Antagonist-induced opioid receptor up-regulation. I. Characterization of supersensitivity to selective mu and kappa agonists.

In this study, chronic opioid antagonist-induced alterations in sensitivity to selective mu- and kappa-opioid agonists were examined. Administration of naloxone (0.5 mg/kg/hr) via osmotic minipumps eliminated the antinociception elicited by the mu-agonist, morphine, but did not affect that induced by the kappa-agonist, U50, 488H. After 1 week of treatment and after pump removal, dose-response curves for the induction of antinociception by morphine against noxious heat, pressure and electrical stimulation were shifted to the left across the entire time course of action: this supersensitivity subsided over a period of 1 week postremoval. No facilitation of the actions of U50,488H was seen. Three days of infusion also induced a significant supersensitivity to morphine but a single, acute high dose of naloxone (3.0 mg/kg) was ineffective. The effect of naloxone was dose-dependent (0.05-0.50 mg/kg/hr). Chronic treatment at 3.0 mg/kg/hr blocked the antinociception induced by both U50,488H and morphine. After 1 week and after pump removal, the antinociceptive action of U50,488H against pressure, but not heat, was enhanced; the antinociceptive action of morphine against both heat and pressure was facilitated. These data, in conjunction with our autoradiographical findings suggest: 1) it is possible to selectively block and up-regulate mu as compared to kappa receptors; 2) chronic treatment with naloxone can induce a supersensitivity to kappa-agonists; and 3) the pool of kappa-receptors acting antinociceptively against pressure may differ from that acting against heat.