Place-conditioning properties of mu, kappa, and sigma opioid agonists

The place-conditioning capacities of morphine, ketocyclazocine, ethylketocyclazocine, bremazocine, U 50488, d,1-N-allylnormetazocine (NAN), d-NAN, 1-NAN, and the effects of the opioid antagonists naloxone, WIN 44,441-3, and MR 2266BS were assessed in adult male rats using a three-chambered place-conditioning apparatus. Morphine, ketocyclazocine, ethylketocyclazocine, d,1-NAN, and 1-NAN at doses ranging from 0.25 to 4 mg/kg induced place-preferences for the compartment that was paired with drug administration during the conditioning process. One, 2, or 4 mg/kg of d-NAN had little effect. Naloxone, at doses of 1, 2, 4, and 10 mg/kg, conditioned strong place-aversions in rats; that is, on test day, rats spent significantly more time in the compartment that was not paired with drug-treatment. Bremazocine (0.05 to 4 mg/kg) and U 50488 (0.4 to 4 mg/kg) also conditioned significant, dose-related place-aversions. The results of the putative kappa opioid antagonists were mixed; MR 2266BS caused a dose-related place-aversion while the WIN 44,441-3 produced place-preference. Two mg/kg, but not 0.02 or 0.2 mg/kg, of naloxone administered prior to conditioning with 4 mg/kg of morphine, ethylketocyclazocine, and d,1-NAN, or 2 mg/kg of ketocyclazocine, resulted in place-aversions similar in magnitude to those found after naloxone-conditioning alone. Thus, the mu agonist morphine, the kappa agonists ketocyclazocine and ethylketocyclazocine, the sigma-agonist d,1-NAN, and the levo isomer of NAN all induce place-preferences in the rat according to the place-conditioning paradigm. In contrast, the kappa agonists bremazocine and U 50488, and the kappa antagonist MR 2266BS, induced place-avoiding responses. Since the development of place-preference after morphine, ketocyclazocine, ethylketocyclazocine, and d,1-NAN was antagonized by a kappa-receptor-antagonist dose of naloxone (2 mg/kg) and not by mu-receptor-antagonist doses, these data provide evidence that these particular mu, kappa, and sigma opioids may share a common underlying pharmacologic action.