Chronic treatment with dexmedetomidine desensitizes α2-adrenergic signal transduction

Abstract Tolerance to the hypnotic response was induced in rats by chronically infusing dexmedetomidine, a novel α 2 -adrenergic agonist. The α 2 -adrenocepter affinity for dexmedtomidine and para -iodoclonidine was significantly reduced in tolerant rats, while B max was uncharged. The ability of pertussis toxin (PTX) to ribosylate guanine nucleotide regulatory proteins (G proteins) ex vivo was reduced in tolerant rats; the quantity of PTX-sensitive G proteins was unchanged. Forskolin-stimulated adenylyl cyclase was less sensitive to inhibition by dexmedetomidine in the tolerant rats; however, acute intraperitoneal injection of dexmedetomidine still reduced cyclic adenosine monophosphate levels in tolerant rats. Both the decrease in ribosylation and the lower α 2 -adrenoceptor binding affinity may reflect a decrease in the ability of the G protein to couple to the α 2 adrenoceptors in the loecus coeruleus of tolerant rats. In this state, the α 2 adrenoceptors are less capable of transducing the effector response (inhibition of adenylyl cyclase).