ISSN:
1432-2072
Keywords:
Kappa-opioid agonist
;
U-62,066E
;
Morphine
;
Analgesia
;
Drug discrimination
;
Rat
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
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-lever 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. These findings indicate that U-62,066E has a potent analgesic effect that is mediated predominantly by kappa-opioid receptors, and that U-62,066E stimulus is, in contrast to its analgesic effect, based not only on the compound's kappa-agonist action and consequent inhibition of dopaminergic activity but also on the non-opioid mechanisms.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF02253585
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