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 largely unexplored. The objective of this study was to establish the activity profile of SDZ 205-557, a 5-HT4 antagonist, on cutaneous (hotplate) and visceral (writhing) models of pain, after peripheral administration. 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 and MDL 72222, a 5-HT3 antagonist, were also evaluated. Drugs were injected 30 min before tests (0, 0.001, 0.01, 0.1 or 1 mg/kg IP). A hypoalgesic effect of SDZ 205-557 on cutaneous pain was found at 0.1 and 1 mg/kg doses, as revealed through an enhanced nociceptive threshold in rats placed on the hotplate. This effect was likely mediated through inactivation of peripheral 5-HT4 receptors. After the 1:1 combination, the hypoalgesic effect disappeared, which indicates that simultaneous inactivation of 5-HT3 and 5-HT4 receptors antagonized peripherally 5-HT4-mediated hypoalgesia by an unknown mechanism. SDZ 205-557 also induced hypoalgesia in the writhing test over the entire dose range tested, and visceral hypoalgesia turned out to be analgesia after 1:1 combination. In summary, findings of the present study imply that: i) antagonism of 5-HT4 receptors mediates antinociception in enteric viscera and, to a lesser extent, in cutaneous terminals, and ii) dual inactivation of both 5-HT4 and 5-HT3 receptors induces visceral analgesia, a fact which might have clinical importance.