title: Upregulation of neuronal nitric oxide synthase in the periphery promotes pain hypersensitivity after peripheral nerve injury.
abstract: Peripheral nerve injury often results in neuropathic pain that is manifested as hyperalgesia, and allodynia. Several studies suggest a functional role for neuronal nitric oxide synthase (nNOS) in the development or maintenance of neuropathic pain, but such a contribution remains unclear. In our current study, we found that intraplantar injection of the NOS substrate L-arginine or NO donor 3-morpholino-synonimine (SIN-1) produced mechanical hypersensitivity that lasted more than 24 h. Following L5 spinal nerve ligation (L5 SNL), immunoreactivity for nNOS in the ipsilateral L5 but not L4 dorsal root ganglion (DRG) was dramatically increased in mainly small- and medium-sized neurons and non-neuronal cells. L5 SNL caused increased nNOS immunoreactivity in the ipsilateral sciatic nerve, mainly in Schwann cells and the ipsilateral glabrous hind paw skin, mainly on the basement membrane. Furthermore, total nNOS protein and mRNA in the ipsilateral sciatic nerve and hind paw skin were markedly upregulated following nerve injury. Intraplantar injection of the NOS inhibitor 7-nitroindazole (7-NI) or the non-specific NOS inhibitor L-N(G)-nitro-arginine methyl ester (L-NAME) effectively suppressed SNL-induced mechanical allodynia. Collectively, these data suggest that in the periphery nNOS upregulation induced by peripheral nerve injury contributes to mechanical hypersensitivity during the maintenance phase of neuropathic pain. Blocking nNOS signaling in the periphery may thus be a novel therapeutic strategy for the treatment of neuropathic pain.
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors.forename: K H
authors.initials: KH
authors.lastname: Kim
authors.forename: J-I
authors.initials: JI
authors.lastname: Kim
authors.forename: J A
authors.initials: JA
authors.lastname: Han
authors.forename: M-A
authors.initials: MA
authors.lastname: Choe
authors.forename: J-H
authors.initials: JH
authors.lastname: Ahn
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D017288:Pain Threshold / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C002385:linsidomine; D001120:Arginine; D008981:Molsidomine; D052248:Nitric Oxide Synthase Type I