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. 2002 Nov 13;48(1):81–90. doi: 10.1016/0165-5728(93)90061-3

β-Endorphin protects mice from neurological disease induced by the murine coronavirus MHV-JHM

Wendy Gilmore 1,∗, Doris S Moradzadeh 1
PMCID: PMC7119610  PMID: 8227310

Abstract

The neurotropic murine coronavirus, MHV-JHM (JHMV) causes encephalitis and paralytic-demyelinating disease in susceptible strains of mice and rats, serving as a model for human demyelinating diseases such as multiple sclerosis. In this communication, we report that a single intracerebral administration of the naturally occurring neuropeptide, β-endorphin, reduced the incidence of JHMV-induced paralytic-demyelinating disease 40–50% in C57Bl/6 mice. Protection from disease was accompanied by significantly reduced virus replication in the brain as early as 3 days post-infection and did not occur in irradiated, or immunoincompetent mice. The data suggest that β-endorphin engages immune mechanisms of host resistance to JHMV infection to protect the mice from disease.

Keywords: Murine coronavirus, Paralytic-demyelinating disease, β-Endorphin, Immune-mediated CNS disease

References

  1. Apte R.N., Durum S.K., Oppenheim J.J. Opioids modulate interleukin-1 production and secretion by bone-marrow macrophages. Immunol. Lett. 1990;24:141–148. doi: 10.1016/0165-2478(90)90026-m. [DOI] [PubMed] [Google Scholar]
  2. Brown S.L., Van Epps D.E. Opioid peptides modulate production of interferon-gamma by human mononuclear cells. Gen. Immunol. 1986;103:19–26. doi: 10.1016/0008-8749(86)90064-x. [DOI] [PubMed] [Google Scholar]
  3. Buchmeier M.J., Dalziel R.G., Koolen M.J.M. Coronavirus-induced CNS disease: a model for virus-induced demyelination. J. Neuroimmunol. 1988;20:111–116. doi: 10.1016/0165-5728(88)90141-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Carr J.J. Vol. 198. 1991. The role of endogenous opioids and their receptors in the immune system; pp. 710–720. (Proc. Exp. Biol. Med.). [DOI] [PubMed] [Google Scholar]
  5. Cheever F.S., Daniels J.B., Pappenheimer A.M., Bailey O.T. A murine virus (JHM) causing disseminated encephalomyelitis with extensive destruction of myelin. I. Isolation and biological properties of the virus. J. Exp. Med. 1949;90:181–194. doi: 10.1084/jem.90.3.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Coons W.J., Vorhies R.W., Johnson T.C. An immune cell population that responds to β-endorphin and is responsible for protecting nude mice from the fatal consequences of a virus infection of the central nervous system. J. Neuroimmunol. 1991;34:133–141. doi: 10.1016/0165-5728(91)90122-n. [DOI] [PubMed] [Google Scholar]
  7. Dal Canto M.C., Rabinowitz S.G. Experimental models of virus-induced demyelination of the central nervous system. Ann. Neurol. 1982;11:109–127. doi: 10.1002/ana.410110202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Deakin J.F.W., Dostrovsky J.O., Smyth D.G. Influence of N-terminal acetylation and C-terminal proteolysis on the analgesic activity of β-endorphin. Biochem. J. 1980;189:501–506. doi: 10.1042/bj1890501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Doll S.C., Johnson T.C. Neuropeptide-induced hypothermia and the course of central nervous system disease mediated by temperature-sensitive mutants of vesicular stomatitis virus. J. Virol. 1985;55:583–587. doi: 10.1128/jvi.55.3.583-587.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Doll S.C., Johnson T.C. β-endorphin alters a viral induced central nervous system disease in normal mice but not in nude mice. J. Neuroimmunol. 1989;24:47–53. doi: 10.1016/0165-5728(89)90097-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dorries R., Schwender S., Imrich H., Harms H. Population dynamics of lymphocyte subsets in the central nervous system of rats with different susceptibility to coronavirus-induced demyelinating encephalitis. Immunology. 1991;74:539–545. [PMC free article] [PubMed] [Google Scholar]
