The role of ghrelin in patients with functional dyspepsia and its potential clinical relevance (Review)

Yagi,Takakazu; Asakawa,Akihiro; Ueda,Hirotaka; Miyawaki,Shouichi; Inui,Akio

doi:10.3892/ijmm.2013.1418

The role of ghrelin in patients with functional dyspepsia and its potential clinical relevance (Review)

Authors:
- Takakazu Yagi
- Akihiro Asakawa
- Hirotaka Ueda
- Shouichi Miyawaki
- Akio Inui
View Affiliations

Affiliations: Department of Orthodontics and Dentofacial Orthopedics, Medical and Dental Hospital, Kagoshima University, Kagoshima 890-8544, Japan, Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan, Department of Orthodontics and Dentofacial Orthopedics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan
Published online on: June 14, 2013 https://doi.org/10.3892/ijmm.2013.1418
Pages: 523-531

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Functional dyspepsia (FD) is a functional gastrointestinal disorder (FGID). According to the Rome III consensus, FD is divided into 2 subgroups: epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). Although multiple mechanisms of FD pathogenesis have been suggested, its underlying etiology and pharmacological therapy remain unclear. Ghrelin is a gut-derived peptide found in the stomach. It plays a role in the regulation of gastric motility and appetite. The ghrelin gene encodes 3 molecular forms, acyl ghrelin, des-acyl ghrelin and obestatin. Acyl ghrelin acts as an endogenous ligand for growth hormone secretagogue receptor; furthermore, it is orexigenic, with effects on food intake, energy homeostasis and gastrointestinal motility. Des-acyl ghrelin exerts an opposite effect to acyl ghrelin. Obestatin exerts an inhibitory effect on the motor activity of the antrum and duodenum in fed animals. These peptides exert differential effects on gut motility and food intake. The therapeutic potential of ghrelin has attracted attention due to its varied bioactivities. Certain studies have shown that total ghrelin levels are significantly lower in patients with FD compared with healthy volunteers and that the acyl ghrelin levels of patients with FD are higher compared with healthy volunteers. However, a recent study demonstrated that acyl ghrelin levels in patients with PDS were lower compared with healthy volunteers; the association between FD and other ghrelin family gene products also remains unclear. Although certain studies have demonstrated the beneficial effects of acyl ghrelin administration and its agonist in patients with FD, only a few clinical reports exist. Further studies are required in order to examine the effects of ghrelin on FD.

View Figures

View References

1	Tack J, Talley NJ, Camilleri M, et al: Functional gastroduodenal disorders. Gastroenterology. 130:1466–1479. 2006. View Article : Google Scholar
2	Geeraerts B and Tack J: Functional dyspepsia: past, present, and future. J Gastroenterol. 43:251–255. 2008. View Article : Google Scholar : PubMed/NCBI
3	Tack J and Talley NJ: Gastroduodenal disorders. Am J Gastroenterol. 105:757–763. 2010. View Article : Google Scholar
4	Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H and Kangawa K: Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 402:656–660. 1999. View Article : Google Scholar : PubMed/NCBI
5	Matsumoto M, Kitajima Y, Iwanami T, et al: Structural similarity of ghrelin derivatives to peptidyl growth hormone secretagogues. Biochem Biophys Res Commun. 284:655–659. 2001. View Article : Google Scholar : PubMed/NCBI
6	Tanaka M, Hayashida Y, Iguchi T, Nakao N, Nakai N and Nakashima K: Organization of the mouse ghrelin gene and promoter: occurrence of a short noncoding first exon. Endocrinology. 142:3697–3700. 2001. View Article : Google Scholar : PubMed/NCBI
7	Hosoda H, Kojima M, Matsuo H and Kangawa K: Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun. 279:909–913. 2000. View Article : Google Scholar : PubMed/NCBI
8	Chen CY, Asakawa A, Fujimiya M, Lee SD and Inui A: Ghrelin gene products and the regulation of food intake and gut motility. Pharmacol Rev. 61:430–481. 2009. View Article : Google Scholar : PubMed/NCBI
9	Asakawa A, Inui A, Kaga T, et al: Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology. 120:337–345. 2001. View Article : Google Scholar : PubMed/NCBI
10	Nakazato M, Murakami N, Date Y, et al: A role for ghrelin in the central regulation of feeding. Nature. 409:194–198. 2001. View Article : Google Scholar : PubMed/NCBI
11	Wren AM, Small CJ, Ward HL, et al: The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology. 141:4325–4328. 2000. View Article : Google Scholar : PubMed/NCBI
12	Inui A: Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci. 2:551–560. 2001. View Article : Google Scholar : PubMed/NCBI
13	An W, Li Y, Xu G, et al: Modulation of ghrelin O-acyltransferase expression in pancreatic islets. Cell Physiol Biochem. 26:707–716. 2010.
