Genetic knockout and pharmacologic inhibition of neuronal nitric oxide synthase attenuate nerve injury-induced mechanical hypersensitivity in mice.
Neuronal nitric oxide synthase (nNOS) is a key enzyme for nitric oxide production in neuronal tissues and contributes to the spinal central sensitization in inflammatory pain. However, the role of nNOS in neuropathic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to examine the effects of genetic knockout and pharmacologic inhibition of nNOS on neuropathic pain induced by unilateral fifth lumbar spinal nerve injury in mice. In contrast to wildtype mice, nNOS knockout mice failed to display nerve injury-induced mechanical hypersensitivity. Furthermore, either intraperitoneal (100 mg/kg) or intrathecal (30 microg/5 microl) administration of L-NG-nitro-arginine methyl ester, a nonspecific NOS inhibitor, significantly reversed nerve injury-induced mechanical hypersensitivity on day 7 post-nerve injury in wildtype mice. Intrathecal injection of 7-nitroindazole (8.15 microg/5 microl), a selective nNOS inhibitor, also dramatically attenuated nerve injury-induced mechanical hypersensitivity. Western blot analysis showed that the expression of nNOS protein was significantly increased in ipsilateral L5 dorsal root ganglion but not in ipsilateral L5 lumbar spinal cord on day 7 post-nerve injury. The expression of inducible NOS and endothelial NOS proteins was not markedly altered after nerve injury in either the dorsal root ganglion or spinal cord. Our findings suggest that nNOS, especially in the dorsal root ganglion, may participate in the development and/or maintenance of mechanical hypersensitivity after nerve injury.
Guan
Yun
Y
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 355 Ross, 720 Rutland Ave,, Baltimore, Maryland 21205, USA. ytau@jhmi.edu
Yaster
Myron
M
Raja
Srinivasa N
SN
Tao
Yuan-Xiang
YX
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005727:Ganglia, Spinal / Q000201:enzymology; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010812:Physical Stimulation; D013116:Spinal Cord / Q000201:enzymology; D013127:Spinal Nerves / Q000293:injuries
D004791:Enzyme Inhibitors; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D019331:NG-Nitroarginine Methyl Ester