MUSCARINIC CHOLINERGIC STIMULATION OF THE NITRIC-OXIDE CYCLIC-GMP SIGNALING SYSTEM IN CULTURED RAT SENSORY NEURONS

Acetylcholine or carbachol stimulated cyclic GMP production in neurona l cultures from embryonic rat dorsal root ganglia but not in non-neuro nal dorsal root ganglia cultures. Acetylcholine stimulation of cyclic GMP production was mediated by muscarinic receptors and required extra cellular Ca2+. Basal cyclic GMP production and acetylcholine-evoked cy clic GMP production were attenuated by Methylene Blue, suggesting the involvement of soluble guanylate cyclase and nitric oxide synthase. L- NG-Monomethyl arginine attenuated basal, acetylcholine or carbachol-st imulated cyclic GMP production; this inhibition of acetylcholine and c arbachol stimulation of cyclic GMP was reversed by L-arginine, These r esults suggest that a nitrosyl factor mediates basal, as well as acety lcholine- and carbachol-stimulated, cyclic GMP production. Selective d estruction of small diameter neurons by capsaicin pretreatment of dors al root ganglion neuronal cultures abolished acetylcholine and capsaic in stimulation of cyclic GMP, but did not affect sodium nitroprusside stimulation of cyclic GMP. These results suggest that acetylcholine ev oked production of a nitrosyl factor in capsaicin-sensitive (small dia meter) sensory neurons, which subsequently stimulated a soluble guanyl ate cyclase and cyclic GMP production in adjacent neuronal and/or non- neuronal cells. These results demonstrate that muscarinic agonists sti mulate the nitric oxide-cyclic GMP signalling system in capsaicin-sens itive sensory neurons. Thus, the noxious character of acetylcholine wh en administered peripherally may be mediated by nitric oxide-cyclic GM P.