Enkephalin release and opioid receptor activation does not mediate the antinociceptive or sedative/hypnotic effects of nitrous oxide

In previous studies using Fos expression as a marker of neuronal activation , we showed that nitrous oxide (N2O) activates bulbospinal noradrenergic ne urons in rats and that destruction of these neuronal pathways leads to loss of N2O antinociceptive action. Based on previous rat studies it has been p roposed that these noradrenergic neurons are activated through opioid recep tors through the release of endogenous opioid ligands in the periaqueductal gray. Using mice with a disrupted preproenkephalin gene (Penk2 -/-) and th e opioid receptor antagonist naltrexone, we investigated the role of enkeph alinergic mechanisms and opioid receptor activation in the behavioral and b ulbospinal neuron responses to N2O in mice. The antinociceptive response to N2O was investigated using the tail-flick, hot-plate, and von Frey assays, the sedative/hypnotic response was measured using rotarod and loss of righ ting reflex, and bulbospinal neuronal activation was assessed with pontine Fos immunostaining. No differences were observed between wild-type and Penk 2 -/- mice for the antinociceptive, sedative/hypnotic, and pontine neuronal activation effects of N2O. Similarly, naltrexone did not block N2O-induced antinociception, sedation, or hypnosis. We conclude that neither enkephali n nor opioid receptors participate in either the antinociceptive or the sed ative/hypnotic actions of N2O in mice. (C) 2001 Elsevier Science B.V. All r ights reserved.