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.