Modulations of spinal serotonin activity affect the development of morphine tolerance.
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 x kg(-1) x h(-1)). Continuous infusion of 5-HT (10 microg x 6 microL(-1) x 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. mu-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 microg), 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 micro-opioid receptors decreased 196% in 5-HT-depleted rats, whereas there was no effect on apparent binding. The infusion of 5-HT (10 microg x 6 microL(-1) x 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.
Li
J Y
JY
Department of Anesthesiology, Chang-Gung Memorial Hospital, Taiwan, ROC.
Wong
C H
CH
Huang
E Y
EY
Lin
Y C
YC
Chen
Y L
YL
Tan
P P
PP
Chen
J C
JC
D015116:5,7-Dihydroxytryptamine / Q000378:metabolism; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004361:Drug Tolerance; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism*
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D018490:Serotonin Agents; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D009020:Morphine