Transient action of the endothelial constitutive nitric oxide synthase (ecNOS) mediates the development of thermal hypersensitivity following peripheral nerve injury

Eur J Neurosci. 2000 Jul;12(7):2323-32. doi: 10.1046/j.1460-9568.2000.00129.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axonal Transport / physiology
  • Electrophysiology
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Enzymologic / physiology
  • Hot Temperature
  • Hyperalgesia / metabolism*
  • Immunohistochemistry
  • Male
  • Mechanoreceptors / drug effects
  • Mechanoreceptors / enzymology
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nerve Endings / enzymology
  • Nerve Fibers, Myelinated / enzymology*
  • Nitric Oxide Synthase / analysis
  • Nitric Oxide Synthase / genetics*
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type III
  • Nociceptors / drug effects
  • Nociceptors / enzymology
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Sciatic Nerve / cytology
  • Sciatic Nerve / enzymology
  • Sciatic Nerve / injuries*


  • Enzyme Inhibitors
  • RNA, Messenger
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • NG-Nitroarginine Methyl Ester