Nitrous oxide is widely used clinically for conscious sedation and also in surgical anesthesia, however, the mechanism of its analgesic action has remained unknow. Other investigators have reported that nitrous oxide-induced analgesia is antagonized by the opiate receptor blocker naloxone and, in preliminary investigations, we have found that exposure to 75% nitrous oxide: 25% oxygen produces a reversible increase in the methionine-enkephalin (ME)-like immunoreactivity in fractions of artificial cerebrospinal fluid collected from ventricular-cisternally-perfused, anesthetized rats. Based upon these findings, we hypothesize that nitrous oxide can induce neuronal release of specific opioid peptides and that this drug action might be associated with the analgesic effect of nitrous oxide.
Our specific aim i s to submit this hypothesis to testing by a set of postulates designed to verify an opiate involvement in a physiological or pharmacological process. These tests will involve 1. antagonism by naloxone, 2. non-antagonism by (+)-naloxone, 3. cross-tolerance with morphine, 4. potentiation by inhibitors of enkephalin metabolism, and 5. demonstration of release of opioid peptides. These tests will be conducted, using nitrous oxide-induced analgesia in behavioral models and nitrous oxide-induced changes in perfusate ME-like immunoreactivity in anesthetized and conscious centrally-perfused rats. Our methods will include the rat tail flick test, the rat hot plate test, ventricular-cisternal perfusion, intrathecal perfusion, radioimmunoassay and high performance liquid chromatography separation or assay of opioid peptides. The long-term objectives of this research are to systemically analyze the drug actions and effects of nitrous oxide and eventually other general anesthetic drugs as well. The findings of this research should contribute to our understanding and knowledge of the pharmacology of nitrous oxide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE006894-02
Application #
3220395
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1984-12-01
Project End
1987-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Marquette University
Department
Type
Schools of Dentistry/Oral Hygn
DUNS #
046929621
City
Milwaukee
State
WI
Country
United States
Zip Code
53201
Nair, Harsha K; Hain, Heather; Quock, Raymond M et al. (2011) Genomic loci and candidate genes underlying inflammatory nociception. Pain 152:599-606
Pruhs, Ronald J; Pena, Roehl T; Quock, Raymond M (2007) Antagonism of phosphoramidon-induced antinociception in mice by mu- but not kappa-opioid receptor blockers. Life Sci 80:1816-20
Quock, R M; Mueller, J L; Vaughn, L K et al. (1996) Nitrous oxide antinociception in BXD recombinant inbred mouse strains and identification of quantitative trait loci. Brain Res 725:23-9
Hara, S; Kuhns, E R; Ellenberger, E A et al. (1995) Involvement of nitric oxide in intracerebroventricular beta-endorphin-induced neuronal release of methionine-enkephalin. Brain Res 675:190-4
Hara, S; Gagnon, M J; Quock, R M et al. (1994) Effect of opioid peptide antisera on nitrous oxide antinociception in rats. Pharmacol Biochem Behav 48:699-702
McDonald, C E; Gagnon, M J; Ellenberger, E A et al. (1994) Inhibitors of nitric oxide synthesis antagonize nitrous oxide antinociception in mice and rats. J Pharmacol Exp Ther 269:601-8
Hodges, B L; Gagnon, M J; Gillespie, T R et al. (1994) Antagonism of nitrous oxide antinociception in the rat hot plate test by site-specific mu and epsilon opioid receptor blockade. J Pharmacol Exp Ther 269:596-600
Quock, R M; Mueller, J L; Vaughn, L K (1993) Strain-dependent differences in responsiveness of mice to nitrous oxide (N2O) antinociception. Brain Res 614:52-6
Quock, R M; Curtis, B A; Reynolds, B J et al. (1993) Dose-dependent antagonism and potentiation of nitrous oxide antinociception by naloxone in mice. J Pharmacol Exp Ther 267:117-22
Quock, R M; Nguyen, E (1992) Possible involvement of nitric oxide in chlordiazepoxide-induced anxiolysis in mice. Life Sci 51:PL255-60

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