Dietary Agonists of TRPV1 Inhibit Gastric Acid Secretion in Mice

Abstract

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.

Key words

capsaicin - 6-gingerol - transient receptor potential vanilloid-1 - TRPV1 - gastric acid secretion - mice

• References

• 1 Szallasi A, Blumberg PM. Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 1999; 51: 159-212
• 2 Gonlachanvit S. Are rice and spicy diet good for functional gastrointestinal disorders?. J Neurogastroenterol Motil 2010; 16: 131-138
• 3 De Masi L, Siviero P, Castaldo D, Cautela D, Esposito C, Laratta B. Agronomic, chemical and genetic profiles of hot peppers (Capsicum annuum ssp.). Mol Nutr Food Res 2007; 51: 1053-1062
• 4 Kang JY, Teng CH, Wee A, Chen FC. Effect of capsaicin and chilli on ethanol induced gastric mucosal injury in the rat. Gut 1995; 36: 664-669
• 5 Dedov VN, Tran VH, Duke CC, Connor M, Christie MJ, Mandadi S, Roufogalis BD. Gingerols, a novel class of vanilloid receptor (VR1) agonists. Br J Pharmacol 2002; 137: 793-798
• 6 Borrelli F, Capasso R, Pinto A, Izzo AA. Inhibitory effect of ginger (Zingiber officinale) on rat ileal motility in vitro . Life Sci 2004; 74: 2889-2896
• 7 Suekawa M, Ishige A, Yuasa K, Sudo K, Aburada M, Hosoya E. Pharmacological studies on ginger. I. Pharmacological actions of pungent constituents, (6)-gingerol and (6)-shogaol. J Pharmacobiodyn 1984; 7: 836-848
• 8 Calixto JB, Kassuya CA, André E, Ferreira J. Contribution of natural products to the discovery of the transient receptor potential (TRP) channels family and their functions. Pharmacol Ther 2005; 106: 179-208
• 9 Cortright DN, Krause JE, Broom DC. TRP channels and pain. Biochim Biophys Acta 2007; 1772: 978-988
• 10 Holzer P. Acid sensing by visceral afferent neurones. Acta Physiol (Oxf) 2011; 201: 63-75
• 11 Horie S, Yamamoto H, Michael GJ, Uchida M, Belai A, Watanabe K, Priestley JV, Murayama T. Protective role of vanilloid receptor type 1 in HCl-induced gastric mucosal lesions in rats. Scand J Gastroenterol 2004; 39: 303-312
• 12 Mózsik G, Debreceni A, Abdel-Salam OM, Szabó I, Figler M, Ludány A, Juricskay I, Szolcsányi J. Small doses of capsaicin given intragastrically inhibit gastric basal acid secretion in healthy human subjects. J Physiol Paris 1999; 93: 433-436
• 13 Imatake K, Matsui T, Moriyama M. The effect and mechanism of action of capsaicin on gastric acid output. J Gastroenterol 2009; 44: 396-404
• 14 Abdel-Salam OM, Debreceni A, Szolcsányi J, Mózsik G. Capsaicin inhibits the pentagastrin-stimulated gastric acid secretion in anaesthetized rats with acute gastric fistula. J Physiol Paris 1999; 93: 461-466
• 15 Shay H, Komalov SA, Fels SS, Meranze D, Gruenstein M, Siplet H. A simple method for the uniform production of gastric ulceration in the rat. J Lab Clin Med 1946; 31: 1384-1386
• 16 Kawakubo K, Coy DH, Walsh JH, Taché Y. Urethane-induced somatostatin mediated inhibition of gastric acid, reversal by the somatostatin 2 receptor antagonist, PRL-2903. Life Sci 1999; 65: PL115-PL120
• 17 Piqueras L, Martínez V. Role of somatostatin receptors on gastric acid secretion in wild-type and somatostatin receptor type 2 knockout mice. Naunyn Schmiedebergs Arch Pharmacol 2004; 370: 510-520
