Effects of morphine, ethylketocyclazocine, U-50,488H and naloxone on the acquisition of a classically conditioned response in the rabbit.

A series of five experiments examined the effects of mu and kappa opioid agonists on acquisition of conditioned responses in the rabbit and the antagonism of their effects by naloxone. Extension of the nictitating membrane was classically conditioned to a tone stimulus presented before delivery of an electric shock unconditioned stimulus to the skin over the paraorbital region of the head. Morphine, ethylketocyclazocine and U-50,488H retarded the acquisition of conditioned responses to the tone conditioned stimulus with ethylketocyclazocine being twice as potent as the more specific kappa agonist U-50,488H, and 40 times more potent than the prototypic mu agonist morphine. Control experiments indicated that the retarded acquisition produced by the three opioids was due to an action on associative learning. Doses of 0.1 and 1.0 mg/kg of naloxone alone did not affect acquisition of conditioned responses, but did significantly antagonize the retardant effects of all three opioid agonists. On the basis of the parallelism of the dose-effect curves for the three opioid agonists, their order of potency which was remarkably different from potency ratios observed for other measures, e.g. analgesia, and on the finding that all three opioids demonstrated approximately equivalent sensitivity to antagonism by naloxone, it was concluded that the effects of all three opioid agonists on the acquisition of conditioned responses may be mediated by a common receptor.