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PAIN MEDICINE

An Investigation of Monoamine Receptors Involved in Antinociceptive Effects of Antidepressants

Fumiko Yokogawa, MD^*, Yuji Kiuchi, MD, PhD, Yuji Ishikawa, MS, Naoki Otsuka, MD, PhD^*, Yutaka Masuda, MD, PhD^*, Katsuji Oguchi, MD, PhD, and Akiyoshi Hosoyamada, MD, PhD^*

*Department of Anesthesiology and First Department of Pharmacology, School of Medicine, and Department of Pathophysiology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan

Address correspondence and reprint requests to Fumiko Yokogawa, MD, Department of Anesthesiology, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan. Address e-mail to yokogawa{at}zj8.so-net.ne.jp

We attempted to determine which monoamine re-ceptor 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 (₁ antagonist) or ketanserin (5-HT₂ 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-HT₃ antagonist) significantly antagonized antinociception by 10 mg/kg of imipramine. In contrast, SDZ-205,557 (5-HT₄ 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 (₂ antagonist) or ondansetron, and was significantly enhanced by intracerebroventricularly administered SDZ-205,557. These findings suggest that ₁ adrenoceptors and 5-HT₂ 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 ₁ adrenoceptors, serotonin (5-HT)₂ receptors, and 5-HT₃ receptors are involved in antidepressant-induced antinociception, suggesting functional interactions between noradrenergic and serotonergic neurons as mechanisms of antidepressant-induced antinociception.

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