• 18 Piqueras L, Taché Y, Martínez V. Peripheral PACAP inhibits gastric acid secretion through somatostatin release in mice. Br J Pharmacol 2004; 142: 67-78
• 19 Aihara E, Hayashi M, Sasaki Y, Kobata A, Takeuchi K. Mechanisms underlying capsaicin-stimulated secretion in the stomach, comparison with mucosal acidification. J Pharmacol Exp Ther 2005; 315: 423-432
• 20 Mozsik G, Abdel Salam OME, Szolcsanyi J. Capsaicin-sensitive afferent nerves in gastric mucosal damage and protection. In: Mozsik G, Abdel Salam OME, Szolcsanyi J, editors Capsaicin-sensitive sensory nerves and gastric acid secretion. Volume 1. Budapest: Akademiai Kiado; 1997: 21-23
• 21 Abdel-Salam OM, Szolcsányi J, Mózsik G. Effect of resiniferatoxin on stimulated gastric acid secretory responses in the rat. J Physiol Paris 1994; 88: 353-358
• 22 Engel MA, Izydorczyk I, Mueller-Tribbensee SM, Becker C, Neurath MF, Reeh PW. Inhibitory CB1 and activating/desensitizing TRPV1-mediated cannabinoid actions on CGRP release in rodent skin. Neuropeptides 2011; 45: 229-237
• 23 Wang L, Wang DH. TRPV1 gene knockout impairs postischemic recovery in isolated perfused heart in mice. Circulation 2005; 112: 3617-3623
• 24 Valenzano KJ, Grant ER, Wu G, Hachicha M, Schmid L, Tafesse L, Sun Q, Rotshteyn Y, Francis J, Limberis J, Malik S, Whittemore ER, Hodges D. N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: I, in vitro characterization and pharmacokinetic properties. J Pharmacol Exp Ther 2003; 306: 377-386
• 25 Pomonis JD, Harrison JE, Mark L, Bristol DR, Valenzano KJ, Walker K. N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl) tetrahydropyrazine-1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: II, in vivo characterization in rat models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 2003; 306: 387-393
• 26 Bhattarai S, Tran VH, Duke CC. Stability of [6]-gingerol and [6]-shogaol in simulated gastric and intestinal fluids. J Pharm Biomed Anal 2007; 45: 648-653
• 27 Gauthier ML, Douat J, Vachon P, Beaudry F. Characterization of [6]-gingerol metabolism in rat by liquid chromatography electrospray tandem mass spectrometry. Biomed Chromatogr 2011; 25: 1150-1158
• 28 Soldani G, Mengozzi G, Intorre L, Pacini F, Evangelista S. Acute intragastric application of capsaicin inhibits 2-deoxy-D-glucose–but not histamine-induced gastric acid secretion in the dog. Neuropeptides 1992; 23: 221-225
• 29 Someya A, Horie S, Yamamoto H, Murayama T. Modifications of capsaicin-sensitive neurons in isolated guinea pig ileum by [6]-gingerol and lafutidine. J Pharmacol Sci 2003; 92: 359-366
• 30 Minowa S, Tsuchiya S, Horie S, Watanabe K, Murayama T. Stimulatory effect of centrally injected capsaicin, an agonist of vanilloid receptors, on gastric acid secretion in rats. Eur J Pharmacol 2001; 428: 349-356
• 31 Minowa S, Tsuchiya S, Someya A, Horie S, Murayama T. Role of neuropeptide receptor systems in vanilloid VR1 receptor-mediated gastric acid secretion in rat brain. Eur J Pharmacol 2004; 486: 317-324
• 32 Suzuki H, Okada S, Hibi T. Proton-pump inhibitors for the treatment of functional dyspepsia. Ther Adv Gastroenterol 2011; 4: 219-226
• 33 Bortolotti M, Coccia G, Grossi G, Miglioli M. The treatment of functional dyspepsia with red pepper. Aliment Pharmacol Ther 2002; 16: 1075-1082