Analgesic and discriminative stimulus properties of U-62,066E, the selective kappa-opioid receptor agonist, in the rat

Abstract

The analgesic and discriminative stimulus properties of U-62,066E, a selective kappa-opioid receptor agonist, were investigated in the rat and compared with those of morphine. In the hot-plate test, U-62,066E produced a potent analgesic effect almost comparable to that of morphine. U-62,066E-induced analgesia was far less sensitive to antagonism by naloxone than was morphine-induced analgesia, but was potently reversed by MR-2266, a kappa-receptor antagonist. Although tolerance occurred to both U-62,066E and morphine analgesia, there was no cross-tolerance between these drugs. U-62,066E did show cross-tolerance to U-50,488H, another selective kappa-receptor agonist. Rats were trained to discriminate either 1.0 mg/kg U-62,066E or 3.2 mg/kg morphine from saline in a two-level food-reinforced procedure. The stimulus effect of U-62,066E was substituted for by U-50,488H and E-2078 a stable dynorphin derivative, but not by morphine. None of the kappa-agonists substituted for the morphine stimulus. Although U-62,066E stimulus by itself was not antagonized by MR-2266 or naloxone up to as high a dose as 10 mg/kg, the U-62,066E-like stimulus effect of U-50,488H was markedly blocked by MR-2266. The dopamine antagonists haloperidol and sulpiride substituted for the U-62,066E stimulus cue that was, however, not attenuated by the dopamine agonist lisuride. Lisuride reversed the U-62,066E-like stimulus induced by U-50,488H.(ABSTRACT TRUNCATED AT 250 WORDS)