Antagonism of the antinociceptive effect of nitrous oxide by inhibition of enzyme activity or expression of neuronal nitric oxide synthase in the mouse brain and spinal cord.
Previous studies have implicated nitric oxide (NO) in the antinociceptive response to the anesthetic gas nitrous oxide (N(2)O). The present study was conducted to confirm this NO involvement using pharmacological and gene knockdown and knockout strategies to inhibit the supraspinal and spinal production of NO. Antinociceptive responsiveness to 70% N(2)O was assessed using the acetic acid (0.6%) abdominal constriction test in NIH Swiss mice following intracerebroventricular (i.c.v.) or intrathecal (i.t.) pretreatment with the NOS-inhibitor l-N(G)-nitro arginine methyl ester (L-NAME) or an antisense oligodeoxynucleotide (AS-ODN) directed against neuronal NOS (nNOS). Experiments were also conducted in mice homozygous for a defective nNOS gene (nNOS(-/-)). Mice that were pretreated i.c.v. or i.t. with L-NAME (1.0 microg) both exhibited 80-90% reduction in the magnitude of the N(2)O-induced antinociceptive response. Mice that were pretreated i.c.v. or i.t. with nNOS AS-ODN (3 x 25microg) exhibited a 60-80% antagonism of the antinociceptive response. Compared to wild-type mice, nNOS knockout mice showed a 60% reduction in N(2)O-induced antinociception. These findings consistently demonstrate that transient or developmental suppression of nNOS expression significantly reduces antinociceptive responsiveness to N(2)O. NO of both supraspinal and spinal origin, therefore, plays an important role in the antinociceptive response to N(2)O.
Cope
Jessica Lack
JL
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, Washington 99164-6534, USA.
Chung
Eunhee
E
Ohgami
Yusuke
Y
Quock
Raymond M
RM
D000700:Analgesics / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002552:Cerebral Ventricles / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D055786:Gene Knockout Techniques; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D009609:Nitrous Oxide / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism
D000700:Analgesics; D004791:Enzyme Inhibitors; D020319:Oligodeoxyribonucleotides, Antisense; D052248:Nitric Oxide Synthase Type I; D009609:Nitrous Oxide