14	Murray CD, Martin NM, Patterson M, et al: Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut. 54:1693–1698. 2005. View Article : Google Scholar : PubMed/NCBI
15	Tack J, Depoortere I, Bisschops R, Verbeke K, Janssens J and Peeters T: Influence of ghrelin on gastric emptying and meal-related symptoms in idiopathic gastroparesis. Aliment Pharmacol Ther. 22:847–853. 2005. View Article : Google Scholar : PubMed/NCBI
16	Tack J, Depoortere I, Bisschops R, et al: Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut. 55:327–333. 2006. View Article : Google Scholar : PubMed/NCBI
17	Mori M, Suzuki H, Masaoka T, et al: Intravenous ghrelin administration enhances gastric acid secretion - evaluation using wireless pH capsule. Aliment Pharmacol Ther. 24:96–103. 2006. View Article : Google Scholar
18	Masuda Y, Tanaka T, Inomata N, et al: Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun. 276:905–908. 2000. View Article : Google Scholar : PubMed/NCBI
19	Castaneda TR, Tong J, Datta R, Culler M and Tschop MH: Ghrelin in the regulation of body weight and metabolism. Front Neuroendocrinol. 31:44–60. 2010. View Article : Google Scholar : PubMed/NCBI
20	Fetissov SO, Laviano A, Kalra S and Inui A: Update on ghrelin. Int J Pept. 2010:9635012010. View Article : Google Scholar
21	Asakawa A, Inui A, Kaga T, et al: A role of ghrelin in neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology. 74:143–147. 2001. View Article : Google Scholar : PubMed/NCBI
22	Hotta M, Ohwada R, Akamizu T, Shibasaki T, Takano K and Kangawa K: Ghrelin increases hunger and food intake in patients with restricting-type anorexia nervosa: a pilot study. Endocr J. 56:1119–1128. 2009. View Article : Google Scholar : PubMed/NCBI
23	Akamizu T, Iwakura H, Ariyasu H, et al: Effects of ghrelin treatment on patients undergoing total hip replacement for osteoarthritis: different outcomes from studies in patients with cardiac and pulmonary cachexia. J Am Geriatr Soc. 56:2363–2365. 2008. View Article : Google Scholar : PubMed/NCBI
24	Miki K, Maekura R, Nagaya N, et al: Ghrelin treatment of cachectic patients with chronic obstructive pulmonary disease: a multicenter, randomized, double-blind, placebo-controlled trial. PloS One. 7:e357082012. View Article : Google Scholar
25	Akamizu T, Iwakura H, Ariyasu H, et al: Repeated administration of ghrelin to patients with functional dyspepsia: its effects on food intake and appetite. Eur J Endocrinol. 158:491–498. 2008. View Article : Google Scholar : PubMed/NCBI
26	Wo JM, Ejskjaer N, Hellstrom PM, et al: Randomised clinical trial: ghrelin agonist TZP-101 relieves gastroparesis associated with severe nausea and vomiting - randomised clinical study subset data. Aliment Pharmacol Ther. 33:679–688. 2011. View Article : Google Scholar
27	Drossman DA and Dumitrascu DL: Rome III: New standard for functional gastrointestinal disorders. J Gastrointestin Liver Dis. 15:237–241. 2006.PubMed/NCBI
28	Miwa H: Why dyspepsia can occur without organic disease: pathogenesis and management of functional dyspepsia. J Gastroenterol. 47:862–871. 2012. View Article : Google Scholar : PubMed/NCBI
29	Miwa H: Life style in persons with functional gastrointestinal disorders - large-scale internet survey of lifestyle in Japan. Neurogastroenterol Motil. 24:464–471. e2172012. View Article : Google Scholar : PubMed/NCBI
30	Norton GR, Norton PJ, Asmundson GJ, Thompson LA and Larsen DK: Neurotic butterflies in my stomach: the role of anxiety, anxiety sensitivity and depression in functional gastrointestinal disorders. J Psychosom Res. 47:233–240. 1999. View Article : Google Scholar : PubMed/NCBI
