Antinociceptive Action of Nitrous Oxide Is Mediated by Stimulation of Noradrenergic Neurons in the Brainstem and Activation of α_2BAdrenoceptors

Abstract

Although nitrous oxide (N 2 O) has been used to facilitate surgery for >150 years, its molecular mechanism of action is not yet defined. Having established that N 2 O-induced release of norepinephrine mediates the analgesic action at α 2 adrenoceptors in the spinal cord, we now investigated whether activation of noradrenergic nuclei in the brainstem is responsible for this analgesic action and which α 2 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 N 2 O were determined. Null mice for each of the three α 2 adrenoceptor subtypes (α 2A , α 2B , and α 2C ), and their wild-type cohorts, were tested for their antinociceptive and sedative response to N 2 O. Exposure to N 2 O 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 N 2 O. Null mice for the α 2B adrenoceptor subtype exhibited a reduced or absent analgesic response to N 2 O, but their sedative response to N 2 O was intact. Our results support a pivotal role for noradrenergic pontine nuclei and α 2B adrenoceptors in the analgesic, but not the sedative effects of N 2 O. Previously we demonstrated that the analgesic actions of α 2 adrenoceptor agonists are mediated by the α 2A subtype; taken together with these data we propose that exogenous and endogenous α 2 adrenoceptor ligands activate different α 2 adrenoceptor subtypes to produce their analgesic action.