Effects of Ginger Constituents on the Gastrointestinal Tract: Role of Cholinergic M₃ and Serotonergic 5-HT₃ and 5-HT₄ Receptors

Abstract

The herbal drug ginger (Zingiber officinale Roscoe) may be effective for treating nausea, vomiting, and gastric hypomotility. In these conditions, cholinergic M₃ receptors and serotonergic 5-HT₃ and 5-HT₄ receptors are involved. The major chemical constituents of ginger are [6]-gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol. We studied the interaction of [6]-gingerol, [8]-gingerol, [10]-gingerol (racemates), and [6]-shogaol with guinea pig M₃ receptors, guinea pig 5-HT₃ receptors, and rat 5-HT₄ receptors. In whole segments of guinea pig ileum (bioassay for contractile M₃ receptors), [6]-gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol slightly but significantly depressed the maximal carbachol response at an antagonist concentration of 10 µM. In the guinea pig myenteric plexus preparation (bioassay for contractile 5-HT₃ receptors), 5-HT maximal responses were depressed by [10]-gingerol from 93 ± 3 % to 65 ± 6 % at an antagonist concentration of 3 µM and to 48 ± 3 % at an antagonist concentration of 5 µM following desensitization of 5-HT₄ receptors and blockade of 5-HT₁ and 5-HT₂ receptors. [6]-Shogaol (3 µM) induced depression to 61 ± 3 %. In rat esophageal tunica muscularis mucosae (bioassay for relaxant 5-HT₄ receptors), [6]-gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol (2–6.3 µM) showed no agonist effects. The maximal 5-HT response remained unaffected in the presence of the compounds. It is concluded that the efficiency of ginger in reducing nausea and vomiting may be based on a weak inhibitory effect of gingerols and shogaols at M₃ and 5-HT₃ receptors. 5-HT₄ receptors, which play a role in gastroduodenal motility, appear not to be involved in the action of these compounds.

Key words

ginger - Zingiber officinale Roscoe - Zingiberaceae - gastrointestinal diseases - cholinergic M₃ receptors - 5‐HT₃ receptors - 5‐HT₄ receptors

