Transient changes in the synthesis of nitric oxide result in long-term as well as short-term changes in acetic acid-induced writhing in mice.
A single injection of nitric oxide (NO) synthase (NOS) inhibitors prevents the development of persistent hyperalgesia induced by various manipulations, suggesting that NO precipitates long-term changes in nociception. We examined the possibility that inhibition of NOS may also be sufficient to produce long-term decreases in nociceptive assays, such as writhing, that are known to be sensitive to the short-term effects of NOS inhibitors. We characterized short- and long-term effects of NOS inhibitors, N(omega)-nitro-L-arginine (L-NAME) or 7-nitro indazole (7-NI) injected intrathecally (i.t.) in mice on acetic acid-induced writhing. Doses of L-NAME that had no effect on hot plate or tail flick latencies inhibited writhing (0. 01-30 nmol) as well as spinal nNOS activity (5 and 100 nmol) when injected i.t. 60-90 min before testing. Anti-nociception was not mimicked by D-NAME but was prevented by co-administration with the NO precursor, L-arginine. Injection i.t. of 7-NI (30 min), a selective inhibitor of neuronal NOS (nNOS), inhibited NOS activity in the spinal cord and produced anti-nociception, confirming that writhing is sensitive to inhibition of nNOS. Although the acute action of both NOS inhibitors dissipated completely by 3-6 h, a delayed and prolonged inhibition of writhing was again observed 24 h after L-NAME (5-100 nmol), a time when spinal NOS activity was no longer inhibited by L-NAME (5 and 100 nmol) or 7-NI (25 nmol). This novel effect appears to be initiated by the transient inhibition of nNOS as delayed anti-nociception was mimicked by 7-NI at doses (10-100 nmol) that no longer inhibited spinal nNOS (25 nmol) at 24 h. Co-administration with L-arginine prevented the delayed (24 h) anti-nociceptive effects of L-NAME (30 nmol). L-Arginine (30 and 100 nmol) was without effect on nociception when administered alone 60 min or 24 h prior to testing. Together these data indicate that brief changes in the activity of nNOS induce both long- as well as short-term changes in nociception.
Larson
A A
AA
Graduate Program in Neuroscience, Department of Veterinary Pathobiology, University of Minnesota, St. Paul 55108, USA. larso011@tc.umn.edu
Kovacs
K J
KJ
Cooper
J C
JC
Kitto
K F
KF
D019342:Acetic Acid; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006358:Hot Temperature; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010147:Pain Measurement / Q000187:drug effects*; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology
D004791:Enzyme Inhibitors; D007191:Indazoles; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019342:Acetic Acid; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester