Interaction of morphine and naltrexone on oral ethanol self-administration in rhesus monkeys.
Opioid antagonists, such as naltrexone (NTX), reduce ethanol consumption and opioid agonists increase or decrease ethanol consumption in rats depending upon the dose. If the opioid antagonist and agonist effects on ethanol consumption are mediated by mu-opioid receptors, then NTX doses that reduce ethanol consumption should be similar to the doses necessary to antagonize the effects of opioid agonists on ethanol consumption. The purpose of these experiments was: (1) to determine whether morphine increases ethanol consumption in rhesus monkeys as it does in rodents; (2) to determine if the mu-receptor mediates the effects of morphine on ethanol consumption by conducting a pK(B) analysis using NTX; and (3) to determine if the mu-receptor also mediates the NTX-induced decreases in ethanol consumption by making comparisons between the NTX doses that affect ethanol consumption and the NTX doses that block the effects of morphine on ethanol consumption. Three male rhesus monkeys responded for 2% ethanol and water for 2 h/day on a fixed-ratio 4 schedule of reinforcement. Morphine doses as low as 0.0032mg/kg failed to increase ethanol fluid deliveries, whereas higher doses produced a dose-related decrease in ethanol fluid deliveries. Although 0.01 mg/kg NTX alone had no effect on ethanol fluid deliveries, it reduced the suppressant effects of morphine with a mu-receptor pK(B) of 8.21 (8.08-8.34). When given alone, 0.1 mg/kg NTX decreased ethanol fluid deliveries but failed to reverse the suppression caused by 1 mg/kg morphine. Therefore, monkeys may differ from rats in their response to morphine when ethanol consumption is the dependent variable. Furthermore, because the NTX dose that reduced the effects of morphine on responding for ethanol was smaller than the NTX doses that suppressed ethanol-reinforced responding when given alone, NTX may exert these two effects through different mechanisms.
Williams
K L
KL
Department of Pharmacology, University of Michigan, Ann Arbor 48109-0632, USA. keithwil@umich.edu
Kane
E C
EC
Woods
J H
JH
D000428:Alcohol Drinking / Q000523:psychology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000187:drug effects; D012054:Reinforcement, Psychology
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D009020:Morphine