SYMPATHOLYTIC AND MINIMUM ANESTHETIC CONCENTRATION-SPARING RESPONSES ARE PRESERVED IN RATS RENDERED TOLERANT TO THE HYPNOTIC AND ANALGESIC ACTION OF DEXMEDETOMIDINE, A SELECTIVE ALPHA(2)-ADRENERGIC AGONIST

Background: The development of tolerance to the sympatholytic and anes thetic-reducing effects of alpha(2) agonists after prolonged administr ation of dexmedetomidine and how the number of available alpha(2) adre noceptors affects these dexmedetomidine-induced responses was studied. Methods: The sympatholytic action of acute and chronic (3 and 10 mu g . kg(-1). h(-1) for 7 days) dexmedetomidine, was assessed by the decr ease in norepinephrine turnover in the locus coeruleus and hippocampus . The anesthetic-reducing effect of chronic a days) dexmedetomidine (5 and 10 mu g . kg(-1). h(-1)) was studied by determining the minimum a lveolar concentration (MAC) for halothane that prevented rats from res ponding to a supramaximal noxious stimulus of dexmedetomidine (10 or 3 0 mu g . kg(-1), doses in the steep part of the dose-response curve. T he receptor reserve for the norepinephrine turnover and anesthetic-spa ring responses to dexmedetomidine was delineated with 0.3-1.0 mg . kg( -1) N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, an irreversible al kylating agent. Results: After chronic administration of dexmedetomidi ne at both doses, acute dexmedetomidine significantly decreased norepi nephrine turnover in the hippocampus and locus coeruleus. The baseline minimum anesthetic concentration (MAC) and the MAC-sparing effect to acutely administered dexmedetomidine were preserved after chronic dexm edetomidine treatment. In the N-ethoxycarbonyl-2-ethoxy-1,2-dihydroqui noline experiments, the dexmedetomidine-induced norepinephrine turnove r effect required less than 20% and greater than 4% alpha(2) adrenocep tor availability in the locus coeruleus and the dexmedetomidine induce d MAC-sparing effect required less than 40% and greater than 20% alpha (2) adrenoceptor availability in the locus coeruleus. Conclusion: Tole rance does not develop for either the sympatholytic or MAC-sparing act ions of dexmedetomidine, although it is present for the hypnotic respo nse. The durable quality of the sympatholytic and MAC-sparing response s to dexmedetomidine after chronic treatment is explained by a compara tively larger receptor reserve than is needed for the hypnotic and ana lgesic responses, which are blunted by the same drug treatment regimen .