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Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the µ-opioid-receptor gene

Abstract

DESPITE tremendous efforts in the search for safe, efficacious and non-addictive opioids for pain treatment, morphine remains the most valuable painkiller in contemporary medicine. Opioids exert their pharmacological actions through three opioid-receptor classes1,2, µ, δ and κ, whose genes have been cloned3. Genetic approaches are now available to delineate the contribution of each receptor in opioid function in vivo. Here we disrupt the μ-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 in these animals. Investigation of the behavioural effects of morphine reveals that a lack of μ receptors abolishes the analgesic effect of morphine, as well as place-preference activity and physical dependence. We observed no behavioural responses related to δ- or κ-receptor activation with morphine, although these receptors are present and bind opioid ligands. We conclude that the µ-opioid-receptor gene product is the molecular target of morphine in vivo and that it is a mandatory component of the opioid system for morphine action.

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Matthes, H., Maldonado, R., Simonin, F. et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the µ-opioid-receptor gene. Nature 383, 819–823 (1996). https://doi.org/10.1038/383819a0

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