THE NITRIC-OXIDE CYCLIC-GMP PATHWAY IS REQUIRED FOR NOCICEPTIVE SIGNALING AT SPECIFIC LOCI WITHIN THE SOMATOSENSORY PATHWAY

The involvement of nitric oxide in nociceptive processing was examined at the main loci of synaptic transmission within the rat somatosensor y pathway from the caudal sural cutaneous nerve. Intrathecal (lumbar 1 -3) administration of the nitric oxide synthase inhibitor, N-omega-nit ro-L-arginine methyl ester (30 mu g), inhibited nitric oxide synthase in this region of the spinal cord by greater than 80% but had no signi ficant effect on nitric oxide synthase in parietal cerebral cortex, th alamus or medulla/pons. In a rat model of peripheral neuropathy (one t o two week ligation of the caudal sural cutaneous nerve), intrathecal administration of the same dose of N-omega-nitro-L-arginine methyl est er prevented the hyperalgesic response to thermal stimuli. Administrat ion of 30 mu g N-omega-nitro-L-arginine methyl ester into the lateral ventricle had no effect on nitric oxide synthase in the lumbar 1-3 reg ion of the spinal cord but gave substantial inhibition in higher areas of the somatosensory pathway (parietal cerebral cortex, thalamus and medulla/pons). Nitric oxide synthase in the parietal cerebral cortex ( but not thalamus) was inhibited to a greater extent in the hemisphere ipsilateral to the site of administration. Administration of 30 mu g N W-nitro-L-arginine methyl ester into the lateral ventricle decreased t hermal hyperalgesia, but only when NW-nitro-L-arginine methyl ester wa s administered contralateral to the ligated caudal sural cutaneous ner ve and therefore ipsilateral to the cortical nociceptive processing fr om this nerve. Intrathecal and intracerebroventricular administration of the selective inhibitor of nitric oxide-sensitive guanylyl cyclase, 1-H-[1,2,4]oxadiazalo[4,3-a]quinoxalin-1-one, also decreased the hype ralgesic response to thermal stimuli. These data demonstrate that, in a model of neuropathic pain, nitric oxide is involved in nociceptive p rocessing at spinal and cerebrocortical synaptic loci of the somatosen sory pathway and that its actions appear to be mediated through guanyl yl cyclase. Copyright (C) 1996 IBRO.