Alpha-adrenoceptor-mediated antinociception and sedation in the rat and dog

The present study compared the potency of a range of alpha-adrenoceptor agonists in producing antinociception and sedation in the rat and dog. In the rat, the selective alpha 2-adrenoceptor agonists, guanabenz, UK 14304 and guanfacine, were more potent as sedative agents than as antinociceptive agents. For compounds which have similar activities at both alpha 1 and alpha 2-adrenoceptors, such as clonidine, alinidine, oxymetazoline and naphazoline, there was little separation between effective doses for antinociception and sedation. In marked contrast, the selective alpha 1-adrenoceptor agonists, ST 587 and methoxamine, were more potent as antinociceptive agents than as sedatives. Similarly, ICI 106,270 and CP 18,534, two agonists with a greater alpha 1 to alpha 2-adrenoceptor ratio than clonidine, were also more potent in antinociceptive tests than in sedative tests. In the conscious dog, clonidine was 8-10 times more potent than ICI 106,270 and CP 18,534 at increasing nociceptive thresholds to mild electrical stimulation of the toothpulp. At equi-antinociceptive doses, the ranked order of potency for inducing sedation was clonidine greater than or equal to ICI 106,270 greater than CP 18,534. Dose-related bradycardia was also induced by each of the three alpha-adrenoceptor agonists at antinociceptive doses. These data suggest that antinociceptive activity can probably be mediated by either alpha 1 or alpha 2-adrenoceptors, whereas sedation appears to be mediated solely by the alpha 2-subtype. Thus, it may be possible to separate the antinociceptive and sedative effects of sympathomimetic agents, but it is unlikely that these agents would be completely devoid of cardiovascular effects.