Excited by fasting? NO.

Nitric oxide (NO) has multiple effects within the gastrointestinal (GI) system, including modulation of GI motility, mucosal function, inflammation and blood flow, as well as the excitability and responsiveness of vagal sensory afferents as well as vagal efferents. In this issue of The Journal of Physiology Kentish et al. (2014) demonstrate, for the first time, that the action of NO to modulate vagal afferent activity in mice is dependent upon the feeding status. These results suggest that the effects of neurotransmitters or modulators to regulate vagal afferents may be more fluid and flexible that assumed previously, and that the effects on GI functions may be altered radically to adapt to physiological as well as pathophysiological conditions. Although the intrinsic neural plexuses of the GI tract allow significant autonomy in the regulation of GI functions, the stomach and upper GI tract in particular are heavily influenced by extrinsic neural inputs, particularly from the parasympathetic pathways. Parasympathetic innervation to the stomach, small intestine and proximal colon is supplied by the vagus nerve, and vagally mediated reflexes play a major role in the homeostatic regulation of GI functions. As a neurotransmitter/modulator, nitric oxide (NO) exerts multiple effects at different sites within the GI system, including GI smooth muscle, blood flow, immune responses and mucosal barrier integrity (Farrugia & Szurszewski, 2014). NO is also an important regulator of extrinsic vagal neurocircuits, decreasing vagal afferent (sensory) neuronal excitability as well as the response to mechanical stimulation of peripheral vagal afferent nerve endings (Kentish et al. 2012). Within hindbrain circuits regulating GI functions, however, NO excites vagal efferent motoneurons (Travagli & Gillis, 1994) and increases gastric motility (Panico et al. 1995). Furthermore, NO released from postganglionic non-adrenergic non-cholinergic (NANC) neurons within the myenteric plexus inhibits gastric motility and tone (reviewed in Travagli et al. 2006). Thus, NO can increase or decrease gastric motility and tone via distinct actions at multiple sites within vagal neurocircuits. The recent study by Kentish et al. (2014) provided some fascinating insight into the potential physiological role of NO within peripheral vagal afferents. In mice fed ad libitum, NO inhibited vagal mucosal afferents via actions involving a guanylyl cyclase-cGMP-dependent pathway that resulted in the production of reactive oxygen species (ROS). In fasted mice, however, NO had the opposite effect, potentiating the response of mucosal and mechanosensitive vagal afferents through a pathway involving activation of hyperpolarizing-activated cyclic nucleotide-gated (HCN) channels. It remains to be determined whether other effects of NO within vagal neurocircuits are similarly modulated by feeding or fasting. It is interesting to note that the majority of in vitro studies investigating vagal control of GI functions are most commonly studied in ad libitum-fed animals whereas in vivo studies are usually conducted in fasted animals. A significant body of work has demonstrated that the response of vagal afferent neurons to a variety of GI neurotransmitters and neuropeptides is altered following fasting or feeding due to an altered complement of neurotransmitter receptors on the neuronal membrane conferring an anorexigenic or orexigenic phenotype (Dockray, 2009). The recent study by Kentish et al. (2014) is the first demonstration that the same neurotransmitter may exert diametrically opposed effects due to the feeding status-dependent recruitment of the different downstream signalling pathways. It remains to be determined whether this phenomenon is generalizable across neurotransmitter systems, or whether it is restricted to the gaseous neurotransmitters for whom receptor externalization or internalization is not an effective means of regulating responses. At face value, the article by Kentish et al. (2014) provides further proof that GI vagal neurocircuits are not static relay systems that merely convey sensory information to the CNS and produce stereotypical output responses, but are, instead, remarkably labile and exhibit a high degree of plasticity, even under physiological conditions. At a deeper level, however, this also implies that experimental methodology is of critical importance when studying vagal neurocircuits, even when using in vitro techniques, since radically different experimental outcomes may result in fundamentally different conclusions being drawn, depending on something as simple as the time of day at which the experiments were conducted (e.g. early morning following overnight feeding ad libitum vs. later afternoon following daytime relative fasting). Standardization of methodology within the field, and the reporting of otherwise ignored experimental details, may allow a greater degree of co-ordination and comparison between different laboratory groups and may avoid costly and extensive efforts to duplicate results. Intriguingly, however, since GI peripheral vagal afferents are relatively more accessible targets for drugs, the timing of therapeutic delivery may present a unique opportunity by which the vagal control of the GI tract may be regulated differentially by taking advantage of the temporally distinct actions of neurotransmitters and neuromodulators.