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PAIN MECHANISMS

The Differential Effect of Cyclosporine on Hypnotic Response and Pain Reaction in Mice

Yuki Sato, MD, PhD^*, Tatsushi Onaka, MD, PhD, Eiji Kobayashi, MD, PhD, and Norimasa Seo, MD, PhD^*

From the Departments of *Anesthesiology and Physiology; and Divisions of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.

Address correspondence and reprint requests to Yuki Sato, MD, PhD, Department of Anesthesiology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Address e-mail to aneyuki{at}jichi.ac.jp.

Abstract

BACKGROUND: The calcineurin inhibitor, cyclosporine, is widely used for preventing allograft rejection in organ transplantation. Systemically administered cyclosporine is prevented from entering into the brain by the action of P-glycoprotein, encoded by the multidrug resistant 1 (mdr1) gene. However, in many transplant recipients, cyclosporine administration causes postoperative neuropsychological side effects, such as confusion, depression, and anxiety. Recently, calcineurin-inhibitor-induced pain syndrome, characterized by severe pain in the lower limbs, has also been recognized in both organ and stem-cell transplantations.

METHODS: In the present study, we developed behavioral models in wild-type and mdr1a knockout mice to reveal whether peripheral or central cyclosporine alters pain reactions and hypnotic sensitivities. Cyclosporine's central actions can be better evaluated in mdr1a knockout mice that lack P-glycoprotein. After intraperitoneal administration of cyclosporine, we examined tail-flick latency in the tail immersion test, or duration of loss of righting reflex in response to pentobarbital and ketamine.

RESULTS: In wild-type mice, the highest dose of cyclosporine significantly prolonged the duration of loss of righting reflex in response to ketamine, but not to pentobarbital. On the other hand, the lower doses of cyclosporine significantly increased both pentobarbital- and ketamine-induced sleep durations in mdr1a knockout mice. Tail-flick latencies in the tail immersion test were significantly shortened in both wild-type and knockout mice by the administration of cyclosporine.

CONCLUSIONS: Our results suggest that centrally accumulated cyclosporine enhances the hypnotic response to pentobarbital and ketamine, but peripheral cyclosporine induces hyperalgesia.