Upregulation of neuronal nitric oxide synthase in the periphery promotes pain hypersensitivity after peripheral nerve injury

• Published in: Neuroscience Vol. 190; pp. 367 - 378
• Main Authors: Kim, K.H, Kim, J.-I, Han, J.A, Choe, M.-A, Ahn, J.-H
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 05.09.2011; Elsevier
• Subjects: Animals; Arginine; Arginine - pharmacology; Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Hyperalgesia - chemically induced; Hyperalgesia - metabolism; Hyperalgesia - physiopathology; Male; mechanical allodynia; Molsidomine - analogs & derivatives; Molsidomine - pharmacology; Neuralgia - metabolism; Neuralgia - physiopathology; Neurology; neuronal nitric oxide synthase; nitric oxide; Nitric Oxide Synthase Type I - genetics; Nitric Oxide Synthase Type I - metabolism; Pain Threshold - physiology; Peripheral Nerve Injuries - metabolism; Peripheral Nerve Injuries - physiopathology; peripheral nerve injury; periphery; Rats; Rats, Sprague-Dawley; Schwann Cells - metabolism; Sensory Receptor Cells - metabolism; Up-Regulation; Vertebrates: nervous system and sense organs; MPE; neurofilament 200; 7-NI; d-N G-nitro-arginine methyl ester; 3-morpholino-synonimine; NF200; d-NAME; 7-nitroindazole; mechanical allodynia; nitric oxide synthase; PBS; nitric oxide; IL; l-NAME; N-methyl- d-aspartate, nNOS, neuronal nitric oxide synthase; IR; calcitonin gene related peptide; L5 SNL; NOS; dorsal root ganglion; L5 spinal nerve ligation; IB4; paw withdrawal thresholds; CGRP; glial fibrillary acidic protein; ATF3; activating transcription factor 3; protein gene peptide 9.5; l-N G-nitro-arginine methyl ester; NO; cyclic guanosine monophosphate; PWTs; maximal possible effect; cGMP; NMDA; peripheral nerve injury; interleukin; periphery; isolectin 4; CCI; neuronal nitric oxide synthase; chronic constriction injury; phosphate buffer saline; TRPV1; GFAP; SIN-1; immunoreactive; PGP9.5; DRG; transient receptor potential cation channel subfamily V member 1; Allodynia; Peripheral nerve; Pain; Enzyme; Nitric oxide; Oxidoreductases; Lesion; Nitric-oxide synthase
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2011.05.064

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 -NG -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.