Modulations of spinal serotonin activity affect the development of morphine tolerance

To test whether modulations of spinal serotonin (5-MT) levels would affect the development of morphine tolerance, we treated rats with either intrathe cal 5-HT or 5,7-dihydroxyhyptamine (5,7-DHT; a 5-HTneurotoxin) in addition to systemic infusion with morphine (2 mg.kg(-1).h(-1)). Continuous infusion of 5-HT (10 mug 6 muL(-1)) into the lumbar subarachnoid space of rats for 9 h accelerated the development of morphine tolerance. The area under the c urve 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. mu -opioid receptor bin ding in the lumbar spinal cord showed a decrease in the Bmax (maximal bindi ng -46.5%), but not the binding affinity (Kd), in 5-HT-infused rats. Howeve r, intrathecal injection of 5,7-DHT (50 mug), which resulted in a 48% reduc tion 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 mu -opioid receptors decreased 196% in 5-HT-de pleted rats, whereas there was no effect on apparent binding. The infusion of 5-HT (10 mug.6 muL(-1).h(-1)) was not analgesic and the 5,7-DHT-induced lesion did not affect acute morphine-induced analgesia. We conclude that ac tivity of spinal 5-HT-containing neurons plays a crucial role during the de velopment of morphine tolerance.