Digestive Diseases and Sciences

, Volume 51, Issue 2, pp 318–325 | Cite as

Morphine-Induced Degradation of the Host Defense Barrier

Role of Intestinal Mucosal Injury
  • Lia Frenklakh
  • Rajani S. Bhat
  • Madhu Bhaskaran
  • Shilpa Sharma
  • Meera Sharma
  • Amit Dinda
  • Pravin C. SinghalEmail author


The effect of morphine on intestinal ulcer formation and on the degradation of the host defense barrier was studied. Mice receiving morphine (MRM) showed mucosal ulcer formation in the ileum and in the upper third of the colon. In in vitro studies, morphine enhanced apoptosis of cultured human colonic cells (HCC). Nitric oxide synthase (NOS) inhibitors attenuated the proapoptotic effect of morphine. Moreover, morphine stimulated NO generation by HCCs. MRM also showed a breach in the host defense barrier as well as injury to peritoneal macrophages. Although NOS inhibitors completely prevented morphine-induced intestinal ulcer formation, it provided only partial protection against a breach in the host defense barrier and peritoneal macrophage injury. Propranolol did not inhibit the induction of intestinal ulcer formation in MRM; nevertheless, propranolol prevented a breach in the host defense barrier as well as macrophage injury in MRM, whereas hemin exacerbated macrophage injury as well as the breach in the host defense barrier of MRM. These findings suggest that morphine-induced intestinal injury is mediated through NO generation. However, the degradation of the host defense barrier correlates with macrophage injury, but not intestinal injury.

Key Words

opiates intestinal ulcers macrophages apoptosis nitric oxide 


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  1. 1.
    Bhaskaran M, Reddy K, Sharma S, et al..: Morphine-induced degradation of the host defense barrier: role of macrophage injury. J Infect Dis 184:1524–1531, 2001CrossRefPubMedGoogle Scholar
  2. 2.
    Hilburger ME, Adler MW, Truant AL, et al.: Morphine induces sepsis in mice. J Infect Dis 176:183–187, 1997PubMedGoogle Scholar
  3. 3.
    Roy S, Cain KJ, Charboneau RG, Barke RA: Morphine accelerates the progression of sepsis in an experimental sepsis model. Adv Exp Med Biol 437:21–31, 1998PubMedGoogle Scholar
  4. 4.
    Roy S, Charboneau RG, Barke RA: Morphine synergizes with lipopolysaccharide in a chronic endotoxemia model. J Neuroimmunol 95:107–114, 1999CrossRefPubMedGoogle Scholar
  5. 5.
    Berg RD: Bacterial translocation from gastrointestinal tract. Adv Exp Med Biol 473:11–30, 1999PubMedGoogle Scholar
  6. 6.
    Alexander JW, Boyce ST, Babcock GF, et al.: The process of microbial translocation. Ann Surg 212:496–512, 1990PubMedGoogle Scholar
  7. 7.
    Conn HO: Bacterial translocation: studies of mice and men. Am J Gastroenterol 93:277–278, 1998CrossRefPubMedGoogle Scholar
  8. 8.
    Valle L, Pol O, Puig MM: Intestinal inflammation enhances the inhibitory effects of opioids of intestinal permeability in mice. J Pharmacol Exp Ther 296:378–387, 2001PubMedGoogle Scholar
  9. 9.
    Boughton-Smith NK, Evans SM, Hawkey CJ, et al.: Nitric oxide synthase activity in ulcerative colitis and Crohn's disease. Lancet 342:338–346, 1993PubMedGoogle Scholar
  10. 10.
    Boughton-Smith NK, Evans SM, Whittle BJR: Elevated nitric oxide synthase activity in inflamed colon from a rat model of colitis. Gut 33(Suppl 2):S12, 1992Google Scholar
  11. 11.
    Miller MJS, Sadowska-Krowieka A, Chotinaruemol S, Kakkis JL, Clark DA: Amelioration chronic ileitis by nitric oxide synthase inhibition. J Pharmacol Exp Ther 264:11–16, 1993PubMedGoogle Scholar
  12. 12.
    Parasher G, Frenklakh L, Goodman DR, Siddiqui T, Nandi J, Levine RA: Nitric oxide inhibitors ameliorate indomethacin-induced enteropathy in rats. Dig Dis Sci 46:2536–2541, 2001CrossRefPubMedGoogle Scholar
  13. 13.
    Singhal PC, Kapasi AA, Franki N, Reddy K: Morphine-induced macrophage apoptosis: the role of transforming growth factor-beta. Immunology 100:57–62, 2000CrossRefPubMedGoogle Scholar
  14. 14.
    Singhal PC, Bhaskaran M, Patel J, et al.: Role of P38 Mitogen-activated protein kinase phosphorylation and Fas-FasL interaction in morphine-induced macrophage apoptosis. J Immunol 168:4025–4033, 200Google Scholar
  15. 15.
    Singhal PC, Sharma P, Kapasi AA, Reddy K, Franki N, Gibbons N: Morphine enhances macrophage apoptosis. J Immunol 160:1886–1893, 1998PubMedGoogle Scholar
  16. 16.
    Herrmann H, Lorenz HM, Voll R, Grunke M, Woith W, Kalden JR: A rapid and simple method for the isolation of apoptotic DNA fragments. Nucleic Acids Res 22:5506–5507, 1994PubMedGoogle Scholar
  17. 17.
    Beckman JS: Oxidative damage and tyrosine nitration from peroxynitrite. Chem Res Toxicol 9:836–844, 1996CrossRefPubMedGoogle Scholar
  18. 18.
    Pryor W, Squadrito G: The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am J Physiol 268:L699–L722, 1995PubMedGoogle Scholar
  19. 19.
    Patel K, Bhaskaran M, Dani D, Reddy K, Singhal PC: Role of heme oxygenase (HO)-1 in morphine-modulated apoptosis and migration of macrophages. J Infect Dis 187:47–54, 2003CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Lia Frenklakh
    • 1
  • Rajani S. Bhat
    • 1
  • Madhu Bhaskaran
    • 1
  • Shilpa Sharma
    • 2
  • Meera Sharma
    • 2
  • Amit Dinda
    • 1
  • Pravin C. Singhal
    • 1
    • 3
    Email author
  1. 1.Department of MedicineNorth Shore University Hospital and Long Island Jewish Medical CenterNew Hyde ParkUSA
  2. 2.Department of MicrobiologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
  3. 3.Division of Kidney Diseases and HypertensionLong Island Jewish Medical CenterNew Hyde Park

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