The nitric oxide-cyclic GMP pathway is required for nociceptive signalling 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 somatosensory pathway from the caudal sural cutaneous nerve. Intrathecal (lumbar 1-3) administration of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (30 micrograms), inhibited nitric oxide synthase in this region of the spinal cord by greater than 80% but had no significant effect on nitric oxide synthase in parietal cerebral cortex, thalamus or medulla/pons. In a rat model of peripheral neuropathy (one to two week ligation of the caudal sural cutaneous nerve), intrathecal administration of the same dose of N omega-nitro-L-arginine methyl ester prevented the hyperalgesic response to thermal stimuli. Administration of 30 micrograms N omega-nitro-L-arginine methyl ester into the lateral ventricle had no effect on nitric oxide synthase in the lumbar 1-3 region 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 micrograms N omega-nitro-L-arginine methyl ester into the lateral ventricle decreased thermal hyperalgesia, but only when N omega-nitro-L-arginine methyl ester was administered contralateral to the ligated caudal sural cutaneous nerve and therefore ipsilateral to the cortical nociceptive processing from 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 hyperalgesic response to thermal stimuli. These data demonstrate that, in a model of neuropathic pain, nitric oxide is involved in nociceptive processing at spinal and cerebrocortical synaptic loci of the somatosensory pathway and that its actions appear to be mediated through guanylyl cyclase.