Pain‐related depression of intracranial self‐stimulation in rats: effects of the kappa opioid agonist U69,593 and the kappa opioid antagonist norbinaltorphimine

Abstract

Selective kappa agonists produce antinociception in many preclinical assays, but unlike mu agonists, they perform poorly as analgesics in humans. This discrepancy may be related to prodepressant effects of kappa agonists. Kappa antagonists do not produce antinociception, but they can produce antidepressant‐like effects. This study tested the hypothesis that the kappa agonist U69,593 and kappa antagonist norbinaltorphimine (norBNI) would produce pronociceptive and antinociceptive effects, respectively, in an assay of pain‐depressed behavior. Effects of U69,593 (0.056–0.56 mg/kg), norBNI (10–32 mg/kg) and morphine (3.2 mg/kg) were evaluated on stimulation of stretching and depression of intracranial self‐stimulation (ICSS) by intraperitoneal administration of dilute lactic acid in rats. U69,593 blocked acid‐stimulated stretching but only exacerbated acid‐induced depression of ICSS. Norbinaltorphimine did not alter either pain‐related behavior, and morphine blocked both pain‐related behaviors. The assay of acid‐depressed ICSS permitted dissociation of mu and kappa agonist effects and failed to reveal an antinociceptive effect of a kappa antagonist. Supported by NIH grant R01‐NS070715 and the Intramural Research Programs of NIDA and NIAAA.