Persisting sensitization of the behavioural response to formalin-induced injury in the rat through activation of serotonin2A receptors.

Serotonin potentiates pain induced by intraplantar injection of other inflammatory mediators through the 5-hydroxytryptamine2A receptor, and 5-hydroxytryptamine2A antagonists dose-dependently block pain induced by formalin. The present study examined the temporal characteristics of 5-hydroxytryptamine-mediated potentiation of pain in the rat. Simultaneous injection of the 5-hydroxytryptamine2 receptor agonist alpha-methyl-5-hydroxytryptamine (10 micrograms) plus prostaglandin E2 (0.1 microgram) produced 10 min of lifting and licking of the injected paw. When alpha-methyl-5-hydroxytryptamine was injected before prostaglandin E2, the response decreased as the interval increased, and by 1 h, it was not different from injection of prostaglandin E2 alone. When prostaglandin E2 was injected prior to alpha-methyl-5-hydroxytryptamine, sensitization to the latter persisted for more than 3 h. It was blocked by the 5-hydroxytryptamine2 antagonist ketanserin (5 micrograms), injected locally 5 min before alpha-methyl-5-hydroxytryptamine. Ketanserin (5 micrograms) or the 5-hydroxytryptamine1A/2A antagonist spiperone (0.3 microgram), injected locally 5 min before alpha-methyl-5-hydroxytryptamine and prostaglandin E2, reduced pain by 80-90%, but only by 40-50% when injected 2 min after. Formalin produced a biphasic pain response. The 5-hydroxytryptamine2 antagonists, ketanserin (50 micrograms), spiperone (3 micrograms) and ritanserin (50 micrograms) injected 5 min before formalin reduced 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. Pretreatment of the paw with 2 micrograms indomethacin did not alter the response to alpha-methyl-5-hydroxytryptamine plus prostagladin E2, indicating that the sensitization was not due to prostaglandin synthesis. These data show that 5-hydroxytryptamine sensitizes tissue to the pain-producing actions of other inflammatory mediators, and that the sensitization produces a persisting change in tissue that can be blocked by pretreatment with an antagonist, but not reversed after it has occurred. The data imply that 5-hydroxytryptamine2A antagonists may act prophylactically to prevent the evolution of pain in injured tissue, but do not reduce already-present pain.