31	Khoo J, Rayner CK, Feinle-Bisset C, Jones KL and Horowitz M: Gastrointestinal hormonal dysfunction in gastroparesis and functional dyspepsia. Neurogastroenterol Motil. 22:1270–1278. 2010. View Article : Google Scholar : PubMed/NCBI
32	Quartero AO, de Wit NJ, Lodder AC, Numans ME, Smout AJ and Hoes AW: Disturbed solid-phase gastric emptying in functional dyspepsia: a meta-analysis. Dig Dis Sci. 43:2028–2033. 1998. View Article : Google Scholar : PubMed/NCBI
33	Geeraerts B, Van Oudenhove L, Fischler B, et al: Influence of abuse history on gastric sensorimotor function in functional dyspepsia. Neurogastroenterol Motil. 21:33–41. 2009. View Article : Google Scholar : PubMed/NCBI
34	Holtmann G, Siffert W, Haag S, et al: G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Gastroenterology. 126:971–979. 2004. View Article : Google Scholar : PubMed/NCBI
35	Toyoshima F, Oshima T, Nakajima S, et al: Serotonin transporter gene polymorphism may be associated with functional dyspepsia in a Japanese population. BMC Med Genet. 12:882011. View Article : Google Scholar : PubMed/NCBI
36	Mearin F, Perez-Oliveras M, Perello A, et al: Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology. 129:98–104. 2005.PubMed/NCBI
37	Drossman DA: The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 130:1377–1390. 2006. View Article : Google Scholar : PubMed/NCBI
38	Danesh J, Lawrence M, Murphy M, Roberts S and Collins R: Systematic review of the epidemiological evidence on Helicobacter pylori infection and nonulcer or uninvestigated dyspepsia. Arch Intern Med. 160:1192–1198. 2000.PubMed/NCBI
39	Kawamura A, Adachi K, Takashima T, et al: Prevalence of functional dyspepsia and its relationship with Helicobacter pylori infection in a Japanese population. J Gastroenterol Hepatol. 16:384–388. 2001. View Article : Google Scholar : PubMed/NCBI
40	Thumshirn M, Camilleri M, Saslow SB, Williams DE, Burton DD and Hanson RB: Gastric accommodation in non-ulcer dyspepsia and the roles of Helicobacter pylori infection and vagal function. Gut. 44:55–64. 1999. View Article : Google Scholar : PubMed/NCBI
41	Sarnelli G, Cuomo R, Janssens J and Tack J: Symptom patterns and pathophysiological mechanisms in dyspeptic patients with and without Helicobacter pylori. Dig Dis Sci. 48:2229–2236. 2003. View Article : Google Scholar : PubMed/NCBI
42	Savarino E, Zentilin P, Dulbecco P, Malesci A and Savarino V: The role of Acid in functional dyspepsia. Am J Gastroenterol. 106:1168–1169. 2011. View Article : Google Scholar : PubMed/NCBI
43	Jin X and Li YM: Systematic review and meta-analysis from Chinese literature: the association between Helicobacter pylori eradication and improvement of functional dyspepsia. Helicobacter. 12:541–546. 2007. View Article : Google Scholar : PubMed/NCBI
44	Moayyedi P, Soo S, Deeks J, et al: Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database Syst Rev. 2006:CD0020962006.PubMed/NCBI
45	Moayyedi P: Helicobacter pylori eradication for functional dyspepsia: what are we treating?: comment on ‘Helicobacter pylori eradication in functional dyspepsia’. Arch Intern Med. 171:1936–1937. 2011. View Article : Google Scholar
46	Suzuki H and Moayyedi P: Helicobacter pylori infection in functional dyspepsia. Nat Rev Gastroenterol Hepatol. 10:168–174. 2013. View Article : Google Scholar
47	Sugano K: Should we still subcategorize Helicobacter pylori-associated dyspepsia as functional disease? J Neurogastroenterol Motil. 17:366–371. 2011. View Article : Google Scholar : PubMed/NCBI
