Non-technical summary Obesity is known to result from energy intake in excess of expenditure. What is not known is how individuals are able to eat in excess of their energy needs. We show that after chronic consumption of a high fat diet (which causes obesity), intestinal sensory nerves are less responsive to chemicals released from the gut during a meal (cholecystokinin and 5-hydroxytryptamine) as well as to distension of the gut as might occur during a meal. This appears to be due to the fact that the ability of the nerve cells to be excited is impaired. This suggests that consumption of an unhealthy diet that leads to obesity causes decreased signalling from the intestine, which may lead to increased food intake and contribute to further weight gain, or allow the maintenance of excess weight and obesity.Abstract Gastrointestinal vagal afferents transmit satiety signals to the brain via both chemical and mechanical mechanisms. There is indirect evidence that these signals may be attenuated in obesity. We hypothesized that responses to satiety mediators and distension of the gut would be attenuated after induction of diet induced obesity. Obesity was induced by feeding a high fat diet (60% kcal from fat). Low fat fed mice (10% kcal from fat) served as a control. High fat fed mice were obese, with increased visceral fat, but were not hyperglycaemic. Recordings from jejunal afferents demonstrated attenuated responses to the satiety mediators cholecystokinin (CCK, 100 nM) and 5-hydroxytryptamine (5-HT, 10 μM), as was the response to low intensity jejunal distension, while responses to higher distension pressures were preserved. We performed whole cell patch clamp recordings on nodose ganglion neurons, both unlabelled, and those labelled by fast blue injection into the wall of the jejunum. The cell membrane of both labelled and unlabelled nodose ganglion neurons was less excitable in HFF mice, with an elevated rheobase and decreased number of action potentials at twice rheobase. Input resistance of HFF neurons was also significantly decreased. Calcium imaging experiments revealed reduced proportion of nodose ganglion neurons responding to CCK and 5-HT in obese mice. These results demonstrate a marked reduction in afferent sensitivity to satiety related stimuli after a chronic high fat diet. A major mechanism underlying this change is reduced excitability of the neuronal cell membrane. This may explain the development of hyperphagia when a high fat diet is consumed. Improving sensitivity of gastrointestinal afferent nerves may prove useful to limit food intake in obesity.

The composition of Na+ currents in dorsal root ganglia (DRG) neurons depends on their neuronal phenotype and innervation target. Two TTX-resistant (TTX-R) Na+ currents [voltage-gated Na channels (Nav)] have been described in small DRG neurons; one with slow inactivation kinetics (Nav1.8) and the other with persistent kinetics (Nav1.9), and their modulation has been implicated in inflammatory pain. This has not been studied in neurons projecting to the colon. This study examined the relative importance of these currents in inflammation-induced changes in a mouse model of inflammatory bowel disease. Colonic sensory neurons were retrogradely labeled, and colitis was induced by instillation of trinitrobenzenesulfonic acid (TNBS) into the lumen of the distal colon. Seven to ten days later, immunohistochemical properties were characterized in controls, and whole cell recordings were obtained from small (<40 pF) labeled DRG neurons from control and TNBS animals. Most neurons exhibited both fast TTX-sensitive (TTX-S)- and slow TTX-R-inactivating Na+ currents, but persistent TTX-R currents were uncommon (<15%). Most labeled neurons were CGRP (79%), tyrosine kinase A (trkA) (84%) immunoreactive, but only a small minority bind IB4 (14%). TNBS-colitis caused ulceration, thickening of the colon and significantly increased neuronal excitability. The slow TTX-R-inactivating Na current density (Nav1.8) was significantly increased, but other Na currents were unaffected. Most small mouse colonic sensory neurons are CGRP, trkA immunoreactive, but not isolectin B4 reactive and exhibit fast TTX-S, slow TTX-R, but not persistent TTX-R Na+ currents. Colitis-induced hyperexcitability is associated with increased slow TTX-R (Nav1.8) Na+ current. Together, these findings suggest that colitis alters trkA-positive neurons to preferentially increase slow TTX-R Na+ (Nav1.8) currents.

Hydrogen sulphide (H 2 S) has been recently proposed as a transmitter in the brain and peripheral tissues. Its role in the gastrointestinal tract is still unknown despite some data which suggest an involvement mediating smooth muscle relaxation. The aim of this study was to investigate the effect of this gas on intestinal segments from mouse jejunum and colon, and muscular strips from the human and rat colon. In isolated segments of mouse colon and jejunum, bath applied sodium hydrogen sulphide (NaHS) (a H 2 S donor) caused a concentration-dependent inhibition of spontaneous motor complexes (MCs) (IC 50 121 lmol L human strips, and 80, 167 and 674 lmol L )1 for rat strips respectively. We conclude that H 2 S strongly inhibits in vitro intestinal and colonic motor patterns. This effect appears to be critically dependent on K channels particularly apamin-sensitive SK channels and glybenclamide-sensitive K (ATP) channels.

Intestinal inflammation induces hyperexcitability of dorsal root ganglia sensory neurons, which has been implicated in increased pain sensation. This study examined whether alteration of sodium (Na+) and/ or potassium (K+) currents underlies this hyperexcitability. Ileitis was induced in guinea pig ileum with trinitrobenzene sulphonic acid (TBNS) and dorsal root ganglion neurons innervating the site of inflammation were identified by Fast Blue or DiI fluorescence labelling. Whole cell recordings were made from acutely dissociated small‐sized neurons at 7–10 days. Neurons exhibited transient A‐type and sustained outward rectifier K+ currents. Compared to control, both A‐type and sustained K+ current densities were significantly reduced (42 and 34 %, respectively; P < 0.05) in labelled neurons from the inflamed intestine but not in non‐labelled neurons. A‐type current voltage dependence of inactivation was negatively shifted in labelled inflamed intestine neurons. Neurons also exhibited tetrodotoxin‐sensitive and resistant Na+ currents. Tetrodotoxin‐resistant sodium currents were increased by 37 % in labelled neurons from the inflamed intestine compared to control (P < 0.01), whereas unlabelled neurons were unaffected. The activation and inactivation curves of these currents were unchanged by inflammation. These data suggest ileitis increases excitability of intestinal sensory neurons by modulating multiple ionic channels. The lack of effect in non‐labelled neurons suggests signalling originated at the nerve terminal rather than through circulating mediators and, given that Na+ currents are enhanced whereas K+ currents are suppressed, one or more signalling pathways may be involved.

Gastrointestinal (GI) inflammation modulates the intrinsic properties of nociceptive dorsal root ganglia neurones, which innervate the GI tract and these changes are important in the genesis of abdominal pain and visceral hyperalgesia neurones exhibit hyperexcitability characterized by a decreased threshold for activation and increased firing rate, and changes in voltages-gated Na(+) and K(+) channels play a major role in this plasticity. This review highlights emerging evidence that specific subsets of channels and signalling pathways are involved and their potential to provide novel selective therapeutics targets for the treatment of abdominal pain.