CHRONIC TREATMENT WITH DEXMEDETOMIDINE DESENSITIZES ALPHA(2)-ADRENERGIC SIGNAL-TRANSDUCTION

Tolerance to the hypnotic response was induced in rats by chronically infusing dexmedetomidine, a novel alpha(2)-adrenergic agonist. The alp ha(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-st imulated adenylyl cyclase was less sensitive to inhibition by dexmedet omidine in the tolerant rats; however, acute intraperitoneal injection of dexmedetomidine still reduced cyclic adenosine monophosphate level s in tolerant rats. Both the decrease in ribosylation and the lower al pha(2)-adrenoceptor binding affinity may reflect a decrease in the abi lity of the G protein to couple to the alpha(2) adrenoceptors in the l oecus coeruleus of tolerant rats. In this state, the alpha(2)-adrenoce ptors are less capable of transducing the effector response (inhibitio n of adenylyl cyclase). (C) 1997 Elsevier Science Inc.