Antagonism of peripheral 5-HT₄ receptors reduces visceral and cutaneous pain in mice, and induces visceral analgesia after simultaneous inactivation of 5-HT₃ receptors

Abstract

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.

Introduction

The neural distribution of 5-HT₄ receptors suggests a role in nociception. These receptors are highly expressed in limbic areas, periaqueductal grey matter and sensory terminals 4, 24, 27, 28. However, the role of 5-HT₄ receptors on cutaneous and visceral pain has been little explored. Nonselective 5-HT₄ agonists such as BIMU1, BIMU8 and cisapride appear to have analgesic properties after systemic administration, and SDZ 205-557, 5-HT₄ antagonist, blocks the antinociceptive effects of these compounds, as evaluated by hotplate, writhing and paw-pressure tests [12]. However, all these effects are seen after high doses, which are outside the effective dose range of 5-HT₄ ligands. It is well known that, at high doses, most 5-HT₄ ligands possess affinity for 5-HT₃ receptors as well, whose effects could mask 5-HT₄-mediated effects [12]. Recently it has been proposed that selective inactivation of peripheral 5-HT₄ receptors reduces inflammatory pain, as revealed through attenuation of formalin-induced hyperalgesia by GR113808A, a highly selective 5-HT₄ antagonist [3].

The objective of this study was to establish the activity profile of SDZ 205-557, 5-HT₄ antagonist, on cutaneous and visceral nociception, as measured by hotplate and writhing tests, respectively. SDZ 205-557 is a selective 5-HT₄ antagonist, although it possesses some affinity for 5-HT₃ receptors at high doses. For this reason, the nociceptive effects of a 1:1 combination of SDZ 205-557 and MDL 72222, a 5-HT₃ antagonist, were also evaluated in order to establish whether or not SDZ 205-557-mediated effects were due to 5-HT₄ antagonism alone. MDL 72222 is a highly selective 5-HT₃ ligand, with a dissociation constant below 10⁻⁹ M 8, 20, 25.