Isoflurane and Nociception
The authors recently established that the analgesic actions of the inhalation anesthetic nitrous oxide were mediated by noradrenergic bulbospinal neurons and spinal ␣ 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 ␣ adrenoceptors mediate this effect. Methods: After selective lesioning of noradrenergic nuclei by intracerebroventricular
... rebroventricular application of the mitochondrial toxin saporin coupled to the antibody directed against dopamine ␤ hydroxylase (D␤H-saporin), the antinociceptive action of isoflurane was determined. Antagonists for the ␣ 1 and ␣ 2 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 ␣ 2 -adrenoceptor subtypes (␣ 2A , ␣ 2B , and ␣ 2C ) and their wild-type cohorts were tested for their antinociceptive response to isoflurane. Results: Both D␤H-saporin treatment and chronic spinal transection enhanced the antinociceptive effects of isoflurane. The ␣ 1 -adrenoceptor antagonist prazosin also enhanced isoflurane antinociception at a supraspinal site of action. The ␣ 2 -adrenoceptor antagonist yohimbine inhibited isoflurane antinociception, and this effect was mediated by spinal ␣ 2 adrenoceptors. Null mice for the ␣ 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 ␣ 1 adrenoceptors; (2) an antinociceptive effect requiring descending noradrenergic neurons and spinal ␣ 2A adrenoceptors; and (3) an antinociceptive effect mediated within the spinal cord for which no role for adrenergic mechanism has been found.