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Intrathecal S-nitroso-N-acetylpenicillamine and L-cysteine attenuate nerve injury-induced allodynia through noradrenergic activation in rats.

Abstract
Spinal norepinephrine release and activation of spinal alpha(2)-adrenergic receptors represent important components of descending control of nociception. Recent studies have shown that nitric oxide is capable of stimulating neuronal norepinephrine release in the presence of thiol-containing compounds such as L-cysteine. In the present study, we tested a hypothesis in a rodent model of neuropathic pain that intrathecal injection of the nitric oxide donor S-nitroso-N-acetylpenicillamine and L-cysteine produces an antiallodynic action mediated by the spinal alpha(2)-adrenergic receptors. Allodynia was induced in rats by ligation of the left lumbar L5/L6 spinal nerves. Mechanical allodynia was quantified by application of von Frey filaments to the left hindpaw. Intrathecal injection of 20-100microg of S-nitroso-N-acetylpenicillamine in the presence of 200microg of L-cysteine, but not D-cysteine, dose-dependently attenuated the allodynia. Intrathecal injection of a combination of 100microg of S-nitroso-N-acetylpenicillamine and 50-200microg of L-cysteine also inhibited the allodynia in a dose-dependent manner. Pretreatment with a nitric oxide scavenger, carboxy-PTIO, or depletion of norepinephrine with a specific neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, prevented the antiallodynic action of intrathecal S-nitroso-N-acetylpenicillamine and L-cysteine. Furthermore, the antiallodynic effect produced by intrathecal injection of a combination of S-nitroso-N-acetylpenicillamine and L-cysteine was abolished by pretreatment with intrathecal injection of a non-specific alpha-adrenergic receptor antagonist, phentolamine, or an alpha(2) receptor antagonist, idazoxan. This study provides the first functional evidence that spinal nitric oxide interacts with the thiol-containing compounds to produce an antiallodynic effect in neuropathic pain. We propose that such an action is mediated by endogenous norepinephrine and spinal alpha(2)-adrenergic receptors.
AuthorsS R Chen, J C Eisenach, H L Pan
JournalNeuroscience (Neuroscience) Vol. 101 Issue 3 Pg. 759-65 ( 2000) ISSN: 0306-4522 [Print] United States
PMID11113324 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Nitric Oxide Donors
  • Nitroso Compounds
  • Receptors, Adrenergic, alpha-2
  • S-Nitrosothiols
  • S-nitro-N-acetylpenicillamine
  • Nitric Oxide
  • Mercaptoethanol
  • S-nitrosomercaptoethanol
  • Penicillamine
  • Cysteine
  • Norepinephrine
Topics
  • Animals
  • Cysteine (pharmacology)
  • Hyperalgesia (drug therapy, metabolism, physiopathology)
  • Injections, Spinal (statistics & numerical data)
  • Male
  • Mechanoreceptors (drug effects, metabolism, physiopathology)
  • Mercaptoethanol
  • Nitric Oxide (metabolism)
  • Nitric Oxide Donors (pharmacology)
  • Nitroso Compounds (metabolism)
  • Norepinephrine (metabolism)
  • Pain Threshold (drug effects, physiology)
  • Penicillamine (analogs & derivatives, pharmacology)
  • Peripheral Nerve Injuries
  • Peripheral Nerves (pathology, physiopathology)
  • Peripheral Nervous System Diseases (drug therapy, metabolism, physiopathology)
  • Physical Stimulation (adverse effects)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-2 (drug effects, metabolism)
  • S-Nitrosothiols
  • Spinal Cord (drug effects, metabolism, physiopathology)

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