Digestive Diseases and Sciences

, Volume 53, Issue 1, pp 88–94 | Cite as

The Effect of Restraint Stress on the Normal Colon and on Intestinal Inflammation in a Model of Experimental Colitis

  • Eran Israeli
  • Tiberiu Hershcovici
  • Eduard Berenshtein
  • Giulliana Zannineli
  • Dov Wengrower
  • Ofra Weiss
  • Mordechai Chevion
  • Eran Goldin
Original Paper


Stress may induce development of inflammation in animal models of colitis. The effects of restraint stress on oxidative damage and on antioxidants in the normal colonic mucosa were studied. The effect of stress on the severity of indicators of inflammation, as well as the importance of mucosal substance P (SP) as a mediator of this effect were investigated in the TNBS-colitis model. Restraint stress significantly increased malondialdehyde levels and reduced levels of low-molecular-weight-antioxidants in the normal colon. ATP and the mucosal “energy charge” decreased substantially with chronic stress. Chronic stress worsened the extent of inflammation in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Mucosal SP content was not affected by exposure to chronic stress but increased after induction of colitis. The increase was greater when colitis was induced after exposure to stress. We conclude that chronic restraint stress causes oxidative damage to the normal colon and aggravates intestinal inflammation induced by TNBS. This effect may be mediated by SP.


