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

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 20-100 mug of S-nitroso-N-acetylpenicillamine in the presence of 200 mug of L-cysteine, but not D-cysteine, dose-dependently attenuated the allodynia. Intrathecal injection of a combination of 100 mug of S-nitroso-N-acetylpenicillamine and 50-200 mug 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 at 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. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.