morphinans and Alcoholism

This paper reviews preclinical research which demonstrates the involvement of the opioid system in the reinforcing effects of alcohol, and the effects of naltrexone, a long-acting, nonselective opioid receptor antagonist to reduce alcohol intake. Naltrexone (50 mg/day) may prevent the return to drinking by blocking the pleasurable effects or "high" associated with alcohol drinking, and relapse rates were reduced. The most common adverse effects reported include nausea and vomiting and it does not appear to be hepatotoxic in dosages recommend. Thus, naltrexone appears to offer significant therapeutic benefits, when used with behavioural treatment for alcohol dependent patients.

Topics: Alcoholism; Humans; Morphinans; Naltrexone

Though it is well known that G protein-coupled receptor kinase 2 [GRK2] is involved in regulation of mu opioid receptor [MOR] desensitization and morphine-related behaviors, the potential role of GRK2 in regulation of kappa opioid receptor [KOR] functions in vivo has not been established yet. A couple of recent studies have found that GRK2 activity desensitizes KOR functions via decreasing G protein-coupled signaling with sensitizing arrestin-coupled signaling. Nalfurafine, a G protein-biased KOR full agonist, produces an inhibitory effect on alcohol intake in mice, with fewer side effects (sedation, aversion, or anxiety/depression-like behaviors). Using RNA sequencing (RNA-seq) analysis, we first identified that nuclear transcript level of grk2 [adrbk1] (but not other grks) was significantly up-regulated in mouse nucleus accumbens shell (NAcs) after chronic excessive alcohol drinking, suggesting alcohol specifically increased NAcs grk2 expression. We then tested whether selective GRK2/3 inhibitor CMPD101 could alter alcohol intake and found that CMPD101 alone had no effect on alcohol drinking. Therefore, we hypothesized that the grk2 increase in the NAcs could modulate the nalfurafine effect on alcohol intake via interacting with the G protein-mediated KOR signaling. Nalfurafine decreased alcohol drinking in a dose-related manner, and pretreatment with CMPD101 enhanced the reduction in alcohol intake induced by nalfurafine, indicating an involvement of GRK2/3 blockade in modulating G protein-biased KOR agonism of nalfurafine. Together, our study provides initial evidence relevant to the transcriptional change of grk2 gene in the NAc shell after excessive alcohol drinking. Pharmacological GRK2/3 blockade enhanced nalfurafine's efficacy, suggesting a GRK2/3-mediated mechanism, probably through the G protein-mediated KOR signaling.

Topics: Alcoholism; Animals; Benzamides; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Ethanol; G-Protein-Coupled Receptor Kinase 2; G-Protein-Coupled Receptor Kinase 3; Humans; Male; Mice; Morphinans; Nucleus Accumbens; Pyridines; Receptors, Opioid, kappa; Spiro Compounds; Triazoles

Alcohol relapse is a treatment goal for alcohol dependence and the target for medications' development. Clinically utilized nalfurafine (NFF) is a potent and selective kappa- opioid receptor (KOP-r) agonist, with fewer side effects (e.g., sedation or anhedonia) than classic KOP-r full agonists. We have recently found that NFF reduces excessive alcohol drinking in mice via a KOP-r-mediated mechanism. Here, we further investigated whether NFF alone (1-10 μg/kg) or in combination with naltrexone (NTX, mu-opioid receptor [MOP-r] antagonist) altered alcohol relapse-like drinking using a mouse alcohol deprivation effect (ADE) paradigm to mimic the relapse episodes in human alcoholics. Nalmefene (NMF, clinically utilized KOP-r partial agonist with MOP-r antagonism) was used as a reference compound for the effects on mouse ADE of new NFF + NTX combination. After exposed to 3-week intermittent- access alcohol drinking (two-bottle choice, 24-h access every other day), both male and female mice displayed excessive alcohol intake and then pronounced ADE after 1-week abstinence. NFF prevented the ADE in a dose-dependent manner in both male and female mice. A combination of NFF with NTX reduced the ADE without sex differences at doses lower than those individual effective ones, suggesting synergistic effects between the two compounds. NMF prevented the ADE in both sexes, while selective KOP-r antagonist nor-BNI had no effect. Our new study suggests that a combination of clinically-utilized, potent KOP-r agonist NFF with low-dose NTX has therapeutic potential in alcohol "relapse" treatment.

