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

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-HT_1A, 5-HT_1B, and 5-HT_2A, in levodopa-induced visceral antinociception. Ketanserin is a 5-HT_2A receptor antagonist that was intracisternally injected and blocked the levodopa-induced antinociception, but neither WAY100635 (5-HT_1A receptor antagonist) nor isomoltane (5-HT_1B 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-HT_2A 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-HT_2A receptors in the central nervous system may play specific roles in levodopa-dopamine D₂ receptor-induced antinociceptive action against colonic distension.