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REGIONAL ANESTHESIA AND PAIN MEDICINE

The Analgesic Interaction Between Intrathecal Clonidine and Glutamate Receptor Antagonists on Thermal and Formalin-Induced Pain in Rats

Tomoki Nishiyama, MD, PhD^*, Laszlo Gyermek, MD, PhD^*, Chingmuh Lee, MD^*, Sachiko Kawasaki-Yatsugi, PhD, Tokio Yamaguchi, PhD, and Kazuo Hanaoka, MD, PhD^§

*Department of Anesthesiology, Harbor-University of California, Los Angeles Medical Center, Torrance, California, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan, §Department of Anesthesiology, The University of Tokyo, Tokyo, Japan

Address correspondence and reprint requests to Tomoki Nishiyama, MD, PhD, 3-2-6-603, Kawaguchi, Kawaguchi-shi, Saitama, 332-0015, Japan. Address e-mail to nishiyam{at}ims.u-tokyo.ac.jp

Clonidine, an ₂ adrenergic receptor agonist, inhibits glutamate release from the spinal cord. We studied the interaction of intrathecally administered clonidine and glutamate receptor antagonists on acute thermal or formalin induced nociception. Sprague-Dawley rats with lumbar intrathecal catheters were tested for their tail withdrawal response by the tail flick test and paw flinches produced by formalin injection after intrathecal administration of saline, clonidine, AP-5 (a N-methyl-D-aspartate receptor antagonist), or YM872 (an -amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist). The combinations of clonidine and the other two agents were also tested by isobolographic analyses. Motor disturbance and behavioral changes were observed as side effects. The ED₅₀ values of clonidine decreased from 0.26 µg (tail flick), 0.12 µg (Phase 1) and 0.13 µg (Phase 2) to 0.036 µg, 0.006 µg, and 0.013 µg with AP-5, and 0.039 µg, 0.057 µg, and 0.133 µg with YM872, respectively. Side effects were attenuated in both combinations. In conclusion, spinally administered clonidine and AP-5 or YM872 exhibited potent synergistic analgesia on acute thermal and formalin-induced nociception with decreased side effects in rats.

Implications: Combinations of a spinally administered ₂ adrenergic receptor agonist and an a N-methyl-D-aspartate receptor antagonist or an -amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist exhibited potent synergistic analgesia in acute thermal and inflammatory-induced nociception with decreased side effects.

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