This study was designed primarily to relate the antinociceptive and hemodynamic effects of clinically available alpha(2)-adrenoceptor agonists to their binding affinity for alpha(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 alpha(2) agonist were incubated with (3)H-UK14304, a selective alpha(2) agonist, and the radioactivity in the reaction mixtures was measured by liquid scintillation spectrometry. Epidural DXM (0.5-10 microg), CL (10-500 microg), and TZ (5-500 microg) 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 alpha(2) agonists may depend on their binding affinities to alpha(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 alpha(2) agonists is well correlated with their binding affinity to spinal alpha(2)-adrenoceptors.