DISRUPTION OF THE KAPPA-OPIOID RECEPTOR GENE IN MICE ENHANCES SENSITIVITY TO CHEMICAL VISCERAL PAIN, IMPAIRS PHARMACOLOGICAL ACTIONS OF THESELECTIVE KAPPA-AGONIST U-50,488H AND ATTENUATES MORPHINE-WITHDRAWAL

mu-, delta- and kappa-opioid receptors are widely expressed in the cen tral nervous system where they mediate the strong analgesic and mood-a ltering actions of opioids, and modulate numerous endogenous functions , To investigate the contribution of the kappa-opioid receptor (KOR) t o opioid function in vivo, we have generated KOR-deficient mice by gen e targeting, We show that absence of KOR does not modify expression of the other components of the opioid sq stem, and behavioural tests ind icate that spontaneous activity is not altered in mutant mice, The ana lysis of responses to various nociceptive stimuli suggests that the KO R gene product is implicated in the perception of visceral chemical pa in, We further demonstrate that KOR is critical to mediate the hypoloc omotor, analgesic and aversive actions of the prototypic kappa-agonist U-50,488H, Finally, our results indicate that this receptor does not contribute to morphine analgesia and reward, but participates in the e xpression of morphine abstinence, Together, our data demonstrate that the KOR-encoded receptor plays a modulatory role in specific aspects o f opioid function.