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BEHAVIORAL PHARMACOLOGY

Chronopharmacology of Analgesic Effect and Its Tolerance Induced by Morphine in Mice

Clinical Pharmacokinetics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

The influence of morphine dosing time on analgesic effect after acute or chronic treatment, recovery of analgesic effect after once developed tolerance, and their pharmacological mechanisms were investigated in ICR male mice under a 12-h light/dark cycle (light on from 7:00 AM to 7:00 PM). There was a significant 24-h rhythm in the latency of thermal response at 30 min after morphine injection. The analgesic effect was significantly greater at the dark phase than at the light phase. The rhythmic pattern resembled overall the rhythm occurring in the latency of thermal response under nondrugged state. The absolute value of morphine analgesic effect (the real time spent on the hot-plate) on days 1 and 2 after morphine daily injection was significantly larger after morphine injection at 9:00 PM than after saline injection at 9:00 PM or after morphine injection at 9:00 AM. The recovery from tolerance of analgesic effect was significantly faster at the dark phase than at the light phase. The time-dependent difference in the analgesic effect after chronic treatment or recovery from tolerance is closely related to that in the expression of µ-opioid receptor. The present study suggests that 24-h rhythm of morphine analgesic effect is consistent with 24-h rhythm of µ-opioid receptor expression.

Address correspondence to: Dr. Shigehiro Ohdo, Department of Medico-Pharmaceutical Sciences, Clinical Pharmacokinetics, Division of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812-8582 Japan. E-mail: ohdo{at}phar.kyushu-u.ac.jp

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