COLLECTION AND ANALYSIS: Two reviewers evaluated and extracted the data independently. The dichotomous data were extracted on an intention-to-treat basis in which the dropouts were assigned as participants with the worst outcomes. The Peto Odds Ratio with the 95% confidence interval was used to assess the dichotomous data. Weighted Mean Difference with 95% confidence interval was used to assess the continuous data. MAIN RESULTS: The short-term (< 3 months) benefits of NTX were shown in three respects, which were number of patients who return to drinking, percentage or number of drinking days and the number of standard drinks of alcohol. However, 6 months after the completion of 12-week NTX treatment, the benefit of decreasing the number of patients who return to drinking were lost. The short-term evidence from a small sample-size study suggested that disulfiram was more effective than NTX in the respects of number of abstinent days, percentage or number of drinking days and number of standard drinks of alcohol. The evidence from another small sample-size study also suggested that NTX plus an aversive agent was superior to an aversive agent alone in the respect of number of patients who return to drinking in short-, medium-, and long-term treatment. From two short-term and small sample-size studies, the benefit of NMF was shown only in the respect of number of patients who return to drinking. REVIEWER'S CONCLUSIONS: Due to the limited evidence, the following conclusions should be viewed as tentative. NTX has some benefits for patients with alcohol dependence, but patients' adherence to treatment should be of concern. Psychosocial treatments should be concurrently given with NTX. The optimal duration of NTX treatment is not yet known. Although NTX is available for treating alcohol dependence in many countries, in the respect of cost-effectiveness, disulfiram should still remain as an alternative. Due to the dearth of evidence, at present, the combination of NTX and disulfiram or NMF alone should not be used in everyday clinical practice. Randomised, double-blind, placebo-controlled trials of NTX treatment in patients with alcohol dependence

Previous studies demonstrated that opioid receptor activation mimics the cardioprotective effect of ischemic preconditioning via KATP channels in the intact heart. However, it is unknown whether this beneficial effect is exerted at the level of the cardiac myocyte or coronary vasculature or is mediated via the sarcolemmal or the mitochondrial KATP channel. Thus, the purpose of the present study was to investigate whether opioid receptor stimulation could mimic the cardioprotective effect of preconditioning in a cardiac myocyte model of simulated ischemia. Cardiac ventricular myocytes cultured from chick embryos 14 days in ovo were used as an in vitro model for ischemic preconditioning. A 5-minute exposure of the myocytes to the opioid receptor agonist morphine protected the myocytes during a subsequent 90-minute period of simulated ischemia, which was manifested as a pronounced reduction in the percentage of cardiac cells killed and the amount of creatine kinase released during ischemia. The preconditioning-like effect of morphine was concentration-dependent, reached a maximal effect at 1 micromol/L, and was reversed by naloxone (0.1 to 10 micromol/L). When KATP channel antagonists, such as glibenclamide, or the mitochondrial selective inhibitor 5-hydroxydecanoic acid were present during preexposure to morphine, they abolished the protective effect of morphine. Thus, cardiac myocytes express functional opioid receptors, and their activation mimics the cardioprotective effect of ischemic preconditioning. These results provide direct evidence that the preconditioning-like effect of morphine in the intact heart can be exerted at the level of cardiac myocytes and is most likely the result of mitochondrial KATP channel activation.