Different roles of two nitric oxide activated pathways in spinal long-term potentiation of C-fiber-evoked field potentials

There is accumulating evidence implicating the involvement of nitric oxide (NO) in spinal central sensitization. The long-term potentiation (LTP) of spinal C-fiber-evoked field potentials is considered as a fundamental mechanism of sensitization of nociceptive neurons in the spinal cord. The present study examined the roles of soluble guanylate cyclase (sGC) or ADP-ribosyltransferase (ADPRT), two potential NO targets, in spinal LTP. The results showed that (1) administration of sGC inhibitors, methyl blue (MB, 4 mM, 20 μl) or 1H-[1,2,4]oxadiazolo[4,3-a]-quiloxalin-1-one (ODQ, 10 μM, 20 μl) before tetanic stimulation, significantly inhibited the induction of spinal LTP, and this was reversed by 8-Br-cGMP, a membrane-permeable cGMP analog. However, the maintenance of spinal LTP was not changed when application of ODQ 2 h after tetanic stimulation. (2) Although our previous experiments have identified a key role for NO in the induction of spinal LTP, NO synthase (NOS) inhibitor, L-NAME (1 mM, 20 μl) or hemoglobin (2 mg/ml, 20 μl), a scavenger of NO, had no effect on established spinal LTP when applied 2 h after the induction of spinal LTP. (3) The mono-ADPRT inhibitor, nicotinamide (10 mM, 20 μl), had no effect on the induction and maintenance of spinal LTP. However, the poly-ADPRT inhibitor, benzamide (100 μM, 20 μl), inhibited its maintenance, but not its induction. The results suggest that NO-stimulated guanylyl cyclase activity plays a critical role in the induction of LTP of C-fiber-evoked field potentials in the spinal cord, whereas NO-related poly-ADPRT activity contributes to the maintenance of spinal LTP.