Molecular pharmacological study on the roles of the central noradreneric neurosis in the higher central actions of morphine

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μ-Opioid receptor, a receptor far morphine, is intensely expressed in the noradrenergic neurons located in the locus coeruleus.. These neurons project into various brain regions including the cerebral cortex, hippocampus and amygdala, and are implicated in memory, emotion and stress responses. However, the molecular bases for the regulation of memory, emotion and stress responses through the opioid system remain to be elucidated. In this study, we generated the genetically modified mouse line in which μ-opioid receptors are expressed only in the not adrenergic neurons by means of the crossbreeding between the μ-opioid receptor KO mouse and the transgenic mouse in which the expression of human μ-opioid receptor gene is regulated by DBH (dopamine β-hydroxyrase) promoter. Using this newly generated mouse line, we showed that the μ-opioid receptors expressed in the noradrenergic neurons are involved in the regulation of stress responses, such as the escape behavior and corticosteroid hormone release induced by the stress. In addition, using the μ-opioid receptor KO mice, we demonstrated that most of the analgesic effect of buprenorphine, one of the analgesics clinically used in Japan, is mediated by μ-opioid receptors. These findings are considered to be useful for the understanding of the roles of μ-opioid receptors in the stress responses and for the improvement of clinical use of buprenorphine.