Kappa opioids in rhesus monkeys. III. Dependence associated with chronic administration

The kappa opioid agonists, Mr 2033 and U-50, 488, or the mu opioid agonist, morphine, were administered chronically to three separate groups of rhesus monkeys. Tolerance developed to the overt signs of intoxication produced by each compound. Monkeys receiving morphine were not cross-tolerant to Mr 2033 or to U-50, 488, and monkeys receiving U-50, 488 were not cross-tolerant to morphine. Monkeys given Mr 2033 chronically were, however, cross-tolerant to morphine. When administration of U-50,488 was interrupted, or the monkeys receiving this compound were given an opioid antagonist, withdrawal behaviors were displayed that were qualitatively different from deprivation or antagonist-induced morphine withdrawal. These signs were suppressed by kappa agonists but not by morphine. Deprivation-induced withdrawal from Mr 2033 resulted in signs similar to those shown by U-50,488-dependent monkeys and some signs were observed in withdrawn morphine-dependent monkeys. Several antagonists, including the mu-selective antagonist beta-funaltrexamine, precipitated signs of withdrawal normally associated with morphine dependence in Mr 2033-dependent monkeys. Withdrawal from Mr 2033 was suppressed by kappa agonists in a stereoselective manner, and by morphine. The asymmetrical cross-tolerance and cross-dependence between Mr 2033 and morphine, and the appearance of morphine-like signs during precipitated withdrawal, suggest that Mr 2033 is kappa receptor selective but not specific. Dependence to U-50,488, however, was qualitatively and pharmacologically distinct from morphine-dependence and is apparently a consequence of specific activity at kappa receptors.