5-Hydroxytryptamine-facilitated release of substance P from rat spinal cord slices is mediated by nitric oxide and cyclic GMP.

The role of nitric oxide (NO) in the control of 5-hydroxytryptamine (5-HT)-induced release of substance P was investigated in rat spinal cord in vitro. 5-HT facilitated the 60 mM K(+)-evoked release of substance P-like immunoreactive materials (SPLI) from the superfused rat dorsal spinal cord slices without affecting spontaneous SPLI release. The facilitatory effect of 5-HT was significantly inhibited by ICS 205-930 or granisetron (potent and specific 5-HT3 receptor antagonists), by NG-monomethyl-L-arginine (NMMA, a NO synthase inhibitor), and by methylene blue or 1H-[1,2,4] oxadiazolo [4,3-a] quinoxaline-1-one (MB or ODQ, respectively; both are inhibitors of soluble guanylyl cyclase) and was mimicked by 2-methylserotonin (2-m-5-HT, a selective 5-HT3 receptor agonist), L-arginine (a precursor of NO), or 8-bromo-cyclic GMP. NMMA, MB, or ODQ inhibited the 2-m-5-HT-induced increase of cyclic GMP levels in the rat dorsal spinal cord slices. These data suggest that the facilitatory effect of 5-HT on the release of SPLI is mediated by the 5-HT3 receptor and that the intracellular signaling is mediated via NO by an increase in cyclic GMP production.