Antinociception by Epidural and Systemic α2-Adrenoceptor Agonists and Their Binding Affinity in Rat Spinal Cord and Brain

This study was designed primarily to relate the antinociceptive and hemodynamic effects of clinically available α2-adrenoceptor agonists to their binding affinity for α2-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 α2 agonist were incubated with 3H-UK14304, a selective α2 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 α2 agonists may depend on their binding affinities to α2-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 α2 agonists is well correlated with their binding affinity to spinal α2-adrenoceptors.