Isoflurane and Nociception

Background: 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 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. THE mechanisms and pathways of anesthetic action are unknown. Part of the difficulty in determining how anesthetics transduce their effects is that the state of anesthesia encompasses a syndrome of “behaviors,” including analgesia (pain relief), hypnosis–sedation, amnesia (loss of memory), and muscle relaxation, and the effects of an anesthetic agent on each of these behaviors may have a unique mechanism of action. Nearly all behavioral investigations of volatile anesthetic mechanisms measure anesthetic potency using the minimum alveolar anesthetic concentration (MAC), which is defined as the alveolar concentration of anesthetic that prevents movement in 50% of subjects in response to a painful stimulus. Which of the behavioral effect or effects (analgesia, hypnosis, or muscle relaxation) contributes to MAC is not fully understood. To better define the mechanism of anesthetic action, we sought to deal with each element of the behavioral response separately. This approach was predicated by our finding that the hypnotic and analgesic responses to the anesthetic agent nitrous oxide (N2O) are mediated at different sites by different signaling pathways. We previously demonstrated that noradrenergic brainstem nuclei and 2B adrenoceptors play a pivotal role in the analgesic, but not the hypnotic effects of N2O. 1 N2O exposure activated noradrenergic brainstem neurons with descending spinal projections, which increased the release of norepinephrine in the spinal cord and evoked an analgesic response that was blocked by a spinally administered 2-adrenoceptor antagonist, evidence supporting the hypothesis that noradrenergic bulbospinal neurons mediate N2O analgesic action. 1–3 The neuropharmacologic basis of N2O-evoked analgesia and hypnosis clearly differ, indicating a need to dissect the mechanisms of action for an anesthetic agent by examining each component of the anesthetic state. Using the methods established in our previous investigations with N2O, we examined the noradrenergic mechanisms and pathways responsible for the analgesic effects of isoflurane on the tail-flick assay in rats. The mechanisms mediating the anesthetic actions of isoflurane are unknown. When isoflurane is selectively administered to just the brain and brainstem, it has a pronociceptive effect as measured by MAC, and concentrations of isoflurane below anesthetic threshold also have a pronociceptive effect on hind-paw radiant heat * Assistant Professor, Department of Functional Restoration, Stanford University and Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System. † Research Associate, ‡ Postdoctoral Fellow, Department of Anesthesiology, Associate Professor, Howard Hughes Medical Institute, Stanford University. § Third Assistant Professor, Department of Anesthesiology, Stanford University, and Anesthesiology Service, Veterans Affairs Palo Alto Health Care System. # Professor, Magill Department of Anaesthetics, Imperial College School of Medicine, London, United Kingdom.