48	Tack J, Caenepeel P, Fischler B, Piessevaux H and Janssens J: Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia. Gastroenterology. 121:526–535. 2001. View Article : Google Scholar : PubMed/NCBI
49	Boeckxstaens GE, Rumessen JJ, de Wit L, Tytgat GN and Vanderwinden JM: Abnormal distribution of the interstitial cells of cajal in an adult patient with pseudo-obstruction and megaduodenum. Am J Gastroenterol. 97:2120–2126. 2002. View Article : Google Scholar : PubMed/NCBI
50	Rhee PL, Kim YH, Son HJ, et al: Evaluation of individual symptoms cannot predict presence of gastric hypersensitivity in functional dyspepsia. Dig Dis Sci. 45:1680–1684. 2000. View Article : Google Scholar : PubMed/NCBI
51	Chrousos GP: Regulation and dysregulation of the hypothalamic-pituitary-adrenal axis. The corticotropin-releasing hormone perspective. Endocrinol Metab Clin North Am. 21:833–858. 1992.PubMed/NCBI
52	Lamberts SW, Verleun T, Oosterom R, de Jong F and Hackeng WH: Corticotropin-releasing factor (ovine) and vasopressin exert a synergistic effect on adrenocorticotropin release in man. J Clin Endocrinol Metab. 58:298–303. 1984. View Article : Google Scholar : PubMed/NCBI
53	Vale W, Spiess J, Rivier C and Rivier J: Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science. 213:1394–1397. 1981. View Article : Google Scholar : PubMed/NCBI
54	Vaughan J, Donaldson C, Bittencourt J, et al: Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature. 378:287–292. 1995. View Article : Google Scholar : PubMed/NCBI
55	Bale TL and Vale WW: CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol. 44:525–557. 2004. View Article : Google Scholar : PubMed/NCBI
56	Ataka K, Kuge T, Fujino K, Takahashi T and Fujimiya M: Wood creosote prevents CRF-induced motility via 5-HT3 receptors in proximal and 5-HT4 receptors in distal colon in rats. Auton Neurosci. 133:136–145. 2007. View Article : Google Scholar : PubMed/NCBI
57	Martinez V, Rivier J, Wang L and Tache Y: Central injection of a new corticotropin-releasing factor (CRF) antagonist, astressin, blocks CRF- and stress-related alterations of gastric and colonic motor function. J Pharmacol Exp Ther. 280:754–760. 1997.
58	Tache Y, Martinez V, Million M and Wang L: Stress and the gastrointestinal tract III. Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors. Am J Physiol Gastrointest Liver Physiol. 280:G173–G177. 2001.PubMed/NCBI
59	O'Mahony SM, Marchesi JR, Scully P, et al: Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry. 65:263–267. 2009. View Article : Google Scholar : PubMed/NCBI
60	Brevet M, Kojima H, Asakawa A, et al: Chronic foot-shock stress potentiates the influx of bone marrow-derived microglia into hippocampus. J Neurosci Res. 88:1890–1897. 2010.PubMed/NCBI
61	Sengupta JN: Visceral pain: the neurophysiological mechanism. Handb Exp Pharmacol. 194:31–74. 2009. View Article : Google Scholar : PubMed/NCBI
62	Shindo T, Futagami S, Hiratsuka T, et al: Comparison of gastric emptying and plasma ghrelin levels in patients with functional dyspepsia and non-erosive reflux disease. Digestion. 79:65–72. 2009. View Article : Google Scholar : PubMed/NCBI
63	Lee KJ, Cha DY, Cheon SJ, Yeo M and Cho SW: Plasma ghrelin levels and their relationship with gastric emptying in patients with dysmotility-like functional dyspepsia. Digestion. 80:58–63. 2009. View Article : Google Scholar : PubMed/NCBI
64	Sarnelli G, Caenepeel P, Geypens B, Janssens J and Tack J: Symptoms associated with impaired gastric emptying of solids and liquids in functional dyspepsia. Am J Gastroenterol. 98:783–788. 2003. View Article : Google Scholar : PubMed/NCBI
65	Asakawa A, Inui A, Ueno N, Makino S, Fujino MA and Kasuga M: Urocortin reduces food intake and gastric emptying in lean and ob/ob obese mice. Gastroenterology. 116:1287–1292. 1999. View Article : Google Scholar : PubMed/NCBI
66	Fujino K, Inui A, Asakawa A, Kihara N, Fujimura M and Fujimiya M: Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats. J Physiol. 550:227–240. 2003. View Article : Google Scholar : PubMed/NCBI
67	Fujimiya M, Itoh E, Kihara N, Yamamoto I, Fujimura M and Inui A: Neuropeptide Y induces fasted pattern of duodenal motility via Y(2) receptors in conscious fed rats. Am J Physiol Gastrointest Liver Physiol. 278:G32–G38. 2000.PubMed/NCBI
68	Fujimiya M, Asakawa A, Ataka K, Kato I and Inui A: Different effects of ghrelin, des-acyl ghrelin and obestatin on gastroduodenal motility in conscious rats. World J Gastroenterol. 14:6318–6326. 2008. View Article : Google Scholar : PubMed/NCBI
69	Peeters TL: Central and peripheral mechanisms by which ghrelin regulates gut motility. J Physiol Pharmacol. 54(Suppl 4): S95–S103. 2003.PubMed/NCBI
70	Venkova K and Greenwood-Van Meerveld B: Application of ghrelin to gastrointestinal diseases. Curr Opin Investig Drugs. 9:1103–1107. 2008.PubMed/NCBI
71	Asakawa A, Inui A, Fujimiya M, et al: Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin. Gut. 54:18–24. 2005. View Article : Google Scholar : PubMed/NCBI
72	Ariyasu H, Takaya K, Iwakura H, et al: Transgenic mice overexpressing des-acyl ghrelin show small phenotype. Endocrinology. 146:355–364. 2005. View Article : Google Scholar : PubMed/NCBI
73	Chen CY, Chao Y, Chang FY, Chien EJ, Lee SD and Doong ML: Intracisternal des-acyl ghrelin inhibits food intake and non-nutrient gastric emptying in conscious rats. Int J Mol Med. 16:695–699. 2005.PubMed/NCBI
74	Chen CY, Inui A, Asakawa A, et al: Des-acyl ghrelin acts by CRF type 2 receptors to disrupt fasted stomach motility in conscious rats. Gastroenterology. 129:8–25. 2005. View Article : Google Scholar : PubMed/NCBI
75	Inhoff T, Monnikes H, Noetzel S, et al: Desacyl ghrelin inhibits the orexigenic effect of peripherally injected ghrelin in rats. Peptides. 29:2159–2168. 2008. View Article : Google Scholar : PubMed/NCBI
76	Qader SS, Hakanson R, Rehfeld JF, Lundquist I and Salehi A: Proghrelin-derived peptides influence the secretion of insulin, glucagon, pancreatic polypeptide and somatostatin: a study on isolated islets from mouse and rat pancreas. Regul Pept. 146:230–237. 2008. View Article : Google Scholar
77	Banks WA, Tschop M, Robinson SM and Heiman ML: Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther. 302:822–827. 2002. View Article : Google Scholar : PubMed/NCBI
78	Martinez V, Barquist E, Rivier J and Tache Y: Central CRF inhibits gastric emptying of a nutrient solid meal in rats: the role of CRF2 receptors. Am J Physiol. 274:G965–G970. 1998.PubMed/NCBI
79	Million M, Maillot C, Saunders P, Rivier J, Vale W and Tache Y: Human urocortin II, a new CRF-related peptide, displays selective CRF(2)-mediated action on gastric transit in rats. Am J Physiol Gastrointest Liver Physiol. 282:G34–G40. 2002. View Article : Google Scholar : PubMed/NCBI
80	Kihara N, Fujimura M, Yamamoto I, Itoh E, Inui A and Fujimiya M: Effects of central and peripheral urocortin on fed and fasted gastroduodenal motor activity in conscious rats. Am J Physiol Gastrointest Liver Physiol. 280:G406–G419. 2001.PubMed/NCBI
81	Zhang JV, Ren PG, Avsian-Kretchmer O, et al: Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science. 310:996–999. 2005. View Article : Google Scholar
82	Chartrel N, Alvear-Perez R, Leprince J, et al: Comment on ‘Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake’. Science. 315:7662007.
