Effects of nitric oxide availability on responses of spinal wide dynamic range neurons to excitatory amino acids

The role of nitric oxide (NO) in responses of spinal dorsal horn neurons to excitatory amino acids and to cutaneous mechanical stimuli was examined. Extracellular recordings were made from wide dynamic range neurons excited with iontophoretically applied excitatory amino acid agonists, N-methyl-d-aspartate (NMDA) and (R,S)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or kainic acid. Nitric oxide availability was decreased by iontophoretic application of NO synthase inhibitors, N^ω-nitro-l-arginine methyl ester (L-NAME) or l-N⁵-(1-iminoethyl)ornithine (L-NIO), or elevated by the NO donating compound, S-nitroso-N-penicillamine (SNAP). When cells were excited with successive application of NMDA and non-NMDA excitatory amino acid receptor agonists, application of NO synthase inhibitors led to a decrease in responses to NMDA in 60% of neurons. In more than a third of the cells tested, inhibition of NO synthase caused reciprocal changes in responses to glutamate receptor agonists: NMDA-evoked responses were significantly decreased whereas responses to the non-NMDA receptor agonists (AMPA or kainic acid) were increased. Application of the NO donating compound, S-nitroso-N-penicillamine, revealed an opposite tendency, increasing responses to NMDA in more than half of the neurons tested. In approximately 40% of the cells, reciprocal changes in responses to excitatory amino acid receptor agonists of NMDA versus non-NMDA types were observed after application of S-nitroso-N-penicillamine, such that the increase in NMDA responses was accompanied by decreases in the responses to kainic acid. The inhibitory effect of N^ω-nitro-l-arginine methyl ester on the basal firing rate evoked by sustained iontophoretic application of NMDA was specific, dose-dependent and prevented by l-arginine. In the presence of N^ω-nitro-l-arginine methyl ester, responses to noxious peripheral stimulation were either unchanged or decreased. Responses to innocuous stimuli, however, were significantly elevated by N^ω-nitro-l-arginine methyl ester. These results suggest that availability of NO at the synapses between primary afferent fibers and secondary dorsal horn neurons may contribute to the dominancy of one type of excitatory amino acid receptor class over the other in transmission of somatosensory information.