Antinociceptive synergistic interaction between clonidine and ouabain on thermal nociceptive tests in the rat

The antinociceptive effect produced by spinal injection of clonidine (an alpha(2)-adrenergic agonist) is mediated by a cholinergic mechanism. We aimed in the current study to evaluate the antinociceptive interaction between intrathecally administered ouabain, an inhibitor of Na(+), K(+)-ATPase, and clonidine. We used rats chronically implanted with lumbar intrathecal catheters to examine the ability of intrathecal clonidine and ouabain and the mixtures of clonidine-ouabain to alter tail-flick latency. To characterize the interaction, isobolographic analysis was performed. Intrathecal clonidine (0.5-10 microg) and ouabain (0.1-5 microg) produced significant dose- and time-dependent antinociception in the tail-flick tests. The median effective dose (ED(50)) values for intrathecally administered ouabain and clonidine were 2.3 microg and 4.7 microg, respectively. The experimental point for the ouabain-clonidine combination decreased significantly (P < .05) below the lines of additivity. Isobolographic analysis exhibited a synergistic interaction after the coadministration of ouabain and clonidine. No motor impairment was observed in the animals after intrathecal administration of the combination of ouabain and clonidine or clonidine alone. Intrathecal pretreatment with atropine but not yohimbine blocked the antinociceptive effect of ouabain and attenuated its interaction with spinal clonidine. These results suggest that the synergistic interaction of ouabain and clonidine were probably mediated, at least in part, via an enhancement of cholinergic transmission in the spinal nociceptive processing system.

Although intrathecal clonidine produces pronounced analgesia, antinociceptive doses of intrathecal clonidine produce several side effects, including hypotension, bradycardia, and sedation. This article presents antinociceptive synergistic interaction between clonidine and ouabain on thermal nociceptive tests in the rat.