Serotonin and pain: evidence that activation of 5-HT 1A receptors does not elicit antinociception against noxious thermal, mechanical and chemical stimuli in mice

Abstract

In this study, we examined whether activation of 5-HT 1A receptors elicits antinociception in response to acute noxious chemical, thermal and mechanical stimuli in mice. In the writhing test, both agonists (e.g., 8-OH-DPAT, S 14671 and WY 50,324) and partial agonists (e.g., buspirone and gepirone) elicited a pronounced antinociception. However, antagonists (e.g., (−)-alprenolol and WAY 100,135) also induced antinociception and, at lower (inactive) doses, failed to modify the action of agonists. In addition, the separation between doses required for induction of antinociception as compared to those required for induction of ataxia (in the rotarod test) was variable and low for both agonists (median: 1.9) and partial agonists (median: 1.3), although it was somewhat greater for antagonists (≳ 3.3). In the hot-plate test, only certain agonists (e.g., 8-OH-DPAT) and partial agonists (e.g., gepirone) elicited antinociception and their actions were not attenuated by 5-HT 1A antagonists which, themselves, were inactive in this paradigm. The 5-HT 1C/2 antagonist, ritanserin, the 5-HT 3 antagonist, ondansetron, the dopamine D 2 receptor antagonist, raclopride, and the α 1-adrenoceptor antagonist, prazosin, were also ineffective in modifying the antinociception evoked by 5-HT 1A agonists and partial agonists in the hot-plate test. In contrast, their actions were strongly attenuated by the α 2-adrenoceptor antagonist, idazoxan. In the tail-flick tests to noxious heat and noxious pressure, 5-HT 1A receptor agonists, partial agonists and antagonists generally failed to induce antinociception. Moreover, modulation of stimulus intensity (from very weak to very intense) did not reveal any influence upon the latency to respond. In conclusion, in the writhing test, the data provide no evidence for a specific antinociceptive effect of the activation of 5-HT 1A receptors. Further, in the hot-plate test, for those 5-HT 1A agonists and partial agonists which induce antinociception, α 2-adrenoceptors rather than 5-HT 1A receptors are implicated in their actions. Finally, in reflexive tests, irrespective of stimulus quality or intensity, 5-HT 1A agonists and partial agonists do not mediate antinociception. These data suggest that the activation of 5-HT 1A receptors does not, under these conditions of acute noxious stimulation, elicit antinociception.