Attenuation of central alpha 2 adrenergic action in diabetic rats.

Molecular components in transmembrane signaling may be dysfunctional in insulin-deficient states. To investigate whether the alpha 2 adrenergic receptor-effector mechanism is functionally altered by insulin deficiency, we determined the hypnotic response to dexmedetomidine [(+)4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, a highly-selective alpha 2 agonist, in streptozotocin-induced diabetic rats. The duration of the loss of righting reflex (sleep time) in response to dexmedetomidine, 0.25 mg.kg-1 IP, was measured in rats pretreated with streptozotocin, 50 mg.kg-1 IP. Dexmedetomidine sleep time was significantly shortened when tested 10 days (-25%), 3 (-29%), 6 (-35%) and 8 (-47%) weeks into the diabetic state. Supplementation of the diabetic rats with insulin normalized alpha 2 responsiveness. Acute hyperglycemia did not reduce dexmedetomidine-induced sleep time. Sleep time was also reduced when dexmedetomidine was administered via the intracerebroventricular (ICV) route at 4 (-21%) and 8 (-29%) weeks after streptozotocin. Thus the central nervous system response to the alpha 2 adrenergic agonist has become attenuated. The mechanism may involve a perturbation of an insulin-sensitive molecular component of the signal transduction pathway responsible for alpha 2 adrenoceptor-mediated anesthetic action.