Capsaicin and 6-gingerol, pungent components of chilli pepper and ginger, are known as dietary agonists of transient receptor potential vanilloid-1. Transient receptor potential vanilloid-1 nerve fibers are recognized to play a role in gastric mucosal integrity in rats. In the present studies, we examined the acute effects of peroral administration of capsaicin and 6-gingerol on gastric acid secretion in conscious mice. These agents were given p. o. 30 min before the pylorus was ligated. Oral administration of capsaicin (1.0–100 mg/kg) or 6-gingerol (1.5–50 mg/kg) significantly and dose-dependently inhibited basal acid secretion. Pretreatment with BCTC, a transient receptor potential vanilloid-1 antagonist, significantly reversed the reduced basal acid secretion by capsaicin or 6-gingerol. The combination of the lowest doses of capsaicin and 6-gingerol markedly inhibited basal acid secretion in conscious mice and this was also significantly reversed by BCTC. Moreover, the combination of the maximal dose of capsaicin and 6-gingerol inhibited basal acid secretion only to the level of a single administration of the maximal dose of capsaicin. These results suggest that the combination of capsaicin and 6-gingerol has an additive effect on the inhibition of gastric acid secretion through activation of transient receptor potential vanilloid-1. In separate experiments, intraduodenal administration of either capsaicin (30 mg/kg) or 6-gingerol (15 mg/kg), whose doses were observed to have a significant inhibitory effect by oral administration, tended to inhibit basal acid secretion compared with the vehicle. These results suggest that the combination of capsaicin and 6-gingerol has an additive effect on inhibition of gastric acid secretion through activation of transient receptor potential vanilloid-1, and oral administration of transient receptor potential vanilloid-1 agonists directly stimulates transient receptor potential vanilloid-1 in the gastric lumen, resulting in a potent reduction of gastric acid secretion.

Allyl isothiocyanate (AITC) activates transient receptor potential ankyrin 1 (TRPA1) channel, which is involved in the control of intestinal mucosal blood flow. However, the mechanism underlying the increased gastric mucosal blood flow (GMBF) in response to AITC remains unknown. We examined the effect of AITC on GMBF in the ex vivo stomachs of normal and sensory deafferented rats using a laser Doppler flowmeter. Mucosal application of AITC increased GMBF in a concentration-dependent manner. Repeated AITC exposure resulted in a marked desensitization. The increased GMBF response induced by AITC was entirely blocked by co-application of TRPA1 channel blockers HC-030031 or AP-18. Increased GMBF in response to AITC was significantly attenuated by chemical deafferentation following systemic capsaicin injections (total dose: 100 mg/kg). In contrast, increased GMBF responses to capsaicin, a transient receptor potential vanilloid 1 (TRPV1) activator, were completely abolished by chemical deafferentation. The increased GMBF response to AITC was markedly inhibited by BIBN 4096, a calcitonin gene-related peptide receptor (CGRP) antagonist, or AGP-8412, an adrenomedullin receptor antagonist. These results suggest that AITC-stimulated TRPA1 activation results in the increased GMBF through the release of CGRP and adrenomedullin.

Functional dyspepsia (FD) is thought to be mainly based on gastric motility dysfunction and chronic hypersensitivity, yet FD animal models has been reported a few. We studied to establish the mouse model of impaired gastric motility induced by a pungent ingredient of wasabi allyl isothiocyanate (AITC), which is reliable to evaluate prokinetic agents. Male ddY mice were used. Gastric motility was measured by ¹³C-acetic acid breath test in conscious mice. AITC (80 mM) was given 60 min before the measurement of motility. Prokinetic agents including itopride (30, 100 mg/kg), mosapride (0.1-1 mg/kg), neostigmine (30 μg/kg), acotiamide (10-100 mg/kg), and daikenchuto (100-1000 mg/kg) were given 40 min before the measurement. AITC impaired gastric motility without mucosal damages, which reverted 24 h after AITC treatment. The decreased motility induced by AITC was restored by prokinetic agents such as itopride, mosapride, neostigmine, and acotiamide. In separate experiment, daikenchuto recovered the decreased motility induced by AITC, although daikenchuto had no effect on motility in normal condition. In conclusion, it is considered that the AITC-induced impaired gastric motility mouse model is useful to develop new prokinetic agents for treatment of FD, and to re-evaluate traditional Japanese herbal medicines.

Daikenchuto is a traditional Kampo medicine used to treat cold sensations and dysmotility in the abdomen. This study investigated the roles of transient receptor potential ankyrin 1- and transient reporter potential vanilloid 1-expressing sensory nerves in daikenchuto-induced gastric mucosal blood flow by pharmacological and immunohistochemical analyses using male Sprague-Dawley rats. Gastric mucosal blood flow was measured in ex vivo stomachs using a laser Doppler flowmeter. Transient receptor potential ankyrin 1 activator allyl isothiocyanate or transient reporter potential vanilloid 1 activator capsaicin were applied for 10 min, and daikenchuto was applied for 10 or 30 min to the rat stomach. Transient reporter potential vanilloid 1 blocker N-(4-t-butylphenyl)-4-(3-chlopyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide and transient receptor potential ankyrin 1 blocker A-967079 were also administered intragastrically. Capsaicin and allyl isothiocyanate increased gastric mucosal blood flow immediately after the intragastric application, which was almost completely inhibited by N-(4-t-butylphenyl)-4-(3-chlopyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide and A-967079, respectively. Daikenchuto increased gastric mucosal blood flow in a concentration-dependent manner. A-967079 significantly inhibited the increase in gastric mucosal blood flow induced by daikenchuto. In contrast, N-(4-t-butylphenyl)-4-(3-chlopyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide inhibited the responses to daikenchuto only in the late phase but not in the initial phase. Interestingly, in the deafferentation of capsaicin-sensitive sensory fiber in rats, the increased gastric mucosal blood flow induced by daikenchuto was only decreased in the late phase. Although transient receptor potential ankyrin 1- and transient reporter potential vanilloid 1-immunoreactive fibers were observed around the submucosal blood vessels of normal subjects, they were completely absent in the deafferentation of capsaicin-sensitive sensory fibers. Thus, daikenchuto increases gastric mucosal blood flow via transient receptor potential ankyrin 1- and transient reporter potential vanilloid 1-co-expressing sensory nerves in rat stomachs. Received: 10 April 2021 Received: 23 September 2021 Accepted: 19 October 2021 Publication Date: 07 March 2022 (online) © 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany