Effects were determined of chronic administration and withdrawal of a highly selective kappa-opioid receptor agonist, U-50,488H, on methionine-enkephalin levels in central and peripheral tissues of male Sprague-Dawley rats. Rats were rendered tolerant to and physically dependent on U-50,488H by twice daily injections of 25 mg/kg of this compound for 5 days. Rats deemed abstinent were injected with this drug for 4 days and sacrificed on 5th day. Methionine-enkephalin concentration increased in the hippocampus of U-50,488H-tolerant-dependent rats, whereas in abstinent rats, its level was elevated only in the hypothalamus. Levels of methionine-enkephalin in the pituitary gland of U-50,488H-tolerant-dependent or abstinent rats were unchanged. Among peripheral tissues, methionine-enkephalin concentration decreased in the adrenal gland of U-50,488H-tolerant-dependent rats. In the U-50,488H-abstinent rats, methionine-enkephalin concentration was elevated in the heart. In tissues of morphine- and U-50,488H-tolerant-dependent and abstinent rats methionine-enkephalin concentrations were affected differentially, suggesting inherent differences in mu- and kappa-opiate-mediated tolerance-dependence and abstinence processes.