ANTAGONISM OF PERIPHERAL 5-HT4 RECEPTORS REDUCES VISCERAL AND CUTANEOUS PAIN IN MICE, AND INDUCES VISCERAL ANALGESIA AFTER SIMULTANEOUS INACTIVATION OF 5-HT3 RECEPTORS

The role of 5-HT4 receptors on cutaneous and visceral pain remains lar gely unexplored. The objective of this study was to establish the acti vity profile of SDZ 205-557, a 5-HT4 antagonist, on cutaneous (hotplat e) and visceral (writhing) models of pain, after peripheral administra tion. Since SDZ 205-557 possesses some affinity for 5-HT3 receptors at high doses, nociceptive effects of a 1:1 combination of SDZ 205-557 a nd MDL 72222, a 5-HT3 antagonist, were also evaluated. Drugs were inje cted 30 min before tests (0, 0.001, 0.01, 0.1 or 1 mg/kg IP). A hypoal gesic effect of SDZ 205-557 on cutaneous pain was found at 0.1 and 1 m g/kg doses, as revealed through an enhanced nociceptive threshold in r ats placed on the hotplate. This effect was likely mediated through in activation of peripheral 5-MT4 receptors. After the 1:1 combination, t he hypoalgesic effect disappeared, which indicates that simultaneous i nactivation of 5-HT3 and 5-HT4 receptors antagonized peripherally 5-HT 4-mediated hypoalgesia by an unknown mechanism. SDZ 205-557 also induc ed hypoalgesia in the writhing test over the entire dose range tested, and visceral hypoalgesia turned out to be analgesia after 1:1 combina tion. In summary, findings of the present study imply that: i) antagon ism of 5-HT4 receptors mediates antinociception in enteric viscera and , to a lesser extent, in cutaneous terminals, and ii) dual inactivatio n of both 5-HT4 and 5-HT3 receptors induces visceral analgesia, a fact which might have clinical importance. (C) 1998 Elsevier Science B.V.