Restraint stress Oxidation Colonic mucosa TNBS-colitis Substance P 


  1. 1.
    Bitton A, Sewitch MJ, Peppercorn MA, deB Edwardes MD, Shah S, Ransil B, Locke SE (2003) Psychosocial determinants of relapse in ulcerative colitis: a longitudinal study. Am J Gastroenterol 98:2203–2208PubMedCrossRefGoogle Scholar
  2. 2.
    Duffy LC, Zielezny MA, Marshall JR, Byers TE, Weiser MM, Phillips JF, Calkins BM, Ogra PL, Graham S (1991) Relevance of major stress events as an indicator of disease activity prevalence in inflammatory bowel disease. Behav Med 7:101–110CrossRefGoogle Scholar
  3. 3.
    North CS, Alpers DH, Helzer JE, Spitznagel EL, Clouse RE (1991) Do life events or depression exacerbate inflammatory bowel disease? A prospective study. Ann Intern Med 114:381–386PubMedGoogle Scholar
  4. 4.
    Qiu BS, Vallance BA, Blennerhassett PA, Collins SM (1999) The role of CD4+ lymphocytes in the susceptibility of mice to stress-induced reactivation of experimental colitis. Nat Med 5:1178–1182PubMedCrossRefGoogle Scholar
  5. 5.
    Collins SM, McHugh K, Jacobson K, Khan I, Riddell R, Murase K, Weingarten HP (1996) Previous inflammation alters the response of the rat colon to stress. Gastroenterology 111:1509–1515PubMedCrossRefGoogle Scholar
  6. 6.
    Milde AM, Murison R (2002) A study of the effects of restraint stress on colitis induced by dextran sulfate sodium in singly housed rats. Integr Physiol Behav Sci 37:140–150PubMedCrossRefGoogle Scholar
  7. 7.
    Soderholm JD, Yang PC, Ceponis P, Vohra A, Riddell R, Sherman PM, Perdue MH (2002) Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine. Gastroenterology 123:1099–1108PubMedCrossRefGoogle Scholar
  8. 8.
    Wilson LM, Baldwin AL (1999) Environmental stress causes mast cell degranulation, endothelial and epithelial changes, and edema in the rat intestinal mucosa. Microcirculation 6:189–198PubMedCrossRefGoogle Scholar
  9. 9.
    Soderholm JD, Yates DA, Gareau MG, Yang PC, MacQueen G, Perdue MH (2002) Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress. Am J Physiol Gastrointest Liver Physiol 283:G1257–G1263PubMedGoogle Scholar
  10. 10.
    Liu J, Wang X, Mori A (1994) Immobilization stress-induced antioxidant effects on rat plasma: effect of treatment with reduced glutathione. Int J Biochem 26:515–517CrossRefGoogle Scholar
  11. 11.
    Liu J, Wang X, Shigenaga MK, Yeo HC, Mori A, Ames BN (1996) Immobilization stress causes oxidative damage to lipid, protein, and DNA in the brain of rats. FASEB J 10:1532–1538PubMedGoogle Scholar
  12. 12.
    Liu J, Mori A (1994) Involvement of reactive oxygen species in emotional stress: a hypothesis based on the immobilization stress-induced oxidative damage and antioxidant defense changes in rat brain and the effect of antioxidant treatment with reduced glutathione. Int J Stress Management 1:249–263CrossRefGoogle Scholar
  13. 13.
    Lih-Brody L, Powell SR, Collier KP, Reddy GM, Cerchia R, Kahn E, Weissman GS, Katz S, Floyd RA, McKinley MJ, Fisher SE, Mullin GE (1996) Increased oxidative stress and decreased antioxidant defenses in mucosa of inflammatory bowel disease. Dig Dis Sci 41:2078–2086PubMedCrossRefGoogle Scholar
  14. 14.
    Keshavarzian AP, Sedghi S, Kanofsky J, List T, Robinson C, Ibrahim C, Winship D (1992) Excessive production of reactive oxygen metabolites by inflamed colon: analysis by chemiluminescence probe. Gastroenterology 103:177–185PubMedGoogle Scholar
  15. 15.
    Buffinton GD, Doe WF (1995) Depleted mucosal antioxidant defences in inflammatory bowel disease. Free Radic Biol Med 19:911–918PubMedCrossRefGoogle Scholar
  16. 16.
    Chowdrey HS, Jessop DS, Lightman SL (1990) Substance P stimulates arginine vasopressin and inhibits adrenocorticotropin release in vivo in the rat. Neuroendocrinology 52:90–93PubMedGoogle Scholar
  17. 17.
    Faria M, Navarra P, Tsagarakis S, Besser GM, Grossman AB (1991) Inhibition of CRH-41 release by substance P, but not substance K, from the rat hypothalamus in vitro. Brain Res 538:76–78PubMedCrossRefGoogle Scholar
  18. 18.
    Mazelin L, Theodorou V, More JL., Emonds-Alt X, Fioramonti J, Bueno L (1998) Comparative effects of nonpeptide tachykinin receptor antagonists on experimental gut inflammation in rats and guinea-pigs. Life Sci 63:293–304PubMedCrossRefGoogle Scholar
  19. 19.
    Israeli E, Berenshtein E, Wengrower D, Aptekar L, Kohen R, Zajicek G, Goldin E (2004) Prophylactic administration of topical glutamine enhances the capability of the rat colon to resist inflammatory damage. Dig Dis Sci 49:1705–1712PubMedCrossRefGoogle Scholar
  20. 20.
    Karck M, Tanaka S, Berenshtein E, Sturm C, Haverich A, Chevion M (2001) The push-and-pull mechanism to scavenge redox-active transition metals: a novel concept in myocardial protection. J Thorac Cardiovasc Surg 21:1169–1178CrossRefGoogle Scholar
  21. 21.
    Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL (1989) Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology 96:795–803PubMedGoogle Scholar
  22. 22.
    Krawisz JE, Sharon P, Stenson WF (1984) Quantitative assay for acute intestinal inflammation based on Myeloperoxidase activity. Assessment of inflammation in rat and hamster models. Gastroenterology 87:1344–1350PubMedGoogle Scholar
  23. 23.
    Sekizuka E, Grisham MB, Li MA, Deitch EA, Granger DN (1988) Inflammation-induced intestinal hyperemia in the rat: role of neutrophils. Gastroenterology 95:1528–1534PubMedGoogle Scholar
  24. 24.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254PubMedCrossRefGoogle Scholar
  25. 25.
    Wohlman A, Yirmiya R, Gallily R, Weidenfeld J (2001) Effect of Mycoplasma fermentans on brain PGE(2): role of glucocorticoids and their receptors. Neuroimmunomodulation 9:141–147PubMedCrossRefGoogle Scholar
  26. 26.
    Lysy J, Karmeli F, Goldin E (1993) Substance P levels in the rectal mucosa of diabetic patients with normal bowel function and constipation. Scand J Gastroenterol 28:49–52PubMedCrossRefGoogle Scholar
  27. 27.
    Kiliaan AJ, Saunders PR, Bijlsma PB, Berin C, Taminiau AJ, Groot AJ, Perdue HM (1998) Stress stimulates transepithelial macromolecular uptake in rat jejunum. Am J Physiol 275:G1037–G1044PubMedGoogle Scholar
  28. 28.
    Tuzun A, Erdil A, Inal V, Aydin A, Bagci S, Yesilova Z, Sayal A, Karaeren N, Dagalp K (2002) Oxidative stress and antioxidant capacity in patients with inflammatory bowel disease. Clin Biochem 35:569–572PubMedCrossRefGoogle Scholar
  29. 29.
    van Hagen PM, Hofland LJ, ten Bokum AM, Lichtenauer-Kaligis EG, Kwekkeboom DJ, Ferone D, Lamberts SW (1999) Neuropeptides and their receptors in the immune system. Ann Med Suppl 2:15–22Google Scholar
  30. 30.
    Santos J, Saperas E, Nogueiras C, Mourelle M, Antolin M, Cadahia A, Malagelada JR (1998) Release of mast cell mediators into the jejunum by cold pain stress in humans. Gastroenterology 114:640–648PubMedCrossRefGoogle Scholar
  31. 31.
    Marnett LJ (2002) Oxy radicals, lipid peroxidation and DNA damage. Toxicology 181–182:219–222PubMedCrossRefGoogle Scholar
  32. 32.
    Gue M, Bonbonne C, Fioramonti J (1997) Stress-induced enhancement of colitis in rats: CRF and arginine vasopressin are not involved. Am J Physiol 272:G84–G91PubMedGoogle Scholar
  33. 33.
    Million M, Tache Y, Anton P (1999) Susceptibility of Lewis and Fischer rats to stress-induced worsening of TNB-colitis: protective role of brain CRF. Am J Physiol 276:G1027–G1036PubMedGoogle Scholar
  34. 34.
    Kishimoto S, Kobayashi H, Machino H, Tari A, Miyoshi A (1994) High concentrations of substance P as a possible transmission of abdominal pain in rats with chemical induced ulcerative colitis. Biomed Res 15:133–140Google Scholar
  35. 35.
    Renzi D, Calabró A, Panerai C, Trmontana M, Evangelista S, Milani S, Surrenti C (1994) Preprotachykinin mRNA expression in the colonic tissue during experimental colitis in rats. Digestion 55(Suppl 2):36Google Scholar
  36. 36.
    Steckler T, Holsboer F (2001) Corticotropin-releasing hormone receptor subtypes and emotion. Biol Psychiatry 46:14580–14588Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Eran Israeli
    • 1
  • Tiberiu Hershcovici
    • 1
  • Eduard Berenshtein
    • 2
  • Giulliana Zannineli
    • 1
  • Dov Wengrower
    • 1
  • Ofra Weiss
    • 1
  • Mordechai Chevion
    • 2
  • Eran Goldin
    • 1
  1. 1.Department of Gastroenterology, Division of MedicineHebrew University-Hadassah Medical CenterJerusalemIsrael
  2. 2.Department of Cellular Biochemistry, Faculty of MedicineHebrew UniversityJerusalemIsrael

Personalised recommendations