title: 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.
abstract: BACKGROUND
  The development of tolerance to the sympatholytic and anesthetic-reducing effects of alpha(2) agonists after prolonged administration of dexmedetomidine and how the number of available alpha(2) adrenoceptors affects these dexmedetomidine-induced responses was studied.
  
  
  METHODS
  The sympatholytic action of acute and chronic (3 and 10 micrograms.kg-1.h-1 for 7 days) dexmedetomidine, was assessed by the decrease in norepinephrine turnover in the locus coeruleus and hippocampus. The anesthetic-reducing effect of chronic (7 days) dexmedetomidine (5 and 10 micrograms.kg-1.h-1) was studied by determining the minimum alveolar concentration (MAC) for halothane that prevented rats from responding to a supramaximal noxious stimulus of dexmedetomidine (10 or 30 micrograms.kg-1), doses in the steep part of the dose-response curve. The receptor reserve for the norepinephrine turnover and anesthetic-sparing responses to dexmedetomidine was delineated with 0.3-1.0 mg.kg-1 N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, an irreversible alkylating agent.
  
  
  RESULTS
  After chronic administration of dexmedetomidine at both doses, acute dexmedetomidine significantly decreased norepinephrine 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 dexmedetomidine treatment. In the N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline experiments, the dexmedetomidine-induced norepinephrine turnover effect required less than 20% and greater than 4% alpha(2) adrenoceptor availability in the locus coeruleus and the dexmedetomidine induced MAC-sparing effect required less than 40% and greater than 20% alpha(2) adrenoceptor availability in the locus coeruleus.
  
  
  CONCLUSIONS
  Tolerance does not develop for either the sympatholytic or MAC-sparing actions of dexmedetomidine, although it is present for the hypnotic response. The durable quality of the sympatholytic and MAC-sparing responses to dexmedetomidine after chronic treatment is explained by a comparatively larger receptor reserve than is needed for the hypnotic and analgesic responses, which are blunted by the same drug treatment regimen.
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, California 94305, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Rabin
authors.forename: K
authors.initials: K
authors.lastname: Reid
authors.forename: T Z
authors.initials: TZ
authors.lastname: Guo
authors.forename: E
authors.initials: E
authors.lastname: Gustafsson
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Maze
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D004361:Drug Tolerance; D006221:Halothane / Q000493:pharmacokinetics / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D020926:Medetomidine; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013565:Sympatholytics / Q000494:pharmacology*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D000777:Anesthetics; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D013565:Sympatholytics; D020926:Medetomidine; D006221:Halothane; D009638:Norepinephrine