Experiments with nitric oxide synthase inhibitors in spinal nerve ligated rats provide no evidence of a role for nitric oxide in neuropathic mechanical allodynia.
We have investigated the effect of treatment with N(omega)-nitro-l-arginine methylester (l-NAME), a non-selective nitric oxide synthase inhibitor (NOS), both before and after the induction of mechanical allodynia by tight ligation of the left L5 and L6 spinal nerves in rats (SNL rats). The degree of mechanical allodynia was measured by tactile threshold for paw flinching with von Frey filaments. Intraperitoneal (i.p.) administration of l-NAME (3-30 mg/kg) 1 week after the spinal nerve ligation produced a dose-dependent reduction of the behavioral signs of mechanical allodynia, but the effect was not reversed by pretreatment with l-arginine (300 mg/kg). N(omega)-Nitro-l-arginine (l-NNA, i.p., 30 mg/kg), aminoguanidine (AG, i.p., 30 mg/kg) and a potent neuronal NOS inhibitor (LY457963, i.p., 30 mg/kg) did not reduce mechanical sensitivity in the SNL rats. Furthermore, using an ex vivo NOS activity assay, l-NAME partially inhibited the spinal NOS activity, whereas LY457963 almost completely inhibited the spinal NOS activity. Prior administration of l-NAME (i.p., 30 mg/kg) or of MK-801 (0.5 mg/kg), an NMDA antagonist, 30 min before the spinal nerve ligation significantly prevented the development of mechanical allodynia after spinal nerve ligation for an extended period of time. High doses of l-arginine (100 mg/kg or 300 mg/kg, i.p.), however, did not reverse the preemptive effect of l-NAME. These results suggest that neither the anti-allodynic nor the preemptive effects of l-NAME are mediated by NOS inhibition.
Lee
Doo H
DH
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. dool@amgen.com
Singh
Jai Pal
JP
Lodge
David
D
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D008026:Ligation; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009437:Neuralgia / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000293:injuries*
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D006146:Guanidines; D009569:Nitric Oxide; D016291:Dizocilpine Maleate; D001120:Arginine; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester