Phosphodiesterase inhibitors potentiate opiate-antagonist discrimination by morphine-dependent rats.
This study was performed to examine the relevance of the quasi-withdrawal syndrome in nondependent rats to the syndrome precipitated by naltrexone in rats physically dependent upon morphine. Morphine-dependent rats trained to discriminate between SC injections of naltrexone (0.1 mg/kg) and saline were pretreated with 10 mg/kg of a phosphodiesterase inhibitor: 3-isobutyl-1-methylxanthine (IBMX), Ro 20-1724, or papaverine. The naltrexone stimulus-generalization curve and dose-response curve for loss of body weight were shifted to the left by IBMX and Ro 20-1724, which produce quasi-withdrawal, but not by papaverine, which does not. IBMX also potentiated the naltrexone-like discriminative effects and loss of body weight induced by cyclazocine, an opioid agonist-antagonist. Butorphanol, another agonist-antagonist, occasioned choice responding appropriate for saline when tested alone but engendered more than 50% naltrexone-appropriate choice responses in rats pretreated with IBMX. Thus, phosphodiesterase inhibitors that produce an opiate quasi-withdrawal syndrome potentiate interoceptive stimuli and weight loss associated with the withdrawal syndrome precipitated by naltrexone in morphine-dependent rats. Furthermore, they appear to enhance the opiate-antagonist activity of opioids with mixed agonist and antagonist properties.
Holtzman
S G
SG
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008297:Male; D009020:Morphine; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology; D010208:Papaverine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D019966:Substance-Related Disorders
D009292:Narcotic Antagonists; D010726:Phosphodiesterase Inhibitors; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D009271:Naltrexone; D009020:Morphine; D010208:Papaverine; D015056:1-Methyl-3-isobutylxanthine