Topics: Alcohol Drinking; Alcoholism; Analgesics, Opioid; Animals; Drinking; Ethanol; Female; Male; Mice; Mice, Inbred C57BL; Morphinans; Naltrexone; Narcotic Antagonists; Receptors, Opioid, kappa; Receptors, Opioid, mu; Recurrence; Secondary Prevention; Spiro Compounds

Drugs that more potently or effectively reduce ethanol-maintained behaviour versus an alternative are considered selective and are considered promising pharmacotherapies for alcoholism. Such results are often obtained using separate groups or multiple schedules where ethanol and the alternative are available alone or sequentially. Recently, we observed that when ethanol and food were available sequentially under a multiple schedule, fluvoxamine and varenicline were selective; yet this selectivity disappeared when ethanol and food were concurrently available.. We examined the generality of these findings by comparing doses of several drugs required to decrease ethanol- and food-maintained responding under a multiple schedule and under a concurrent schedule. Effects were determined for chlordiazepoxide, 2,5-dimethoxy-4-iodoamphetamine (DOI), meta-chlorophenylpiperazine (mCPP), morphine, naltrexone and d-amphetamine.. Under the multiple schedule, ED50 values for decreases in ethanol-maintained responding were significantly different and lower than ED50 s for decreases in food-maintained responding (demonstrating selectivity) for each drug except for chlordiazepoxide (which was equipotent) and naltrexone (which did not affect responding). However, this selectivity vanished or even inverted under the concurrent schedule, such that ED50 values for decreasing ethanol- and food-maintained responding were not different (or, following DOI, the ED50 for food-maintained responding was lower than for ethanol-maintained responding).. Results are consistent with those seen following fluvoxamine and varenicline administration, and suggest that selectivity is assay-dependent. These results indicate the need for careful interpretation of selective drug effects, especially when obtained in situations where ethanol or the alternative is the only programmed reinforcement available.

Topics: Alcoholism; Amphetamines; Animals; Chlordiazepoxide; Dextroamphetamine; Dose-Response Relationship, Drug; Drug Administration Schedule; Eating; Ethanol; Food; Male; Morphinans; Naltrexone; Piperazines; Rats; Rats, Inbred Lew

Substituted aryl and aliphatic amide analogues of 6-naltrexamine were synthesized and used to characterize the binding to and functional activity of human mu-, delta-, and kappa-opioid receptors. Competition binding assays showed 11-25 and 27-31 bound to the mu (K(i) = 0.05-1.2 nM) and kappa (K(i) = 0.06-2.4 nM) opioid receptors. Compounds 11-18 possessed significant binding affinity for the delta receptor (K(i) = 0.8-12.4 nM). Functional assays showed several compounds acted as partial or full agonists of delta or kappa receptors while retaining an antagonist profile at the mu receptor. Structure-activity relationship for aryl amides showed that potent compounds possessed lipophilic groups or substituents capable of hydrogen bonding. Metabolic stability studies showed that 11, 12, and 14 possessed considerable stability in the presence of rat, mouse, or human liver preparations. The ED 50 of inhibition of 10% ethanol self-administration in trained rats, using operant techniques for 11, was 0.5 mg/kg.

Topics: Alcohol Drinking; Alcoholism; Amides; Animals; Binding, Competitive; Drug Evaluation, Preclinical; Ethanol; Humans; Hydrogen Bonding; Liver; Mice; Microsomes, Liver; Molecular Structure; Morphinans; Naltrexone; Rats; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Stereoisomerism; Structure-Activity Relationship

Topics: Adult; Alcoholism; Barbiturates; Cannabis; Diazepam; Drug Combinations; Drug Therapy, Combination; Female; Germany, West; Hospitals, General; Humans; Male; Methadone; Morphinans; Opium; Promethazine; Psychotherapy; Substance Withdrawal Syndrome; Substance-Related Disorders; Thiazines

Topics: Alcoholism; Amphetamine; Barbiturates; California; Cannabis; Cocaine; Drug Prescriptions; Ethanol; Hallucinogens; Humans; Hypnotics and Sedatives; Morphinans; Narcotics; Nicotiana; Nonprescription Drugs; Plants, Toxic; Societies, Medical; Solvents; Substance-Related Disorders; Tranquilizing Agents

According to a recently proposed hypothesis, physical dependence upon alcohol is due to the formation of an endogenous opiate. We tested the hypothesis by determining whether or not ethanol-dependent mice would show typical opiate-dependent behavior (withdrawal jumping syndrome) when challenged with the opiate antagonist naloxone. Our results do not support the hypothesis.

Topics: Alcoholism; Animals; Dopamine; Ethanol; Humans; Isoquinolines; Male; Mice; Morphinans; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Adolescent; Adult; Aged; Alcoholism; Amphetamine; Analgesics; Barbiturates; Cannabis; Cocaine; Female; Hallucinogens; Heroin; Humans; Hypnotics and Sedatives; Male; Middle Aged; Morphinans; Opium; Phytotherapy; Prognosis; Substance-Related Disorders; Tranquilizing Agents