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 20-100microg 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.
Chen
S R
SR
Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Eisenach
J C
JC
Pan
H L
HL
D000818:Animals; D003545:Cysteine / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007278:Injections, Spinal / Q000706:statistics & numerical data; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008623:Mercaptoethanol; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000473:pathology / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D010812:Physical Stimulation / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism; D026403:S-Nitrosothiols; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology
D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D018341:Receptors, Adrenergic, alpha-2; D026403:S-Nitrosothiols; C110881:S-nitro-N-acetylpenicillamine; D009569:Nitric Oxide; D008623:Mercaptoethanol; C032635:S-nitrosomercaptoethanol; D010396:Penicillamine; D003545:Cysteine; D009638:Norepinephrine