Cannabinoid CB1 Receptors Mediate the Gastroprotective Effect of Neurotensin

Document Type : Original Article


Research Centre for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran


Several lines of evidence indicate that neuropeptides exhibit protective properties against gastroduodenal ulcers. Neurotensin, a gut-brain neuropeptide, is implicated in a number of physiological processes in the central nervous system and peripheral tissues including gastrointestinal tract. In the present study, we aimed to investigate the gastroprotective potential of either peripherally or centrally administered neurotensin with a look at the role of the cannabinoid CB1 receptors which are located in brain areas implicated in the regulation of gastric functions.       
Materials and Methods
Gastric mucosal damage was induced by intragastric administration of acidified ethanol in male Wistar rats. One hour later, gastric lesions were evaluated macroscopically. In gastroprotection study, neurotensin was administered either intravenously (1.5, 3, and 5 µM/kg) or intracerebroventricularly (0.5, 1, and 2.5 nM/rat) 30 min before the ethanol challenge. In order to evaluate the involvement of central CB1 receptors in the gastroprotective effect of neurotensin, the CB1 receptor antagonist AM251 (5, 10, and 15 nM/rat) was given i.c.v. 30 min prior to the administration of neurotensin. The effects of AM251 on the intact stomach and ethanol-induced gastric lesions were also evaluated.
Acidified ethanol induced large areas of gastric lesions which were significantly reduced bythe highest dose of neurotensin in i.v. or i.c.v. application. The gastroprotective effect of neurotensin was prevented by pretreatment with 15 nM/rat AM251. AM251 had no effect by itself.
Peripherally or centrally given neurotensin protects gastric mucosa against damage induced by acidified ethanol through the activation of central cannabinoid CB1 receptors.


