Isoflurane and nociception -: Spinal α2A adrenoceptors mediate antinociception while supraspinal α1 adrenoceptors mediate pronociception

Background The authors recently established that the analgesic actions of the inhalation anesthetic nitrous oxide were mediated by noradrenergic bulbospinal neurons and spinal alpha(2B) 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 a, and a. 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 alpha(2)-adrenoceptor subtypes (alpha(2A), alpha(2B), and alpha(2C)) 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 alpha(1)-adrenoceptor antagonist prazosin also enhanced isoflurane antinociception at a supraspinal site of action. The alpha(2)-adrenoceptor antagonist yohimbine inhibited isoflurane antinociception, and this effect was mediated by spinal alpha(2) adrenoceptors. Null mice for the alpha(2A)-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 alpha(1) adrenoceptors; (2) an antinociceptive effect requiring descending noradrenergic neurons and spinal alpha(2A) adrenoceptors; and (3) an antinociceptive effect mediated within the spinal cord for which no role for adrenergic mechanism has been found.