Hyperbaric oxygen (HBO2) therapy induces analgesia in various conditions of pain in humans. In mice, HBO2 treatment evokes an acute antinociceptive response in the abdominal constriction test. To demonstrate the dependence of HBO2-induced antinociception on nitric oxide (NO), antinociceptive responsiveness to HBO2 was assessed after three different approaches that interfered with NO production. HBO2-induced antinociception was significantly attenuated by intracerebroventricular and intrathecal pretreatment with an inhibitor of NO synthase (NOS) enzyme and also by an antisense oligodeoxynucleotide directed against neuronal NOS. The antinociceptive effect was also significantly reduced in mice homozygous for a defective neuronal NOS gene. On the basis of these results, we conclude that neuronal NO is critical in the expression of the acute antinociceptive effect of HBO2.

Previous research has found that hyperbaric oxygen (HBO 2 ) produces an acute antinociceptive effect that is dependent on nitric oxide (NO). The present study was undertaken to determine whether HBO 2 -induced acute antinociception might involve a NO-cyclic GMP-protein kinase G-ATP-sensitive potassium (K ATP ) channel pathway. Male NIH Swiss mice were subjected to a 5-min HBO 2 treatment (100% oxygen at 3.5 absolute atmospheres) and antinociception was assessed over the next 6 min still under HBO 2 using the acetic acid abdominal constriction test. Pretreatment with 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide (carboxy-PTIO, an NO scavenger), 1H-[1,2,4]-oxadiazolo-[4,3-a]quinoxalin-1-one) (a soluble guanylyl cyclase-inhibitor, Rp-8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphorothioate (a protein kinase G-inhibitor) or glibenclamide (an ATP-sensitive potassium channel-inhibitor) all led to antagonism of the HBO 2 -induced acute antinociception in a dose-dependent manner. These findings suggest that HBO 2 -induced acute antinociception might be due to activation of a NO-cyclic GMP-protein kinase G-K ATP channel pathway. KeywordsHyperbaric oxygen; antinociception; nitric oxide; cyclic GMP; protein kinase G; potassium channels; mice © 2010 Elsevier B.V. All rights reserved. * Corresponding author. Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, P.O. Box 646534, Pullman, WA 99164-6534, USA. Fax: +1-509-335-5902. quockr@wsu.edu (R.M. Quock).. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Research Highlights •Hyperbaric oxygen (HBO 2 ) induces antinocicepton in the mouse abdominal constriction test.• HBO 2 antinociception depends on NO, cyclic GMP, PKG and the K ATP channel.NIH Public Access

The antinociceptive effect of nitrous oxide (N2O) is dependent on nitric oxide (NO); however, the next step in the pathway activated by NO is undetermined. The present study was conducted to test the hypothesis that a N2O action involves sequential activation of NO synthase, soluble guanylyl cyclase and protein kinase G to induced an antinociceptive effect in mice. The antinociceptive responsiveness of male NIH Swiss mice to N2O was assessed using the acetic acid abdominal constriction test. Different groups of mice were pretreated with either saline, the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide (carboxy-PTIO), the guanylyl cyclase-inhibitor (1H-[1,2,4]-oxadiazolo-[4,3-a]quinoxalin-1-one) (ODQ), the protein kinase G-inhibitor Rp-isomer of 8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphorothioate (Rp-8-pCPT-cGMPS) or the selective phosphodiesterase V-inhibitor 1,2-dihydro-2-[(2-methyl-4-pyridinyl)methyl]-1-oxo-8-(2-pyrimidinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (T 0156). Vehicle (saline)-pretreated mice responded to N2O in a concentration-dependent manner. This antinociceptive effect was antagonized by systemic pretreatment with carboxy-PTIO and ODQ and central pretreatment with Rp-8-pCPT-cGMPS. In each case, the dose-response curve for N2O was progressively shifted to the right by increasing doses of each pretreatment drug. On the other hand, N2O-induced antinociception was enhanced by systemic pretreatment with T 0156; the dose-response curve for N2O was shifted to the left. The ATP-sensitive potassium channel blocker glibenclamide was without influence on the anti-nociceptive effect of N2O. These results support the hypothesis that N2O-induced antinociception in mice is mediated by a NO–cyclic GMP–PKG pathway.