title: Improved effect of the combination naltrexone/D-penicillamine in the prevention of alcohol relapse-like drinking in rats.
abstract: Opioid antagonists are licensed drugs for treating alcohol use disorders; nonetheless, clinical studies have evidenced their limited effectiveness. Preclinical findings indicate that opioid receptor (OR) antagonists, such as naltrexone (NTX), reduce the alcohol deprivation effect (ADE). However, a detailed analysis of published data shows the existence of a delayed increase in ethanol consumption after continuous OR blockade, a phenomenon originally called as 'delayed ADE'. We have recently reported that D-penicillamine (DP) is able to prevent ADE through a mechanism dependent on the inactivation of acetaldehyde, the main metabolite of ethanol. Hypothetically, OR activation would be triggered by acetaldehyde after ethanol consumption. Hence, we conjecture that the combination of NTX and DP, due to their distinct but complementary mechanisms to impede OR activation, may be more efficacious in the prevention of the ADE and, specifically, the 'delayed ADE'. Herein, we compare the effects of the combination NTX/DP (NTX: 2×5 mg/kg SC injection daily/DP: SC infusion (0.25 mg/h)) versus NTX on the ADE in long-term ethanol-experienced rats. As expected, NTX-treated animals displayed a delayed ADE. However, NTX/DP treatment prevented this delayed effect. Our present data indicate that this combination therapy shows an adequate anti-relapse preclinical efficacy being able to overcome the preclinical limitations of NTX alone.
authors.affiliation: Departament de Farmàcia i Tecnologia Farmacèutica, Universitat de València, Burjassot, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Orrico
authors.forename: Lucía
authors.initials: L
authors.lastname: Martí-Prats
authors.forename: María J
authors.initials: MJ
authors.lastname: Cano-Cebrián
authors.forename: Luis
authors.initials: L
authors.lastname: Granero
authors.forename: Ana
authors.initials: A
authors.lastname: Polache
authors.forename: Teodoro
authors.initials: T
authors.lastname: Zornoza
mesh_terms: D000427:Alcohol Deterrents / Q000008:administration & dosage / Q000627:therapeutic use; D000428:Alcohol Drinking / Q000188:drug therapy* / Q000517:prevention & control*; D000818:Animals; D004359:Drug Therapy, Combination; D055104:Infusions, Subcutaneous; D007279:Injections, Subcutaneous; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D010396:Penicillamine / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D055502:Secondary Prevention
chemical_list: D000427:Alcohol Deterrents; D009292:Narcotic Antagonists; D009271:Naltrexone; D010396:Penicillamine
keywords: D-penicillamine; acetaldehyde; ethanol relapse prevention; mu-opioid receptor; naltrexone