title: Enkephalin release and opioid receptor activation does not mediate the antinociceptive or sedative/hypnotic effects of nitrous oxide.
abstract: In previous studies using Fos expression as a marker of neuronal activation, we showed that nitrous oxide (N(2)O) activates bulbospinal noradrenergic neurons in rats and that destruction of these neuronal pathways leads to loss of N(2)O antinociceptive action. Based on previous rat studies it has been proposed that these noradrenergic neurons are activated through opioid receptors through the release of endogenous opioid ligands in the periaqueductal gray. Using mice with a disrupted preproenkephalin gene (Penk2 -/-) and the opioid receptor antagonist naltrexone, we investigated the role of enkephalinergic mechanisms and opioid receptor activation in the behavioral and bulbospinal neuron responses to N(2)O in mice. The antinociceptive response to N(2)O was investigated using the tail-flick, hot-plate, and von Frey assays, the sedative/hypnotic response was measured using rotarod and loss of righting reflex, and bulbospinal neuronal activation was assessed with pontine Fos immunostaining. No differences were observed between wild-type and Penk2 -/- mice for the antinociceptive, sedative/hypnotic, and pontine neuronal activation effects of N(2)O. Similarly, naltrexone did not block N(2)O-induced antinociception, sedation, or hypnosis. We conclude that neither enkephalin nor opioid receptors participate in either the antinociceptive or the sedative/hypnotic actions of N(2)O in mice.
authors.affiliation: Department of Functional Restoration, Stanford University School of Medicine, Stanford, CA, USA. wkingery@stanford.edu
authors.forename: W S
authors.initials: WS
authors.lastname: Kingery
authors.forename: S
authors.initials: S
authors.lastname: Sawamura
authors.forename: G S
authors.initials: GS
authors.lastname: Agashe
authors.forename: M F
authors.initials: MF
authors.lastname: Davies
authors.forename: J D
authors.initials: JD
authors.lastname: Clark
authors.forename: A
authors.initials: A
authors.lastname: Zimmer
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004745:Enkephalins / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009271:Naltrexone / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D009609:Nitrous Oxide / Q000494:pharmacology*; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement; D011498:Protein Precursors / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D011957:Receptors, Opioid / Q000502:physiology*
chemical_list: D000700:Analgesics; D004745:Enkephalins; D006993:Hypnotics and Sedatives; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D011957:Receptors, Opioid; D009271:Naltrexone; C033660:preproenkephalin; D009609:Nitrous Oxide