title: Isoflurane and nociception: spinal alpha2A adrenoceptors mediate antinociception while supraspinal alpha1 adrenoceptors mediate pronociception.
abstract: BACKGROUND
  The authors recently established that the analgesic actions of the inhalation anesthetic nitrous oxide were mediated by noradrenergic bulbospinal neurons and spinal alpha2B adrenoceptors. They now determined whether noradrenergic brainstem nuclei and descending spinal pathways are responsible for the antinociceptive actions of the inhalation anesthetic isoflurane, and which alpha adrenoceptors mediate this effect.
  
  
  METHODS
  After selective lesioning of noradrenergic nuclei by intracerebroventricular application of the mitochondrial toxin saporin coupled to the antibody directed against dopamine beta hydroxylase (DbetaH-saporin), the antinociceptive action of isoflurane was determined. Antagonists for the alpha1 and alpha2 adrenoceptors were injected at spinal and supraspinal sites in intact and spinally transected rats to identify the noradrenergic pathways mediating isoflurane antinociception. Null mice for each of the three alpha2-adrenoceptor subtypes (alpha2A, alpha2B, and alpha2C) and their wild-type cohorts were tested for their antinociceptive response to isoflurane.
  
  
  RESULTS
  Both DbetaH-saporin treatment and chronic spinal transection enhanced the antinociceptive effects of isoflurane. The alpha1-adrenoceptor antagonist prazosin also enhanced isoflurane antinociception at a supraspinal site of action. The alpha2-adrenoceptor antagonist yohimbine inhibited isoflurane antinociception, and this effect was mediated by spinal alpha2 adrenoceptors. Null mice for the alpha2A-adrenoceptor subtype showed a reduced antinociceptive response to isoflurane.
  
  
  CONCLUSIONS
  The authors suggest that, at clinically effective concentrations, isoflurane can modulate nociception via three different mechanisms: (1) a pronociceptive effect requiring descending spinal pathways, brainstem noradrenergic nuclei, and supraspinal alpha1 adrenoceptors; (2) an antinociceptive effect requiring descending noradrenergic neurons and spinal alpha2A adrenoceptors; and (3) an antinociceptive effect mediated within the spinal cord for which no role for adrenergic mechanism has been found.
authors.affiliation: Department of Anesthesia, Stanford University, Stanford, California, USA.
authors.forename: Wade S
authors.initials: WS
authors.lastname: Kingery
authors.forename: Geeta S
authors.initials: GS
authors.lastname: Agashe
authors.forename: Tian Z
authors.initials: TZ
authors.lastname: Guo
authors.forename: Shigehito
authors.initials: S
authors.lastname: Sawamura
authors.forename: M Frances
authors.initials: MF
authors.lastname: Davies
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kobilka
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D004299:Dopamine beta-Hydroxylase / Q000494:pharmacology / Q000633:toxicity; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009619:Nociceptors / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects*; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects
chemical_list: C547769:Adra2a protein, mouse; D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D018685:Anesthetics, Inhalation; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D007530:Isoflurane; D004299:Dopamine beta-Hydroxylase