Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of α2B adrenoceptors

Abstract

Although nitrous oxide (N2O) has been used to facilitate surgery for >150 years, its molecular mechanism of action is not yet defined. Having established that N2O-induced release of norepinephrine mediates the analgesic action at α2 adrenoceptors in the spinal cord, we now investigated whether activation of noradrenergic nuclei in the brainstem is responsible for this analgesic action and which α2 adrenoceptor subtype mediates this property. In rats, Fos immunoreactivity was examined in brainstem noradrenergic nuclei after exposure to nitrous oxide. After selective lesioning of noradrenergic nuclei by intracerebroventricular application of the mitochondrial toxin saporin, coupled to the antibody directed against dopamine β hydroxylase (DβH-saporin), the analgesic and sedative actions of N2O were determined. Null mice for each of the three α2 adrenoceptor subtypes (α2A, α2B, and α2a), and their wild-type cohorts, were tested for their antinociceptive and sedative response to N2O. Exposure to N2O increased expression of Fos immunoreactivity in each of the pontine noradrenergic nuclei (A5, locus coeruleus, and A7). DβH-saporin treatment eliminated nearly all of the catecholamine-containing neurons in the pons and blocked the analgesic but not the sedative effects of N2O. Null mice for the α2B adrenoceptor subtype exhibited a reduced or absent analgesic response to N2O, but their sedative response to N2O was intact. Our results support a pivotal role for noradrenergic pontine nuclei and α2B adrenoceptors in the analgesic, but not the sedative effects N2O. Previously we demonstrated that the analgesic actions α2 adrenoceptor agonists are mediated by the α2A subtype taken together with these data we propose that exogenous endogenous α2 adrenoceptor ligands activate different α2 adrenoceptor subtypes to produce their analgesic action.