Involvement of a NO-cyclic GMP-PKG signaling pathway in nitrous oxide-induced antinociception in mice

作者：Zhang Yao; Quock Lindsay P; Chung Eunhee; Ohgami Yusuke; Quock Raymond M^*

来源：European Journal of Pharmacology, 2011, 654(3): 249-253.

DOI：10.1016/j.ejphar.2011.01.006

• Nitrous oxide
• Antinociception
• Nitric oxide
• Cyclic GMP
• Protein kinase G
• (Mouse)

The antinociceptive effect of nitrous oxide (N(2)O) 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 N(2)O action involves sequential activation of NO synthase, soluble guanylyl cyclase and protein kinase G to induce an antinociceptive effect in mice. The antinociceptive responsiveness of male NIH Swiss mice to N(2)O 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-pCFT-cGMPS) or the selective phosphodiesterase V-inhibitor 12-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 (T0156). Vehicle (saline)-pretreated mice responded to N(2)O 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 N(2)O was progressively shifted to the right by increasing the dose of each pretreatment drug. On the other hand, N(2)O-induced antinociception was enhanced by systemic pretreatment with T 0156; the dose-response curve for N(2)O was shifted to the left. The ATP-sensitive potassium channel blocker glibenclamide was without influence on the antinociceptive effect of N(2)O. These results support the hypothesis that N(2)O-induced antinociception in mice is mediated by a NO-cyclic GMP-PKG pathway.

• 出版日期2011-3-11