Journal of Biomedical Science

, Volume 12, Issue 2, pp 431–440 | Cite as

Effects of naltrexone on lipopolysaccharide-induced sepsis in rats

  • Shinn-Long Lin
  • Yen-Mei Lee
  • Hsin-Yi Chang
  • Yu-Wen Cheng
  • Mao-Hsiung Yen
Article

Abstract

Naltrexone, an opioid antagonist, has been reported to possess an anti-inflammatory effect via blockade of opioid receptor. The aim of this study is to evaluate the protective effect of naltrexone on LPS-induced septic shock in rats. Sepsis was induced by administration of LPS (10 mg/kg, i.v.) in anesthetized rats. Results demonstrated that pretreatment with naltrexone (10 mg/kg, i.v.) significantly ameliorated hypotension and bradycardia of rats 6 h after LPS administration. In isolated blood vessel, study showed that pretreatment with naltrexone significantly improved norepinephrine-induced vasoconstriction and ACh-induced vasorelaxation in aorta of endotoxemic animals. Naltrexone significantly reduced the elevation of serum glutamate-oxalacetate transaminase and glutamate-pyruvate transaminase (as index of hepatic function) induced by LPS. The infiltration of polymorphonuclear neutrophils into liver 48 h after LPS treatment in mice was also reduced by naltrexone. On the other hand, naltrexone significantly decreased the levels of plasma TNF-α and inhibited overproduction of superoxide anions in aortic rings. However, naltrexone did not suppress the overproduction of NO (measured by its metabolites nitrite/nitrate in plasma) and iNOS expression in lungs induced by LPS. In in vitro study, naltrexone did not attenuate non-enzymatic iron-induced lipid peroxidation in rat brain homogenates. In conclusion, pretreatment with naltrexone significantly improved circulatory failure and hepatic dysfunction in sepsis. These effects were associated with reduction of TNF-α levels and superoxide anion formation, which may be attributed to antagonism of opioid receptors.