References

• 1 Afzal M, Al-Hadidi D, Menon M, Pesek J, Dhami M S. Ginger: an ethnomedical, chemical and pharmacological review.  Drug Metabol Drug Interact. 2001;  18 159-190
• 2 Chrubasik S, Pittler M H, Roufogalis B D. Zingiberis rhizoma: a comprehensive review on the ginger effect and efficacy profiles.  Phytomedicine. 2005;  12 684-701
• 3 Ali B H, Blunden G, Tanira M O, Nemmar A. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research.  Food Chem Toxicol. 2008;  46 409-420
• 4 Mowrey D B, Clayson D E. Motion sickness, ginger, and psychosis.  Lancet. 1982;  1 655-657
• 5 Phillips S, Ruggier R, Hutchinson S E. Zingiber officinale (ginger) – an antiemetic for day case surgery.  Anaesthesia. 1993;  48 715-717
• 6 Fischer-Rasmussen W, Kjaer S K, Dahl C, Asing U. Ginger treatment of hyperemesis gravidarum.  Eur J Obstet Gynecol Reprod Biol. 1991;  38 19-24
• 7 Micklefield G H, Redeker Y, Meister V, Jung O, Greving I, May B. Effects of ginger on gastroduodenal motility.  Int J Clin Pharmacol Ther. 1999;  37 341-346
• 8 Kemper K J. Ginger (Zingiber officinale). The Longwood Herbal Task Force, 1999. Available at. http://www.longwoodherbal.org/ginger/ginger.pdf Accessed January 31, 2011
• 9 Yamahara J, Rong H Q, Iwamoto M, Kobayashi G, Hisashi Matsuda H, Fujimura H. Active components of ginger exhibiting anti-serotonergic action.  Phytother Res. 1989;  3 70-71
• 10 Lien H C, Sun W M, Chen Y H, Kim H, Hasler W, Owyang C. Effects of ginger on motion sickness and gastric slow-wave dysrhythmias induced by circular vection.  Am J Physiol Gastrointest Liver Physiol. 2003;  284 G481-G489
• 11 Abdel-Aziz H, Windeck T, Ploch M, Verspohl E J. Mode of action of gingerols and shogaols on 5-HT₃ receptors: binding studies, cation uptake by the receptor channel and contraction of isolated guinea-pig ileum.  Eur J Pharmacol. 2006;  530 136-143
• 12 Yamahara J, Rong H Q, Naitoh Y, Kitani T, Fujimura H. Inhibition of cytotoxic drug-induced vomiting in suncus by a ginger constituent.  J Ethnopharmacol. 1989;  27 353-355
• 13 Kawai T, Kinoshita K, Koyama K, Takahashi K. Anti-emetic principles of Magnolia obovata bark and Zingiber officinale rhizome.  Planta Med. 1994;  60 17-20
• 14 Sharma S S, Kochupillai V, Gupta S K, Seth S D, Gupta Y K. Antiemetic efficacy of ginger (Zingiber officinale) against cisplatin-induced emesis in dogs.  J Ethnopharmacol. 1997;  57 93-96
• 15 Pillai A K, Sharma K K, Gupta Y K, Bakhshi S. Anti-emetic effect of ginger powder versus placebo as an add-on therapy in children and young adults receiving high emetogenic chemotherapy.  Pediatr Blood Cancer. 2011;  56 234-238
• 16 Riyazi A, Hensel A, Bauer K, Geissler N, Schaaf S, Verspohl E J. The effect of the volatile oil from ginger rhizomes (Zingiber officinale), its fractions and isolated compounds on the 5-HT₃ receptor complex and the serotoninergic system of the rat ileum.  Planta Med. 2007;  73 355-362
• 17 Yamahara J, Huang Q, Li Y, Xu L, Fujimura H. Gastrointestinal motility enhancing effect of ginger and its active constituents.  Chem Pharm Bull. 1990;  38 430-431
• 18 Sharma S S, Gupta Y K. Reversal of cisplatin-induced delay in gastric emptying in rats by ginger (Zingiber officinale).  J Ethnopharmacol. 1998;  62 49-55
• 19 Gale J D, Reeves J J, Bunce K T. Antagonism of the gastroprokinetic effect of metoclopramide by GR 125487, a potent and selective 5-HT₄ receptor antagonist.  J Gastrointest Motil. 1993;  5 192
• 20 Hedge S S, Wong A G, Perry M R, Ku P, Moy T M, Loeb M, Eglen R M. 5-HT₄ receptor mediated stimulation of gastric emptying in rats.  Naunyn Schmiedebergs Arch Pharmacol. 1995;  351 589-595
• 21 Tonini M. Recent advances in the pharmacology of gastrointestinal prokinetics.  Pharmacol Res. 1996;  33 217-226
• 22 Denniff P, Macleod I, Whiting D A. Syntheses of the (±)-[n]-gingerols (pungent principles of ginger) and related compounds through regioselective aldol condensations: relative pungency assays.  J Chem Soc [Perkin I]. 1981;  82-87
• 23 Buchheit K H, Engel G, Mutschler E, Richardson B. Study of the contractile effect of 5-hydroxytryptamine (5-HT) in the isolated longitudinal muscle strip from guinea-pig ileum.  Naunyn Schmiedebergs Arch Pharmacol. 1985;  329 36-41
• 24 Craig D A, Eglen R M, Walsh L K M, Perkins L A, Whiting R L, Clarke D E. 5-Methoxytryptamine and 2-methyl-5-hydroxytryptamine-induced desensitization as a discriminative tool for the 5-HT₃ and putative 5-HT₄ receptors in guinea pig ileum.  Naunyn Schmiedebergs Arch Pharmacol. 1990;  342 9-16
• 25 Akbarali H I, Bieger D, Triggle C R. Tetrodotoxin-sensitive and -insensitive relaxations in the rat oesophageal tunica muscularis mucosae.  J Physiol (London). 1986;  381 49-63
• 26 Veyrat-Follet C, Farinotti R, Palmer J L. Physiology of chemotherapy-induced emesis and antiemetic therapy. Predictive models for evaluation of new compounds.  Drugs. 1997;  53 206-234
• 27 Abdel-Aziz H, Nahrstedt A, Petereit F, Windeck T, Ploch M, Verspohl E J. 5-HT₃ receptor blocking activity of arylalkanes isolated from the rhizome of Zingiber officinale.  Planta Med. 2005;  71 609-616
• 28 Visalyaputra S, Petchpaisit N, Somcharoen K, Choavaratana R. The efficacy of ginger root in the prevention of postoperative nausea and vomiting after outpatient gynaecological laparoscopy.  Anaesthesia. 1998;  53 506-510
• 29 Stewart J J, Wood M J, Wood C D, Mims M E. Effects of ginger on motion sickness susceptibility and gastric function.  Pharmacology. 1991;  42 111-120
• 30 Stott J R, Barnes G R, Wright R J, Ruddock C J. The effect on motion sickness and oculomotor function of GR 38032F, a 5-HT₃-receptor antagonist with anti-emetic properties.  Br J Clin Pharmacol. 1989;  27 147-157
• 31 Ghayur M N, Khan A H, Gilani A H. Ginger facilitates cholinergic activity possibly due to blockade of muscarinic autoreceptors in rat stomach fundus.  Pakistan J Pharm Sci. 2007;  20 231-235
• 32 Phillips S, Hutchinson S, Ruggier R. Zingiber officinale does not affect gastric emptying rate. A randomised, placebo-controlled, crossover trial.  Anaesthesia. 1993;  48 393-395
• 33 Hoyer D, Clarke D E, Fozard J R, Hartig P R, Martin G R, Mylecharane E J, Saxena P R, Humphrey P P A. VII. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin).  Pharmacol Rev. 1994;  46 157-203
• 34 Bockaert J, Fozard J R, Dumuis A, Clarke D E. The 5-HT₄ receptor: a place in the sun.  Trends Pharmacol Sci. 1992;  13 141-145
• 35 Tokita Y, Yuzurihara M, Sakaguchi M, Satoh K, Kase Y. The pharmacological effects of Daikenchuto, a traditional herbal medicine, on delayed gastrointestinal transit in rat postoperative ileus.  J Pharmacol Sci. 2007;  104 303-310
• 36 Ghayur M N, Gilani A H. Species differences in the prokinetic effects of ginger.  Int J Food Sci Nutr. 2006;  57 65-73
• 37 Ernst E, Pittler M H. Efficacy of ginger for nausea and vomiting: a systematic review of randomized clinical trials.  Br J Anaesth. 2000;  84 367-371