  12. Fleming J.O., Stohlman S.A., Harmon R.C., Lai M.M.C., Frelinger J.A., Weiner L.P. Antigenic relationships of murine coronaviruses: analysis using monoclonal antibodies to JHM (MHV-4) virus. Virology. 1983;131:296–307. doi: 10.1016/0042-6822(83)90498-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fleming J.O., Trousdale M.D., El-Zaatari F.A.K., Stohlman S.A., Weiner L.P. Pathogenicity of antigenic variants murine coronavirus JHM selected with monoclonal antibodies. J. Virol. 1986;58:869–875. doi: 10.1128/jvi.58.3.869-875.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fleming J.O., Trousdale M.D., Bradbury J., Stohlman S.A., Weiner L.P. Experimental demyelination induced by coronavirus JHM (MHV-4): molecular identification of a viral determinant of paralytic disease. Microb. Pathog. 1987;3:9–20. doi: 10.1016/0882-4010(87)90033-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fleming J.O., Wang F.I., Trousdale M.D., Hinton D.R., Stohlman S.A. Immunopathogenesis of demyelination induced by MHV-4. Adv. Exp. Med. Biol. 1990;276:565–572. doi: 10.1007/978-1-4684-5823-7_78. [DOI] [PubMed] [Google Scholar]
  16. Gilman S.C., Schwartz J.M., Milner R.J., Bloom F.E., Feldman J.D. Vol. 79. 1982. Beta-endorphin enhances lymphocyte proliferative responses; pp. 4171–4174. (Proc. Natl. Acad. Sci.). [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gilmore W., Weiner L.P. β-endorphin enhances interleukin-2 (IL-2) production in murine lymphocytes. J. Neuroimmunol. 1988;18:125–138. doi: 10.1016/0165-5728(88)90061-6. [DOI] [PubMed] [Google Scholar]
  18. Gilmore W., Weiner L.P. The opioidspecificity of BetaBeta-endorphin enhancement of murine lymphocyte proliferation. Immunopharmacology. 1989;17:19–30. doi: 10.1016/0162-3109(89)90004-0. [DOI] [PubMed] [Google Scholar]
  19. Gilmore W., Moloney M., Berinstein T. The enhancement of polyclonal T cell proliferation by Beta-endorphin. Brain Res. Bull. 1990;24:687–692. doi: 10.1016/0361-9230(90)90008-n. [DOI] [PubMed] [Google Scholar]
  20. Haspel M.V., Lampert P.W., Oldstone M.B.A. Vol. 75. 1978. Temperature sensitive mutants of mouse hepatitis virus produce a high incidence of demyelination; pp. 4033–4936. (Proc. Natl. Acad. Sci. USA). [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Heagy W., Laurance M., Cohen E., Finberg R. Neurohormones regulate T cell function. J. Exp. Med. 1990;171:1625–1633. doi: 10.1084/jem.171.5.1625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Heijnen C.J., Kavelaars A., Ballieux R.E. β-endorphin: cytokine and neuropeptide. Immunol. Rev. 1991;119:41–63. doi: 10.1111/j.1600-065x.1991.tb00577.x. [DOI] [PubMed] [Google Scholar]
  23. Hummer H.J., Coons W.J., Watts S.A., Johnson T.C. β-endorphin alters the course of nervous system disease induced by a temperature-sensitive vesicular stomatitis virus in reconstituted nude mice. J. Neuroimmunol. 1990;28:73–82. doi: 10.1016/0165-5728(90)90042-l. [DOI] [PubMed] [Google Scholar]
  24. Knobler R.L., Haspel M.V., Oldstone M.B.A. Mouse hepatitis virus type 4 (JHM strain)-induced fatal central nervous system disease. I. Genetic control and the murine neuron as the susceptible site of disease. J. Exp. Med. 1981;153:832–843. doi: 10.1084/jem.153.4.832. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Knobler R.L., Lampert P.W., Oldstone M.B.A. Virus persistence and recurring demyelination produced by a temperature-sensitive mutant of MHV-4. Nature. 1982;298:279–280. doi: 10.1038/298279a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Koolen M.J.M., Osterhaus A.D.M.E., van Steenis G., Horzinek M.C., van der Zeijst B.A.M. Temperature-sensitive mutants of mouse hepatitis strain A59: Isolation, characterization and neuropathogenic properties. Virology. 