Glucocorticoid hormone regulates the circadian coordination of μ-opioid receptor expression in mouse brainstem

The 24-h variation in glucocorticoid secretion from the adrenal cortex is observed not only in nocturnally active rodents but also in diurnally active humans. Although the cyclic change in circulating glucocorticoid levels is thought to influence the efficacy and/or toxicity of many drugs, the mechanism underlying the influence remains poorly understood. In this study, we demonstrate that the 24-h variation in circulating glucocorticoid levels modulates the analgesic effect of morphine by regulating the expression of the μ-opioid receptor. Significant time-dependent variations in the mRNA levels of the μ-opioid receptor and its binding capacity were observed in mouse brainstem. The analgesic effect of morphine was enhanced by administering the drug when μ-opioid receptor levels were increased. However, corticotrophin-releasing hormone (CRH)-deficient mice, disrupting the 24-h rhythm of glucocorticoid secretion, showed no significant time-dependent variation in the expression of the μ-opioid receptor. As a consequence, there was no significant dosing time-dependent difference in the analgesic effect of morphine in CRH-deficient mice. A single administration of corticosterone significantly induced the expression of the μ-opioid receptor in the CRH-deficient mouse brainstem and also enhanced the analgesic effect of morphine. These findings suggest a mechanism underlying the time-dependent variation in μ-opioid receptor function and provide clues to select the most appropriate time of day for administration of morphine.