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.

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…In the CCI model of the rat, 2 days after injury (but not later) eNOS accumulation was revealed in damaged axons without appearance of nNOS or iNOS (427). At this early time point, local nonselective NOS inhibition (unlike selective nNOS or iNOS inhibition) reduced heat hyperalgesia and ectopic mechanosensitivity of injured A-fibers in a teased fiber preparation.…”

Norepinephrine-induced nociception and vasoconstrictor hypersensitivity in rats with chronic post-ischemia pain

“…NOS is usually thought to be pronociceptive spinally (Tao et al, 2004), and intrathecal as well as systemic eNOS inhibitors attenuate pain in various pain models (Osborne & Coderre, 1999;Doursout et al, 2003;Naik et al, 2006). In neuropathic pain, NO is often thought to play a pro-nociceptive role by generating nitrogen free radicals and causing vasodilatation that facilitates inflammatory processes (Ialenti et al, 1992;Levy et al, 2000;Levy & Zochodne, 2004). We hypothesize that in SMP, chronic tissue ischemia and vasoconstrictor hypersensitivity are over-riding factors that allow the major vasodilator role of endothelial NO to be beneficial rather than pro-nociceptive.…”

Upregulation of chondroitin 6-sulphotransferase-1 facilitates Schwann cell migration during axonal growth

“…Another possibly related immediate response involves the release of galectin-1 from damaged axons and Schwann cells (Fukuya et al, 2003). Injury-induced production of nitric oxide into the extracellular environment mediates conversion of galectin-1 to the oxidised form (Levy et al, 2000). Given that oxidised galectin-1 stimulated peritoneal macrophages to produce soluble factors that promoted Schwann cell migration in vitro (Horie et al, 2004), injuryinduced activation of resident, endoneurial macrophages in vivo (Mueller et al, 2001) could likewise facilitate the conversion of myelinating Schwann cells to a mobile phenotype that scavenges myelin debris.…”