Background and purpose: Transient receptor potential ankyrin 1 (TRPA1) channels are expressed by primary afferent neurones and activated by irritant chemicals including allyl isothiocyanate (AITC). Here we investigated whether intracolonic AITC causes afferent input to the spinal cord and whether this response is modified by mild colitis, morphine or a TRPA1 channel blocker. Experimental approach: One hour after intracolonic administration of AITC to female mice, afferent signalling was visualized by expression of c-Fos in laminae I-IIo of the spinal dorsal horn at sacral segment S1. Mild colitis was induced by dextran sulphate sodium (DSS) added to drinking water for 1 week. Key results: Relative to vehicle, AITC (2%) increased expression of c-Fos in the spinal cord. Following induction of mild colitis by DSS (2%), spinal c-Fos responses to AITC, but not vehicle, were augmented by 41%. Colonic inflammation was present (increased myeloperoxidase content and disease activity score), whereas colonic histology, locomotion, feeding and drinking remained unchanged. Morphine (10 mg·kg ) inhibited the spinal c-Fos response to AITC, in control and DSS-pretreated animals, whereas the response to intracolonic capsaicin (5%) was blocked by morphine but not HC-030031. Conclusions and implications: Activation of colonic TRPA1 channels is signalled to the spinal cord. Mild colitis enhanced this afferent input that, as it is sensitive to morphine, is most likely of a chemonociceptive nature. As several irritant chemicals can be present in chyme, TRPA1 channels may mediate several gastrointestinal pain conditions.

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Involvement of m-and k-, but not d-, opioid receptors in the peristaltic motor depression caused by endogenous and exogenous opioids in the guinea-pig intestine 1 Opiates inhibit gastrointestinal propulsion, but it is not clear which opioid receptor types are involved in this action. For this reason, the eect of opioid receptor ± selective agonists and antagonists on intestinal peristalsis was studied. 2 Peristalsis in isolated segments of the guinea-pig small intestine was triggered by a rise of the intraluminal pressure and recorded via the intraluminal pressure changes associated with the peristaltic waves. 3 m-Opioid receptor agonists (DAMGO, morphine), k-opioid receptor agonists (ICI-204,448 and BRL-52,537) and a d-opioid receptor agonist (SNC-80) inhibited peristalsis in a concentrationrelated manner as deduced from a rise of the peristaltic pressure threshold (PPT) and a diminution of peristaltic eectiveness. 4 Experiments with the d-opioid receptor antagonists naltrindole (30 nM) and HS-378 (1 mM), the k-opioid receptor antagonist nor-binaltorphimine (30 nM) and the m-opioid receptor antagonist cyprodime (10 mM) revealed that the antiperistaltic eect of ICI-204,448 and BRL-52,537 was mediated by k-opioid receptors and that of morphine and DAMGO by m-opioid receptors. In contrast, the peristaltic motor inhibition caused by SNC-80 was unrelated to d-opioid receptor activation. 5 Cyprodime and nor-binaltorphimine, but not naltrindole and HS-378, were per se able to stimulate intestinal peristalsis as deduced from a decrease in PPT. 6 The results show that the neural circuits controlling peristalsis in the guinea-pig small intestine are inhibited by endogenous and exogenous opioids acting via m-and k-, but not d-, opioid receptors.

Gastric acid challenge of the rat and mouse stomach is signalled to the brainstem as revealed by expression of c-Fos. The molecular sensors relevant to the detection of gastric mucosal acidosis are not known. Since the acid-sensing ion channels ASIC2 and ASIC3 are expressed by primary afferent neurons, we examined whether knockout of the ASIC2 or ASIC3 gene modifies afferent signalling of a gastric acid insult in the normal and inflamed stomach. The stomach of conscious mice (C57BL/6) was challenged with intragastric HCl; two hours later the activation of neurons in the nucleus tractus solitarii (NTS) of the brainstem was visualized by c-Fos immunocytochemistry. Mild gastritis was induced by addition of iodoacetamide (0.1 %) to the drinking water for 7 days. Exposure of the gastric mucosa to HCl (0.25 M) caused a 3-fold increase in the number of c-Fos-positive neurons in the NTS. This afferent input to the NTS remained unchanged by ASIC3 knockout, whereas ASIC2 knockout augmented the c-Fos response to gastric HCl challenge by 33 % (P<0.01). Pretreatment of wild-type mice with iodoacetamide induced mild gastritis, as revealed by increased myeloperoxidase activity, and enhanced the number of NTS neurons responding to gastric HCl challenge by 41 % (P<0.01). This gastric acid hyperresponsiveness was absent in ASIC3 knockout mice but fully preserved in ASIC2 knockout mice. The current data indicate that ASIC3 plays a major role in the acid hyperresponsiveness associated with experimental gastritis. In contrast, ASIC2 appears to dampen acid-evoked input from the stomach to the NTS. KeywordsAcid-sensing ion channels; gastric acid hyperresponsiveness; gastritis; expression of c-Fos; nucleus of the solitary tract; vagal afferent neurons

There is a gender-related comorbidity of pain-related and inflammatory bowel diseases with psychiatric diseases. Since the impact of experimental gastrointestinal inflammation on the emotional-affective behaviour is little known, we examined whether experimental gastritis modifies anxiety, stress coping and circulating corticosterone in male and female Him:OF1 mice. Gastritis was induced by adding iodoacetamide (0.1 %) to the drinking water for at least 7 days. Inflammation was assessed by gastric histology and myeloperoxidase activity, circulating corticosterone determined by enzyme immunoassay, anxiety-related behaviour evaluated with the elevated plus maze and stress-induced hyperthermia tests, and depression-like behaviour estimated with the tail suspension test. Iodoacetamide-induced gastritis was associated with gastric mucosal surface damage and an increase in gastric myeloperoxidase activity, this increase being significantly larger in female mice than in male mice. The rectal temperature of male mice treated with iodoacetamide was enhanced, whereas that of female mice was diminished. The circulating levels of corticosterone were reduced by 65 % in female mice treated with iodoacetamide but did not significantly change in male mice. On the behavioural level, iodoacetamide treatment caused a decrease in nocturnal homecage activity, drinking and feeding. While depression-related behaviour remained unaltered following induction of gastritis, behavioural indices of anxiety were significantly enhanced in female but not male mice. There was no correlation between the oestrous cycle and anxiety as well as circulating corticosterone. Radiotracer experiments revealed that iodoacetamide did not readily enter the brain, the blood-brain ratio being 20:1. Collectively, these Correspondence: Peter Holzer, Ph.D., Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz, Austria; telephone: +43 316 3804500; fax: +43 316 3809645; peter.holzer@meduni-graz.at. Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts data show that iodoacetamide treatment causes gastritis in a gender-related manner, its severity being significantly greater in female than in male mice. The induction of gastritis in female mice is associated with a reduction of circulating corticosterone and an enforcement of behavioural indices of anxiety. Gastric inflammation thus has a distinct gender-dependent influence on emotional-affective behaviour and its neuroendocrine control. KeywordsIodoacetamide-induced gastritis; anxiety; elevated plus maze test; tail suspension test; myeloperoxidase activity; corticosterone Population-based surveys show that a history of gastroenteritis as well as neurotic and psychiatric disorders are risk factors for developing pain-related (functional) bowel disorders such as functional dyspepsia and irritable bowel syndrome . Accordingly, there is a considerable comorbidity of inflammatory bowel disease (IBD) and pa...