Mechanisms of nitrous oxide-induced analgesic effects

The underlying mechanisms of nitrous oxide (N2O)-induced analgesic effects have been partly elucidated during the last several decades. N2O induces opioid peptide release in the periaqueductal grey area of the midbrain, leading to inhibition of GABAergic neurons that are tonically inhibiting the descending inhibitory pathways, which results in activation the descending noradrenergic inhibitory neurons. The A7 noradrenergic nuclei in the brainstem are the key elements of this process, for which several neuronal networks may be working in concert. In the spinal cord, activation of the descending noradrenergic inhibitory neurons results in modulation of the pain processing by at least two neuronal systems, i.e., direct inhibition through activation of the α2 adrenoceptors and indirect inhibition by the activation of GABAergic inhibitory neurons through α1 adrenoceptors. The relative importance of each neuronal pathway in the brainstem and the spinal cord on the analgesic effects of N2O remains yet to be clarified as does the mechanisms underlying opioid peptide release by N2O, as well as the initial site of action by N2O.