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

Authors

  • Dan Levy,

    1. Department of Clinical Neurosciences and the Neuroscience Research Group, University of Calgary, 3330 Hospital Drive, N.W Calgary, Alberta T2N 4N1 Canada
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  • Michael Tal,

    1. Department of Anatomy and Cell Biology, Hebrew University, PO Box 1172, Jerusalem, Israel
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  • Ahmet Höke,

    1. Department of Clinical Neurosciences and the Neuroscience Research Group, University of Calgary, 3330 Hospital Drive, N.W Calgary, Alberta T2N 4N1 Canada
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  • Douglas W. Zochodne

    1. Department of Clinical Neurosciences and the Neuroscience Research Group, University of Calgary, 3330 Hospital Drive, N.W Calgary, Alberta T2N 4N1 Canada
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  • *

    Present address: Department of Anesthesia, Harvard Medical School and Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA

: Dr D. W. Zochodne, as above.
Email: dzochodn@ucalgary.ca

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.

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