Keywords

hepatic dysfunction naltrexone nitric oxide reactive oxygen species sepsis TNF-α 

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References

  1. Barron, R.L. 1993Clinical frontiers: pathophysiology of septic shock and implications for therapyClin. Pharm.12829845PubMedGoogle Scholar
  2. Okusawa, S., Gelfand, J.A., Ikejima, T., Connolly, R.J., Dinarello, C.A. 1988Interleukin the 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J. Clin Invest.8111621172PubMedGoogle Scholar
  3. Endo, S., Inada, K., Nakae, H. 1995Plasma levels of type II phospholipase A2 and cytokines in patents with Sepsis.Res. Commun. Mol. Path. Pharmacol.90413421Google Scholar
  4. Guan , Z., Baier, L.D., Morrison, A.R. 1997p38 mitogen-activated protein kinase down-regulates nitric oxide and up-regulates prostaglandin E2 biosynthesis stimulated by interleukin-1βJ. Biol Chem.27280838089CrossRefPubMedGoogle Scholar
  5. Iaz, A., Chepetial, K.P., Korn, J.H., Reginato, A.M., Jimenez, S.A. 1998Differential regulation of cyclooxygenase 1 and 2 by interleukin-1B, tumor necrosis factor-α transforming growth factor-B1 in human lung fibroblasts.Exp Cell Rev.241222229CrossRefGoogle Scholar
  6. Moncada, S., Higgs, A. 1993Mechanisms of disease the L-arginine-nitric oxide pathwayNew Engl. J. Med.3292022012CrossRefGoogle Scholar
  7. Abraham, E. 1999Why immunomodulatory therapies have not worked in sepsis Intensive Care Med.25556566CrossRefPubMedGoogle Scholar
  8. Kayal, S., Jais, J.P., Aguini, N., Chaudiere, J., Labrousse, J. 1998Elevated circulating E-selectin, intracellular adhesion molecule 1 and von Willebrand factor in patients with severe infection. Am. J. Respir. Crit Care Med.157776784PubMedGoogle Scholar
  9. Sessler , C.N., Windsor, A.C., Schwartz, M., Watson, L., Fisher, B.J., Sugerman, B.J., Flowler, A.A. 1995Circulating ICAM-1 is increased in septic shock.Am. J. Respir. Crit Care Med.15114201427PubMedGoogle Scholar
  10. Glauser , M.P., Zanetti, G., Baumgartner, J.D., Cohen, J. 1991Septic shock pathogenesisLancet338732736CrossRefPubMedGoogle Scholar
  11. Goldstin, A., Tachibana, S., Lowney, L.I., Hunkapiller, M., Hood, L. 1979Dynorphin-(1–13) an extraordinarily potent opioid peptide. Proc. Natl. Acad Sci. USA 7666666670PubMedGoogle Scholar
  12. Stern, A.S., Lewis, R.V., Kimura, S., Rossier, J., Gerber, L.D., Brink, L., Stein, S., Udenfriend, S. 1979Isolation of the opioid heptapeptide met-enkephalin (Arg6Phe7) from bovine adrenal medullary granules and striatum.Proc. Natl. Acad Sci. USA 7666806683PubMedGoogle Scholar
  13. Frederichson , R.C.A. 1977Enkephalin pentapeptides–a review of current evidence for a physiological role in vertebrate neurotransmission Life Sci.212341CrossRefPubMedGoogle Scholar
  14. Hokfelt, T., Ljungdahl, A., Terenius, L., Elde, R., Nilsson, G. 1977Immunohistochemical analysis of peptide pathways possibly related to pain and analgesia enkephalin and substance PProc. Natl. Acad. Sci. USA7430813085PubMedGoogle Scholar
  15. Li , C.H. 1977β-Endorphin a pituitary peptide with potent morphine-like activityArch. Biochem. Biophys.183592604CrossRefPubMedGoogle Scholar
  16. Terenius , L. 1978Endogenous peptides and analgesia. Annu. Rev. Pharmacol. Toxicol.18189204PubMedGoogle Scholar
  17. Bloom , F., Segal, D., Ling, N., Guillemin, R. 1976Endorphins profound behavioral effects in rats suggest new etiological factors in mental illnessScience194630632PubMedGoogle Scholar
  18. Holaday, J.W 1978and Faden A.I., Naloxone reversal of endotoxin hypotension suggests role of endorphins in shock.Nature275450451PubMedGoogle Scholar
  19. Holaday , J.W. 1983Cardiovascular effects of endogenous opiate system.Annu. Rev. Pharmacol Toxicol.23541594PubMedGoogle Scholar
  20. Baker, C.H., Sutton, E.T., Zhou, Z, Reynolds, D.G. 1990Reduced microvascular adrenergic receptor activity due to opioids in endotoxin shock.Circulatory Shock32101112PubMedGoogle Scholar
  21. Peng, X., Mosser, D.M., Adler, M.W., Rogers, T.J., Meissler, J.J.,Jr, Eisenstein, T.K. 2000Morphine enhances interleukin-12 and the production of other pro-inflammatory cytokines in mouse peritoneal macrophages.J. Leukoc Biol.68723728PubMedGoogle Scholar
  22. Wu , C.C., Chiao, C.W., Hsiao, G., Chen, A., Yen, M.H. 2001Melatonin prevents endotoxin-induced circulatory failure in rats.J. Pineal Res.30147156PubMedGoogle Scholar
  23. Chen, A., Chou, W.Y., Ding, S.L., Shaio, M.F. 1992Glomerular localization of nephritogenic protein complex on nonimmunological basis. Lab Invest.67175185Google Scholar
  24. Hong, H.J., Loh, S.H., Yen, M.H. 2000Suppression of the development of hypertension by the inhibitor of inducible nitric oxide synthase.Br. J Pharmacol.131631637PubMedGoogle Scholar
  25. Hsiao, G., Teng, C.M., Sheu, J.R., Cheng, Y.W., Lam, K.K., Lee, Y.M., Wu, T.S., Yen, M.H. 2001Cinnamophilin as a novel antiperoxidative cytoprotectant and free radical scavenger.Biochim Biophys. Acta 152515257788Google Scholar
  26. Laubie, M., Schmitt, H., Vincent, M., Remond, G. 1977Central cardiovascular effects of morphinomimetic peptides in dogs. Eur. J Pharmacol.466771PubMedGoogle Scholar
  27. Almqvist, P.M., Knigge, K.M., Kuenzig, M., Joseph, S.A., Pilcher, W.H, Schwartz, S.I. 1985Pulmonary platelet trapping induced by beta-endorphin injection in the cerebrospinal fluid in dogs.Surgy98344349Google Scholar
  28. Molina, P.E. 2001Opiate modulation of hemodynamic, hormonal, and cytokine responses to hemorrhage.Shock15471478PubMedGoogle Scholar
  29. Greeneltch , K.M., Haudenschild, C.C., Keegan, A.D., Shi, Y. 2004The opioid antagonist naltrexone blocks acute endotoxic shock by inhibiting tumor necrosis factor-α production.Brain Behav Immun.18476484PubMedGoogle Scholar
  30. Horn , K.D. 1998Evolving strategies in the treatment of sepsis and systemic inflammatory response syndrome (SIRS).Quart. J. Med.91265277Google Scholar
  31. Beckman, J.S., Beckman, T.W., Chen, J., Marshall, P.A., Freeman, B.A. 1990Apparent hydroxyl radical production by peroxynitrite Implication for endothelial injury from nitric oxide and superoxideProc. Natl. Acad. Sci. USA8716201624PubMedGoogle Scholar
  32. Cuzzocrea, S., Zingarelli, B., Costantino, G., Sottile, A., Teti, D., Caputi, A.P. 1999Protective effect of poly (ADP-ribose) synthetase inhibition on multiple organ failure after zymosan-induced peritonitis in the rat.Crit Care Med.2715171523PubMedGoogle Scholar
  33. Lysle, D.T., How, T. 1999Endogenous opioids regulate the expression of inducible nitric oxide synthase by splenocytes.J. Pharmacol. Exp Ther.288502508PubMedGoogle Scholar

Copyright information

© National Science Council, Taipei 2005

Authors and Affiliations

  • Shinn-Long Lin
    • 1
  • Yen-Mei Lee
    • 2
  • Hsin-Yi Chang
    • 3
  • Yu-Wen Cheng
    • 4
  • Mao-Hsiung Yen
    • 2
  1. 1.Department of AnesthesiologyTri-Service General HospitalTaipeiTaiwan
  2. 2.Department of PharmacologyNational Defense Medical CenterTaipeiTaiwan
  3. 3.Department of Pharmacy PracticeTri-Service General HospitalTaipeiTaiwan
  4. 4.Department of PharmacyTaipei Medical UniversityTaipeiTaiwan

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