INTRATHECAL CLONIDINE AND TIZANIDINE IN CONSCIOUS DOGS - COMPARISON OF ANALGESIC AND HEMODYNAMIC-EFFECTS

Intrathecal delivery of alpha(2)-adrenergic agonists produces an analg esic effect. However, hemodynamic side effects limit their clinical us age. To more fully characterize the effects on heart rate and arterial blood pressure of alpha(2)-adrenergic agonists, clonidine and tizanid ine were injected intrathecally in conscious dogs. Both compounds prod uced a potent inhibition of thermal foot-withdrawal latencies at 1000 mu g, which was blocked by the alpha(2)-adrenergic antagonist yohimbin e. Tizanidine (250-500 mu g) did not change heart rate. Clonidine (500 -2000 mu g) and tizanidine (1000-2000 mu g) decreased heart rate. The tizanidine effect was inhibited by yohimbine and the alpha(2)/imidazol ine antagonist idazoxan, as well as the parasympathetic blocker glycop yrrolate. No drug completely inhibited the clonidine-induced bradycard ia. Clonidine had a biphasic effect on arterial blood pressure, a decr ease at 500 mu g and an increase at 2000 mu g. Tizanidine decreased ar terial blood pressure at all doses. The results indicate that, while t he analgesic effects of both drugs are similar, the hemodynamic respon ses differ. While the decrease in heart rate with tizanidine is consis tent with alpha(2)-adrenergic binding and vagal action, the bradycardi a induced by clonidine is more complex. In addition, the increased art erial blood pressure with high doses of clonidine, which is suggestive of a peripheral vasoconstrictive effect, does not occur with tizanidi ne.