Persisting sensitization of the behavioural response to formalin-induced injury in the rat through activation of serotonin 2A receptors

Abstract

Serotonin potentiates pain induced by intraplantar injection of other inflammatory mediators through the 5-hydroxytryptamine 2A receptor, and 5-hydroxytryptamine 2A 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-hydroxytryptamine 2 receptor agonist α-methyl-5-hydroxytryptamine (10 μg) plus prostaglandin E 2 (0.1 μg) produced 10 min of lifting and licking of the injected paw. When α-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 prostaglandin E 2 was injected prior to α-methyl-5-hydroxytryptamine, sensitization to the latter persisted for more than 3 h. It was blocked by the 5-hydroxytryptamine 2 antagonist ketanserin (5 μg), injected locally 5 min before α-methyl-5-hydroxytryptamine. Ketanserin (5 μg) or the 5-hydroxytryptamine 1A/2A antagonist spiperone (0.3 μg), injected locally 5 min before α-methyl-5-hydroxytryptamine and prostaglandin E 2, reduced pain by 80–90%, but only by 40–50% when injected 2 min after. Formalin produced a biphasic pain response. The 5-hydroxytryptamine 2 antagonists, ketanserin (50 μg), spiperone (3 μg) and ritanserin (50 μg) 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 μg indomethacin did not alter the response to α-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-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-hydroxytryptamine 2A antagonists may act prophylactically to prevent the evolution of pain in injured tissue, but do not reduce already-present pain.