Pharmacological analysis of alpha-2 adrenergic mechanisms in nociception and ataxia

In order to assess the involvement of alpha-2 adrenergic receptors in nociception, the in vitro potencies of seven alpha-2 adrenergic agonists (clonidine, guanabenz, guanfacine, BHT-920, ICI 106270, xylazine and lofexidine) were compared with their ability to prevent the writhing response elicited by i.p. administration of phenyl-p-guinone. Administration of each compound elicited antinociception, and this effect was attenuated by pretreatment with the alpha-2 adrenergic antagonists, yohimbine. The potency of these compounds to cause antinociception was correlated with their potency to displace [3H]clonidine from its binding site on brain membranes and with their ability to inhibit the twitch of the electrically stimulated vas deferens, suggesting an alpha-2 involvement in the antinociceptive action. In addition to causing antinociception, administration of these agonists also impaired rotorod performance in mice. These agonists were 2.5 to 72 times more potent in inhibiting writhing than in impairing rotorod performance, and, except for ICI 106270, there was a correlation between antinociceptive and ataxic potency. ICI 106270 was a notable exception to this correlation, however, producing only minimal ataxia, which unlike the other agonists was not reversed by yohimbine. These results indicate that alpha-2 adrenergic agonists can produce antinociception and further suggest that this may be dissociable from the ataxia.