PERSISTING SENSITIZATION OF THE BEHAVIORAL-RESPONSE TO FORMALIN-INDUCED INJURY IN THE RAT THROUGH ACTIVATION OF SEROTONIN(2A) RECEPTORS

Serotonin potentiates pain induced by intraplantar injection of other inflammatory mediators through the 5-hydroxytryptamine(2A) receptor, a nd 5-hydroxytryptamine(2A) antagonists dose-dependently block pain ind uced by formalin. The present study examined the temporal characterist ics of 5-hydroxytryptamine-mediated potentiation of pain in the rat. S imultaneous injection of the 5-hydroxytryptamine(2) receptor agonist a lpha-methyl-5-hydroxytryptamine (10 mu g) plus prostaglandin E(2) (0.1 mu g) produced 10 min of lifting and licking of the injected paw. Whe n alpha-methyl-5-hydroxytryptamine was injected before prostaglandin E (2), the response decreased as the interval increased, and by 1 h, it was not different from injection of prostaglandin E(2) alone. When pro staglandin E(2) was injected prior to alpha-methyl-5-hydroxytryptamine , sensitization to the latter persisted for more than 3 h. It was bloc ked by the 5-hydroxytryptamine(2) antagonist ketanserin (5 mu g), inje cted locally 5 min before alpha-methyl-5-hydroxytryptamine. Ketanserin (5 mu g) or the 5-hydroxytryptamine(1A/2A) antagonist spiperone (0.3 mu g), injected locally 5 min before alpha-methyl-5-hydroxytryptamine and prostaglandin E(2), reduced pain by 80-90%, but only by 40-50% whe n injected 2 min after. Formalin produced a biphasic pain response. Th e 5-hydroxytryptamine(2) antagonists, ketanserin (50 mu g), spiperone (3 mu g) and ritanserin (50 mu g) injected 5 min before formalin reduc ed the pain response by 70, 90 and 74%, respectively, but only by 40, 30 and 24% when injected at the beginning of the second phase. Pretrea tment of the paw with 2 mu g indomethacin did not alter the response t o alpha-methyl-5-hydroxytryptamine plus prostaglandin E(2), indicating that the sensitization was not due to prostaglandin synthesis. These data show that 5-hydroxytryptamine sensitizes tissue to the pain-produ cing actions of other inflammatory mediators, and that the sensitizati on produces a persisting change in tissue that can be blocked by pretr eatment with an antagonist, but not reversed after it has occurred. Th e data imply that 5-hydroxytryptamine(2A) antagonists may act prophyla ctically to prevent the evolution of pain in injured tissue, but do no t reduce already-present pain. (C) 1997 IBRO.