5-HT2A receptors but not cannabinoid receptors in the central nervous system mediate levodopa-induced visceral antinociception in conscious rats.

Abstract

We have recently demonstrated that levodopa acts centrally to induce antinociceptive action against colonic distension through dopamine D2 receptors in rats. Since serotonin (5-HT) and cannabinoid are involved in the regulation of visceral sensation, we hypothesized that they may contribute to levodopa-induced visceral antinociception. We evaluated visceral sensation by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneously administered levodopa increased the threshold of colonic distension-induced AWR; moreover, an intracisternal injection of methiothepin, an unspecific 5-HT receptor antagonist, blocked the levodopa-induced visceral antinociception. Subsequently, we examined the roles of three 5-HT receptor subtypes: 5-HT1A, 5-HT1B, and 5-HT2A, in levodopa-induced visceral antinociception. Ketanserin is a 5-HT2A receptor antagonist that was intracisternally injected and blocked the levodopa-induced antinociception, but neither WAY100635 (5-HT1A receptor antagonist) nor isomoltane (5-HT1B receptor antagonist) did so. Antagonists AM251 (cannabinoid 1 receptor antagonist) or AM630 (cannabinoid 2 receptor antagonist) did not change the levodopa-induced visceral antinociception, suggesting that cannabinoid signaling may not be implicated in levodopa-induced visceral antinociception. We also examined the relation between dopamine D2 and 5-HT2A receptor signaling in the control of visceral sensation. Ketanserin, but not WAY100635, potently blocked the visceral antinociception by quinpirole, which is a dopamine D2 agonist. These results suggest that 5-HT2A receptors in the central nervous system may play specific roles in levodopa-dopamine D2 receptor-induced antinociceptive action against colonic distension.