Fig. 1. Putative neuronal pathway for the analgesic effect of nitrous oxide (N2O). Nitrous oxide causes activation of opioidergic neurons, which release endogenous opioids at their terminals in the periaqueductal gray region of the midbrain. Opiate receptors on GABAergic interneurons are stimulated, resulting in an inhibition of these inhibitory interneurons. In turn, this results in a disinhibition of excitatory neurons of the descending noradrenergic neurons in the medulla–pons region. The descending noradrenergic neuron releases norepinephrine at its terminals in the spinal cord, which stimulate at least two species of adrenergic receptors, namely, α1subtypes on γ-aminobutyric acid–mediated (GABAergic) interneurons or α2Badrenergic receptors located postsynaptically on the second-order neuron. The effect of stimulating these two sets of receptors in the dorsal horn of the spinal cord decreases firing of the second-order neuron and hence results in a reduction in pain impulses ascending into the supraspinal regions. Black triangle = excitatory synapse; white triangle = inhibitory synapse; black oval = nucleus of an active cell; white oval = nucleus of an inactive cell. AR = adrenoceptor; ExNT = excitatory neurotransmitters; ExR = receptors for excitatory neurotransmitters; GABA =γ-aminobutyric acid; GABA-R = GABA receptor; LC = locus ceruleus; NE = norepinephrine; Op = opioid peptides; Op-R = opiate receptor.