1. Saxena A, Shukla S, Prasad KN, Ghoshal UC. Virulence attributes of Helicobacter pylori isolates and their association with gastroduodenal disease. Indian J Med Res 2011; 133:514-520.
2. Yacyshyn BR, Thomson AB. Critical review of acid suppression in nonvariceal, acute, upper gastrointestinal bleeding. Dig Dis 2000; 18:117-128.
3. Conrad SA. Acute upper gastrointestinal bleeding in critically ill patients: causes and treatment modalities. Crit Care Med 2002; 30: S365-S368.
4. Faisy C, Guerot E, Diehl JL, Iftimovici E, Fagon JY. Clinically significant gastrointestinal bleeding in critically ill patients with and without stress-ulcer prophylaxis. Intensive Care Med 2003; 29:1306-1313.
5. Yacyshyn BR, Thomson AB. Critical review of acid suppression in nonvariceal, acute, uppergastrointestinal bleeding. Dig Dis 2000; 18:117-128.
6. Cook DJ, Fuller HD, Guyatt GH, Marshall JC, Leasa D, Hall R, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994; 330:377-381.
7. Konturek SJ, Brzozowski T, Konturek PC, Schubert ML, Pawlik WW, Padol S, et al. Brain-gut and appetite regulating hormones in the control of gastric secretion and mucosal protection. J Physiol Pharmacol 2008; 59:7-31.
8. Konturek SJ, Konturek PC, Pawlik T, Sliwowski Z, Ochmanski W, Hahn EG. Duodenal mucosal protection by bicarbonate secretion and its mechanisms. J Physiol Pharmacol 2004; 55:5-17.
9. Kaneko H, Mitsuma T, Nagai H, Mori S, Iyo T, Kusugami K, Tache Y. Central action of adrenomedullin to prevent ethanol-induced gastric injury through vagal pathways in rats. Am J Physiol 1998; 274:R1783-R1788.
10. Tache Y, Yoneda M, Kato K, Kiraly A, Suto G, Kaneko H. Intracisternal thyrotropin-releasing hormone-induced vagally mediated gastric protection against ethanol lesions: central and peripheral mechanisms. J Gastroenterol Hepatol 1994; 9:S29-S35.
11. Schaffer M, Beiter T, Becker HD, and Hunt TK. Neuropeptides: mediators of inflammation and tissue repair? Arch Surg 1998; 133:1107–1116.
12. Brzozowski T, Konturek PC, Sliwowski Z, Drozdowicz D, Kwiecien S, Pawlik M, et al. Neural aspects of ghrelin-induced gastroprotection against mucosal injury induced by noxious agents. J Physiol Pharmacol 2006; 57:63-76.
13. Morini G, De Caro G, Guerrini R, Massi M, Polidori C. Nociceptin/orphanin FQ prevents ethanol-induced gastric lesions in the rat. Regul Pept 2005; 124:203-207.
14. Carraway RE, Leeman SE. The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem 1973; 248:6854–6861.
15. Kitabgi P, De Nadai F, Labbe-Jullie C, Dubuc I, Nouel D, Costentin J, et al. Functional and pharmacological aspects of central neuropeptidergic transmission mediated by neurotensin and neuromedin. Clin Neuropharmacol 1992; 15:313A-314A.
16. Boudin H, Pelaprat D, RosteneW, Beaudet A. Cellular distribution of neurotensin receptors in rat brain: immunohistochemical study using an antipeptide antibody against the cloned high affinity receptor. J Comp Neurol 1996; 373:76–89.
17. Chen L, Yung KKL, Yung WH. Neurotensin selectively facilitates glutamatergic transmission in globus pallidus. Neuroscience  2006; 141:1871–1878.
18. Mustain WC, Rychahou PG, Evers BM. The role of neurotensin in physiologic and pathologic processes. Curr Opin Endocrin Diabetes Obes 2011; 18:75–82.
19. Bueno L,Fioramonti J, Fargeas MJ, Primi MP. Neurotensin: a central neuromodulator of gastrointestinal motility in the dog. Am J Physiol 1985; 248:G15-G19.
20. Dobner PR. Neurotensin and pain modulation. Peptides 2006; 27: 2405–2414.
21. Pellissier S, Eribon O, Chabert J, Gully D, Roche M. Peripheral neurotensin participates in the modulation of pre- and postprandial intestinal motility in rats. Neuropeptides 1996; 30:412-419.
22. Fletcher DR, Shulkes A, Hardy KJ. The effect of neurotensin and secretin on gastric secretion and mucosal blood flow in man. Regul Pept 1985; 11:217–226.
23. Brun P, Mastrotto C, Beggiao E, Stefani A, Barzon L, Sturniolo GC, et al. Neuropeptide neurotensin stimulates intestinal wound healing following chronic intestinal inflammation. Am J Physiol Gastrointest Liver Physiol  2005; 288:G621-G629.
24. Goldman R, Bar-Shavit Z, Romeo D. Neurotensin modulates human neutrophil locomotion and phagocytic capability. FEBS Lett 1983; 159:63–67.
25. Miller LA, Cochrane DE, Carraway RE, Feldberg G. Blockade of mast cell histamine secretion in response to neurotensin by SR-48692, a nonpeptide antagonist of the neurotensin brain receptor. Br J Pharmacol 1995; 114:1466–1470.
26. Riegler M, Castagliuolo I, Wang C, Wlk M, Sogukoglu T, Wenzl E, et al. Neurotensin stimulates Cl- secretion in human colonic mucosa in vitro: role of adenosine. Gastroenterology 2000; 119:348–357.
27. Massa F, Monory K. Endocannabinoids and the gastrointestinal tract. J Endocrinol Invest 2006; 29:47-57.
28. Mackie K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol 2005; 168:299-325.
29. Partosoedarso ER, Abrahams TP, Scullion RT, Moerschbaecher JM, Hornby PJ. Cannabinoid 1 receptor in the dorsal vagal complex modulates lower oesophageal sphincter relaxation in ferrets. J Physiol  2003; 550:149-158.
30. Konturek SJ, Brzozwski T, Piastucki I, Radecki T. Prevention of ethanol and aspirin-induced gastric mucosal lesions by paracetamol and salicylate in rats: role of endogenous prostaglandins. Gut 1982; 23: 536-540.
31. Robert A, Nezamis JE, Lancaster C, Hanchar AJ. Cytoprotection by prostaglandins in rats: prevention of gastric necrosis produced by alcohol, HCI, NaOH, hypertonic NaCI and thermal injury. Gastroenterology 1979; 77: 433-443.
32. Aronin N, Carraway RE, Ferris CF, Hammer RA, Leeman SE. The stability and metabolism of intravenously administered neurotensin in the rat. Peptides 1982; 3: 637-642.
33. Parolaro D, Sala M, Crema G, Spazzi L, Gori E. Effect on intestinal transit of neurotensin administered intracerebroventricularly to rats. Life Sci 1983; 33:485-488.
34. Fernandez-Solari J, Prestifilippo JP, Vissio P, Ehrhart-Bornstein M, Bornstein SR, Rettori V, et al. Anandamide injected into the lateral ventricle of the brain inhibits submandibular salivary secretion by attenuating parasympathetic neurotransmission. Braz J Med Biol Res  2009; 42:537-544.
35. Erin N, Yegen BC, Oktay S. The protective effect of 5-HT3 receptor antagonist in thyrotropin releasing hormone-induced gastric lesions. Peptides 1997; 18:893-898.
36. Gyires K, Mullner K, Ronai AZ. Activation of central opioid receptors may induce gastric mucosal defence in the rat. J Physiol 2001; 95:189–196.
37. Kasckow J, Nemeroff CB. The neurobiology of neurotensin: focus on neurotensin–dopamine interactions. Regul Pept 1991; 36:153–164.
38. Nishikawa K, Amagase K, Takeuchi K. Effect of dopamine on the healing of acetic acid-induced gastric ulcers in rats. Inflammopharmacology 2007; 15:209-213.
39. Izzo AA, Pinto L, Borrelli F, Capasso R, Mascolo N, Capasso F. Central and peripheral cannabinoid modulation of gastrointestinal transit in physiological states or during the diarrhoea induced by croton oil. Br J Pharmacol 2000; 129:1627-1632.
40. Landi M, Croci T, Rinaldi-Carmona M, Maffrand JP, Le Fur G, Manara L. Modulation of gastric emptying and gastrointestinal transit in rats through intestinal cannabinoid CB(1) receptors. Eur J Pharmacol 2002; 450:77-83.
41. Dembinski A, Warzecha Z, Ceranowicz P, Dembinski M, Cieszkowski J, Pawlik WW, et al. Cannabinoids in acute gastric damage and pancreatitis. J Physiol Pharmacol 2006; 57:137-154.
42. Germano MP, D’Angelo V, Mondello MR, Pergolizzi S, Capasso F, Capasso R, et al. Cannabinoid CB1-mediated inhibition of stress-induced gastric ulcers in rats. Naunyn Schmiedebergs Arch Pharmacol 2001; 363:241-244.
43. Rutkowska M, Fereniec-Goltbiewska L. ACEA (arachidonyl-2-chloroethylamide), the selective cannabinoid CB1 receptor agonist, protects against aspirin-induced gastric ulceration. Pharmazie 2006; 61:341-342.
44. Nakamura M, Nishida T, Ofuji K, Reid TW, Mannis MJ, Murphy CJ. Synergistic effect of SP with epidermal growth factor on epithelial migration in rabbit cornea. Exp Eye Res 1997; 65:321-329.
45. Kingery WS. Role of neuropeptide, cytokine, and growth factor signaling in complex regional pain syndrome. Pain Med  2010; 11:1239-1250.