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The Journal of Neuroscience, June 3, 2009, 29(22):7246-7255; doi:10.1523/JNEUROSCI.6099-08.2009

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Behavioral/Systems/Cognitive
Nitric Oxide as an Endogenous Peripheral Modulator of Visceral Sensory Neuronal Function

Amanda J. Page,^1,2,3 Tracey A. O'Donnell,¹ Nicole J. Cooper,¹ Richard L. Young,^1,2 and L. Ashley Blackshaw^1,2,3

¹Nerve-Gut Research Laboratory, Hanson Institute, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia, and Disciplines of ²Medicine and ³Physiology, School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, South Australia 5000, Australia

Correspondence should be addressed to Amanda J. Page, Nerve-Gut Research Laboratory, Room 1-216-H, Level 1, Hanson Institute, Frome Road, Adelaide, SA 5000, Australia. Email: amanda.page{at}health.sa.gov.au

Nitric oxide (NO) plays important roles in CNS and smooth muscle function. Here we reveal an additional function in peripheral sensory transmission. We hypothesized that endogenous NO modulates the function of gastrointestinal vagal afferent endings. The nonselective NO synthase (NOS) inhibitor N^G-nitro-L-arginine methyl ester hydrochloride increased responses to tactile mechanical stimuli of mucosal afferent endings in two species, in some cases severalfold. This was mimicked by a neuronal NOS inhibitor but not an endothelial NOS inhibitor. NOS inhibitors did not affect the responsiveness of smooth muscle afferent endings, suggesting that the endogenous source of NO is exclusively accessible to mucosal receptors. The role of the NO-soluble guanylyl cyclase (sGC)–cGMP pathway was confirmed using the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one and the cGMP phosphodiesterase 5' inhibitor sildenafil. The first enhanced and the second inhibited mechanosensory function. Exogenous NO, from the donor S-nitroso-N-acetylpenicillamine, significantly reduced mechanosensitivity of both types of ending. Up to one-third of stomach-projecting afferent neurons in the nodose ganglia expressed neuronal NOS (nNOS). However, anterograde-traced vagal endings were nNOS negative, indicating NOS is not transported peripherally and there are alternative sources of NO for afferent modulation. A subpopulation of enteroendocrine cells in the gut mucosa were nNOS positive, which were found anatomically in close apposition with mucosal vagal afferent endings. These results indicate an inhibitory neuromodulatory role of epithelial NO, which targets a select population of vagal afferents. This interaction is likely to play a role in generation of symptoms and behaviors from the upper gastrointestinal system.

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Received Dec. 21, 2008; revised March 29, 2009; accepted April 22, 2009.

Correspondence should be addressed to Amanda J. Page, Nerve-Gut Research Laboratory, Room 1-216-H, Level 1, Hanson Institute, Frome Road, Adelaide, SA 5000, Australia. Email: amanda.page{at}health.sa.gov.au

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