83	Holst B, Egerod KL, Schild E, et al: GPR39 signaling is stimulated by zinc ions but not by obestatin. Endocrinology. 148:13–20. 2007. View Article : Google Scholar : PubMed/NCBI
84	Tremblay F, Perreault M, Klaman LD, Tobin JF, Smith E and Gimeno RE: Normal food intake and body weight in mice lacking the G protein-coupled receptor GPR39. Endocrinology. 148:501–506. 2007. View Article : Google Scholar : PubMed/NCBI
85	Bassil AK, Haglund Y, Brown J, et al: Little or no ability of obestatin to interact with ghrelin or modify motility in the rat gastrointestinal tract. Br J Pharmacol. 150:58–64. 2007. View Article : Google Scholar : PubMed/NCBI
86	Bresciani E, Rapetti D, Dona F, et al: Obestatin inhibits feeding but does not modulate GH and corticosterone secretion in the rat. J Endocrinol Invest. 29:RC16–RC18. 2006. View Article : Google Scholar : PubMed/NCBI
87	Ataka K, Inui A, Asakawa A, Kato I and Fujimiya M: Obestatin inhibits motor activity in the antrum and duodenum in the fed state of conscious rats. Am J Physiol Gastrointest Liver Physiol. 294:G1210–G1218. 2008. View Article : Google Scholar : PubMed/NCBI
88	Takamori K, Mizuta Y, Takeshima F, et al: Relation among plasma ghrelin level, gastric emptying, and psychologic condition in patients with functional dyspepsia. J Clin Gastroenterol. 41:477–483. 2007. View Article : Google Scholar : PubMed/NCBI
89	Nishizawa T, Suzuki H, Nomoto Y, et al: Enhanced plasma ghrelin levels in patients with functional dyspepsia. Aliment Pharmacol Ther. 24(Suppl 4): S104–S110. 2006. View Article : Google Scholar
90	Shinomiya T, Fukunaga M, Akamizu T, et al: Plasma acylated ghrelin levels correlate with subjective symptoms of functional dyspepsia in female patients. Scand J Gastroenterol. 40:648–653. 2005. View Article : Google Scholar : PubMed/NCBI
91	Kim YS, Lee JS, Lee TH, et al: Plasma levels of acylated ghrelin in patients with functional dyspepsia. World J Gastroenterol. 18:2231–2237. 2012. View Article : Google Scholar : PubMed/NCBI
92	Taniguchi H, Ariga H, Zheng J, et al: Endogenous ghrelin and 5-HT regulate interdigestive gastrointestinal contractions in conscious rats. Am J Physiol Gastrointest Liver Physiol. 295:G403–G411. 2008. View Article : Google Scholar : PubMed/NCBI
93	Tack J, Janssen P, Masaoka T, Farre R and Van Oudenhove L: Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. Clin Gastroenterol Hepatol. 10:1239–1245. 2012. View Article : Google Scholar : PubMed/NCBI
94	Seto Y, Yoshida N and Kaneko H: Effects of mosapride citrate, a 5-HT4-receptor agonist, on gastric distension-induced visceromotor response in conscious rats. J Pharmacol Sci. 116:47–53. 2011. View Article : Google Scholar : PubMed/NCBI
95	Lee JW, Sung KW, Lee OY, Lee SE and Sohn CI: The effects of 5-HT4 receptor agonist, mosapride citrate, on visceral hypersensitivity in a rat model. Dig Dis Sci. 57:1517–1524. 2012. View Article : Google Scholar : PubMed/NCBI
96	Fujitsuka N, Asakawa A, Amitani H, Hattori T and Inui A: Efficacy of ghrelin in cancer cachexia: clinical trials and a novel treatment by rikkunshito. Crit Rev Oncog. 17:277–284. 2012. View Article : Google Scholar : PubMed/NCBI
97	Arai M, Matsumura T, Tsuchiya N, et al: Rikkunshito improves the symptoms in patients with functional dyspepsia, accompanied by an increase in the level of plasma ghrelin. Hepatogastroenterology. 59:62–66. 2012.PubMed/NCBI
98	Takeda H, Sadakane C, Hattori T, et al: Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology. 134:2004–2013. 2008. View Article : Google Scholar : PubMed/NCBI
99	Matsumura T, Arai M, Yonemitsu Y, et al: The traditional Japanese medicine Rikkunshito increases the plasma level of ghrelin in humans and mice. J Gastroenterol. 45:300–307. 2010. View Article : Google Scholar : PubMed/NCBI