LOSS OF MORPHINE-INDUCED ANALGESIA, REWARD EFFECT AND WITHDRAWAL SYMPTOMS IN MICE LACKING THE MU-OPIOID-RECEPTOR GENE

DESPITE tremendous efforts in the search for safe, efficacious and non -addictive opioids for pain treatment, morphine remains the most valua ble painkiller in contemporary medicine. Opioids exert their pharmacol ogical actions through three opioid-receptor classes(1,2), mu, delta a nd kappa, whose genes have been cloned(3). Genetic approaches are now available to delineate the contribution of each receptor in opioid fun ction in vivo. Here we disrupt the mu-opioid-receptor gene in mice by homologous recombination and find that there are no overt behavioural abnormalities or major compensatory changes within the opioid system i n these animals. Investigation of the behavioural effects of morphine reveals that a lack of mu receptors abolishes the analgesic effect of morphine, as well as place-preference activity and physical dependence . We observed no behavioural responses related to delta- or kappa-rece ptor activation with morphine, although these receptors are present an d bind opioid ligands. We conclude that the mu-opioid-receptor gene pr oduct is the molecular target of morphine in vivo and that it is a man datory component of the opioid system for morphine action.