We attempted to determine which monoamine receptor subtypes are predominantly involved in antidepressant-induced antinociception. Antinociceptive effects were evaluated by using formalin tests with rats. Antidepressants acting as potent inhibitors of norepinephrine reuptake (nisoxetine, nortriptyline, and maprotiline) or inhibiting reuptake of both norepinephrine and serotonin (5-HT) (imipramine and milnacipran) induced dose-dependent antinociception. Simultaneous intraperitoneal administration of antidepressants and either prazosin (alpha(1) antagonist) or ketanserin (5-HT(2) antagonist) significantly antagonized antinociceptive effects. Fluvoxamine (selective serotonin reuptake inhibitor) induced antinociception less potently than other antidepressants and was significantly antagonized by ketanserin, but not prazosin. Ondansetron (5-HT(3) antagonist) significantly antagonized antinociception by 10 mg/kg of imipramine. In contrast, SDZ-205,557 (5-HT(4) antagonist) markedly enhanced antinociception by small-dose (2.5 mg/kg) imipramine. Imipramine-induced antinociception was significantly antagonized by intracerebroventricular administration of prazosin or ketanserin, but not by yohimbine (alpha(2) antagonist) or ondansetron, and was significantly enhanced by intracerebroventricularly administered SDZ-205,557. These findings suggest that alpha(1) adrenoceptors and 5-HT(2) receptors in the brain are involved in antidepressant-induced antinociception. In addition, the results suggested functional interactions between noradrenergic and serotonergic neurons as mechanisms for antidepressant-induced antinociception.
Implications: Formalin tests of rats treated with antidepressants and antagonists of monoamine receptors indicate that alpha(1) adrenoceptors, serotonin (5-HT)(2) receptors, and 5-HT(3) receptors are involved in antidepressant-induced antinociception, suggesting functional interactions between noradrenergic and serotonergic neurons as mechanisms of antidepressant-induced antinociception.