Insulin-Dependent Attenuation in α 2-Adrenoreceptor–Mediated Nociception in Experimental Diabetes

Abstract

Diabetes mellitus is associated with abnormalities in central noradrenergic dynamics, a system that appears to be involved in the regulation of nociception in both humans and experimental animals. To this end, we investigated the responsiveness of nociceptive threshold to the actions of clonidine (an α 2-adrenoreceptor agonist) and yohimbine (an α 2-adrenoreceptor antagonist) during diabetes. The induction of diabetes was achieved by the administration of streptozotocin (STZ) (55 mg/kg, intravenously). Nociceptive threshold, as indicated by the tail-flick latency of the tail immersion test, was progressively elevated as a function of the duration of diabetes. Systemic administration of clonidine and yohimbine respectively produced dose-dependent analgesic and hyperalgesic effects in control animals. Both of these phenomena were impaired in chronically diabetic animals. In contrast, insulin-treated diabetics displayed supersensitivity to clonidine's antinociceptive effect, especially at low doses. Acute hyperglycemia did not interfere with the α 2-agonist–mediated elevation in nociceptive threshold. Attenuation in clonidine antinociceptive effect was also observed following its intrathecal administration to diabetic animals. Overall, these data suggest that the impaired responsiveness of diabetic rats might be due to a central α 2-adrenoreceptor desensitization and/or biochemical defect in the postreceptor events.