mu, delta, kappa opioid receptors are target molecules for analgesia, reward and many physiological functions of opiates. Opioid receptor knockout mice generated by gene-targeting technology which can introduce mutation into specified locus provide invaluable animal models to elucidate the in vivo function of opiates and develop new therapeutic drugs. The disruptions of mu receptor expression decreases the nociceptive threshold to thermal stimuli and increases the threshold to visceral chemical stimuli paradoxically. Analgesia, reward, respiratory depression, constipation, immunosuppression and physical dependence induced by morphine are absent in mice lacking the mu receptor. These data show that the mu receptor is a molecular target for most effects of morphine, both therapeutic and side effects. mu Receptor expression is required for most delta receptor-mediated and some kappa receptor analgesic effects. These results support substantial roles for mu receptor in the analgesic properties of delta, kappa receptors. Cocaine and ethanol reward require mu receptor systems' intactness. Mice lacking the mu receptor will be a useful tool to study complex interactions between endogenous opiate and dopamine systems.