title: Transient action of the endothelial constitutive nitric oxide synthase (ecNOS) mediates the development of thermal hypersensitivity following peripheral nerve injury.
abstract: Neuropathic pain is a disabling feature of peripheral nerve injury. Following injury, local inflammation and the release of mediators may contribute to ectopic mechanosensitivity of the nerve-trunk and pain hypersensitivity. In the present study we investigated whether nitric oxide (NO) action and local nitric oxide synthase (NOS) expression play a role in pain hypersensitivity and A fibre-mediated ectopic hyperexcitability following a chronic constriction injury to a rat sciatic nerve. Using immunohistochemical methods we provide evidence for a unique endothelial constitutive nitric oxide synthase (ecNOS) immunoreactivity localized in early axonal endbulb-like structures of injured peripheral nerve axons. Moreover, we show that following nerve injury there is increased ecNOS-mRNA expression within the lumbar sympathetic ganglia, and that axoplasmic transport in sympathetic and other axons rather than local non-neural synthesis accounts for its accumulation in nerve fibres. We also demonstrate here that local inhibition of NOS action with the broad-spectrum inhibitor NG-nitro-L-arginine-methyl ester (L-NAME), but not more specific inhibitors of other NOS isoforms, has stereospecific, dose- and time-dependent analgesic effects that were reversed by local administration of L-arginine, the natural precursor of NO. In further work, using a teased fibre preparation, we show that administration of L-NAME, but not D-NAME, to the injury site also blocks ectopic mechanosensitivity of injured A-fibres. Our results indicate that an early and transient local ecNOS expression within early axonal endbulb-like structures, some arising from sympathetic axons, plays a critical role in the development of neuropathic pain.
authors.affiliation: Department of Clinical Neurosciences and the Neuroscience Research Group, University of Calgary, Alberta, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Levy
authors.forename: M
authors.initials: M
authors.lastname: Tal
authors.forename: A
authors.initials: A
authors.lastname: Höke
authors.forename: D W
authors.initials: DW
authors.lastname: Zochodne
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009411:Nerve Endings / Q000201:enzymology; D009413:Nerve Fibers, Myelinated / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D009619:Nociceptors / Q000187:drug effects / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000166:cytology / Q000201:enzymology / Q000293:injuries*
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019331:NG-Nitroarginine Methyl Ester