J Neurogastroenterol Motil  https://doi.org/10.5056/jnm19014
Vagal TRPA1 mediates stress-exacerbated visceral mechanonociception after antral cold exposure
Xin Chen1, Qingqing Luo1, Xiujuan Yan1, Wenting Li1, Shengliang Chen1*
Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
Received: December 20, 2018; Revised: April 10, 2019; Accepted: May 16, 2019; Published online: June 12, 2019.
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

Abstract
Background/Aims
Abdominal pain can be evoked or exacerbated after gastrointestinal cold stimulation in some patients with diarrhea-predominant irritable bowel syndrome (IBS-D), indicating a low temperature-induced sensitization of visceral perception. We investigated the role of vagal transient receptor potential ankyrin 1 (TRPA1, a cold-sensing ion channel) in cold-aggravated visceral mechanonociception in a stress-induced IBS animal model.
Methods
TRPA1 expression was examined in antral biopsies of healthy controls and IBS-D patients. Abdominal symptoms were assessed before and after warm or cold water intake. The visceromotor response (VMR) to colorectal distention (CRD) following intra-antral infusion of cold saline was measured in animals undergoing sham or chronic water avoidance stress. TRPA1 expression, extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation, and neuronal calcium influx in vagal afferents were assessed.
Results
Compared to healthy controls, IBS-D patients displayed elevated antral TRPA1 expression, which was associated with symptom scores after cold (4C) water intake. Intra-antral infusion of cold saline increased VMR to CRD in naive rats, an effect dependent on vagal afferents. In stressed rats, this effect was greatly enhanced. Functional blockade and gene deletion of TRPA1 abolished the cold effect on visceral nociception. TRPA1 expression in vagal (but not spinal) afferents increased after stress. Moreover, the cold-induced, TRPA1-dependent ERK1/2 activation and calcium influx in nodose neurons were more robust in stressed rats.
Conclusion
Stress-exaggerated visceral mechanonociception after antral cold exposure may involve up-regulation of TRPA1 expression and function on vagal afferents. Our findings reveal a novel mechanism for abnormal gastrointestinal cold sensing in IBS.
Keywords: Cold temperature, Stress, psychological, TRPA1 cation channel, Vagus nerve, Visceral pain


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