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2-Adrenoceptor Agonists and Their Binding Affinity in Rat Spinal Cord and Brain
Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu City, Gifu, Japan
Address correspondence and reprint requests to Shuji Dohi, MD, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, 40 Tsukasamachi, Gifu City, Gifu 500-8705, Japan. Address e-mail to shu-dohi{at}cc.gifu-u.ac.jp
This study was designed primarily to relate the antinociceptive and hemodynamic effects of clinically available 
2-adrenoceptor agonists to their binding affinity for 2-adrenoceptors in the spinal cord and brain. In rats with chronic indwelling epidural catheters, the percentage maximal possible effect on tail-flick latency was measured after epidural or IM dexmedetomidine (DXM), clonidine (CL), or tizanidine (TZ) administration. To examine their binding affinities, isolated spinal cord and brain membranes with an 2 agonist were incubated with 3H-UK14304, a selective 2 agonist, and the radioactivity in the reaction mixtures was measured by liquid scintillation spectrometry. Epidural DXM (0.5–10 µg), CL (10–500 µg), and TZ (5–500 µg) all produced dose-dependent antinociceptive effects; the rank order of potencies was DXM > CL > TZ, the same as for their systemic administration. The antinociceptive effects were blocked by epidural yohimbine. The receptor binding affinities expressed as the concentration that inhibits 50% for spinal cord and brain, respectively, were 0.25 and 1.3 nM (DXM), 10.8 and 12.5 nM (CL), and 48.2 and 96.8 nM (TZ). The changes in arterial blood pressure and heart rate evoked by antinociceptive doses did not correlate with the rank order of antinociceptive potencies. The relative antinociceptive potencies of epidural 2 agonists may depend on their binding affinities to 2-adrenoceptors in the spinal cord, but their cardiovascular effects may result from actions both inside and outside the central nervous system.
Implications: Spinal antinociception caused by the epidural administration of 2 agonists is well correlated with their binding affinity to spinal 2-adrenoceptors.
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