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PAIN MEDICINE

Modulations of Spinal Serotonin Activity Affect the Development of Morphine Tolerance

Department of Anesthesiology, Chang-Gung Memorial Hospital, and Department of Pharmacology, Chang-Gung University, Taiwan, ROC, and *Department of Pharmacology, National Defense Medical Center, Taiwan, ROC

Address correspondence and reprint requests to Dr. Jin-Chung Chen, Department of Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Tao-Yuan, Kwei-Shan, Taiwan, ROC. Address e-mail to Jinchen{at}mail.cgu.edu.tw

Abstract

To test whether modulations of spinal serotonin (5-HT) levels would affect the development of morphine tolerance, we treated rats with either intrathecal 5-HT or 5,7-dihydroxytryptamine (5,7-DHT; a 5-HT neurotoxin) in addition to systemic infusion with morphine (2 mg · kg^-1 · h^-1). Continuous infusion of 5-HT (10 µg · 6 µL^-1 · h^-1) into the lumbar subarachnoid space of rats for 9 h accelerated the development of morphine tolerance. The area under the curve for the tail-flick latency test was 454.1 ± 35.1 in the Sham Control group vs 327.6 ± 41.0 in the 5-HT-Infused group. µ-opioid receptor binding in the lumbar spinal cord showed a decrease in the Bmax (maximal binding -46.5%), but not the binding affinity (Kd), in 5-HT-infused rats. However, intrathecal injection of 5,7-DHT (50 µg), which resulted in a 48% reduction in 5-HT and 51% reduction in 5-hydroxyindoleacetic acid concentrations, led to an attenuation of morphine tolerance (the area under the curve was 613.0 ± 24.7 in the 5,7-DHT-Lesioned group). The binding study indicated that the affinity of lumbar µ-opioid receptors decreased 196% in 5-HT-depleted rats, whereas there was no effect on apparent binding. The infusion of 5-HT (10 µg · 6 µL^-1 · h^-1) was not analgesic and the 5,7-DHT-induced lesion did not affect acute morphine-induced analgesia. We conclude that activity of spinal 5-HT-containing neurons plays a crucial role during the development of morphine tolerance.

Implications: Spinal cord serotonin (5-HT) levels seem to be critical in the development of morphine tolerance. Reduction of 5-HT levels in the spinal cord prolonged the development of tolerance to morphine. Manipulation of 5-HT levels could be a valuable method for altering the efficacy of opioid analgesia, particularly during patient-controlled analgesia.

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