Abstract
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.
Footnotes
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This work was supported by Grant-in-Aid for the Encouragement of Young Scientists from the Japan Society for the Promotion of Science 16790116 (to M.Y.) and Grant 056001 from the Central Research Institute of Fukuoka University.
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doi:10.1124/jpet.105.091488.
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ABBREVIATIONS: SCN, suprachiasmatic nuclei; HPA, hypothalamus-pituitary-adrenal; CRH, corticotrophin-releasing hormone; [3H]DAMGO, [d-ala2,N-methyl-phe4,glyol5][tyrosyl-3,5-3H]-enkephalin; PCR, polymerase chain reaction; RT-PCR, reverse transcription-polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; RU486, 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one; GR, glucocorticoid receptor; GRE, glucocorticoid-response element.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received June 22, 2005.
- Accepted August 17, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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