1983;125:393–402. doi: 10.1016/0042-6822(83)90211-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. LaMonica N., Banner L.R., Morris V.L., Lai M.M.C. Localization of extensive deletions in the structural genes of two neurotropic variants of murine coronavirus JHM. Virology. 1991;182:883–888. doi: 10.1016/0042-6822(91)90635-O. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lampert P.W., Sims J.K., Kniazeff A.J. Mechanism of demyelination in JHM virus encephalomyelitis. Electron microscopic studies. Acta Neuropathol. 1973;24:76–85. doi: 10.1007/BF00691421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lieberman A.P., Pitha P.M., Shin H.S., Shin M.L. Vol. 86. 1989. Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus; pp. 6348–6352. (Proc. Natl. Acad. Sci. USA). [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lipton H.L. Theiler's virus infection in mice: An unusual biphasic disease process leading to demyelination. Infect. Immun. 1975;11:1147–1155. doi: 10.1128/iai.11.5.1147-1155.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Nemeroff C.B., Osbahr A.J., Manberg P.J., Ervin G.N., Prange A.J. Vol. 76. 1979. Alterations in nociception and body temperature after intracisternal administration of neurotensin, β-endorphin, other endogenous peptides, and morphine; pp. 5368–5371. (Proc. Natl. Acad. Sci. USA). [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sacerdote P., Panerai A.E. Analysis of the beta-endorphin structure-related activity on human monocyte chemotaxis: Importance of the N- and C-terminal. Peptides. 1989;10:565–569. doi: 10.1016/0196-9781(89)90143-5. [DOI] [PubMed] [Google Scholar]
  33. Saland L.C., Van Epps D.E., Ortiz E., Samora A. Acute injections of opioid peptides into the rat cerebral ventricle: a macrophage-like cellular response. Brain Res. Bull. 1983;10:523–528. doi: 10.1016/0361-9230(83)90150-8. [DOI] [PubMed] [Google Scholar]
  34. Saland L.C., Ortiz E., Samora A. Chronic infusion of opioid peptides to rat cerebrospinal fluid with osmotic minipumps. Anat. Rec. 1984;210:115–123. doi: 10.1002/ar.1092100114. [DOI] [PubMed] [Google Scholar]
  35. Sethna M.P., Lampson L.A. Immune modulation within the brain: recruitment of inflammatory cells and increased major histocompatibility antigen expression following intracerebral injection of interferon-gamma. J. Neuroimmunol. 1991;34:121–132. doi: 10.1016/0165-5728(91)90121-m. [DOI] [PubMed] [Google Scholar]
  36. Sibinga N.E.S., Goldstein A. Opioid peptides and opioid receptors in cells of the immune system. Annu. Rev. Immunol. 1988;6:219–249. doi: 10.1146/annurev.iy.06.040188.001251. [DOI] [PubMed] [Google Scholar]
  37. Sorensen O., Perry D., Dales S. In vivo and in vitro models of demyelinating diseases. III. JHM virus infection of rats. Arch. Neurol. 1980;37:478–484. doi: 10.1001/archneur.1980.00500570026003. [DOI] [PubMed] [Google Scholar]
  38. Stohlman S.A., Weiner L.P. Chronic central nervous system demyelination in mice after JHM virus infection. Neurology. 1981;31:38–44. doi: 10.1212/wnl.31.1.38. [DOI] [PubMed] [Google Scholar]
  39. Stohlman S.A., Brayton P.R., Fleming J.O., Weiner L.P., Lai M.M.C. Murine coronaviruses: isolation and characterization of two plaque morphology variants of the JHM neurotropic strain. J. Gen. Virol. 1982;63:265–275. doi: 10.1099/0022-1317-63-2-265. [DOI] [PubMed] [Google Scholar]
  40. Stohlman S.A., Matsushima G.K., Casteel N., Weiner L.P. In vivo effects of coronavirus-specific T cell clones: DTH inducer cells prevent a lethal infection but do not inhibit virus replication. J. Immunol. 1986;136:3052–3056. [PubMed] [Google Scholar]
  41. Sussman M.A., Shubin R.A., Kyuwa S., Stohlman S.A. T-cell-mediated clearance of mouse hepatitis virus strain JHM from the central nervous system. J. Virol. 1989;63:3051–3056. doi: 10.1128/jvi.63.7.3051-3056.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Van Epps D.E.V., Saland L. β-endorphin and met-enkephalin stimulate human peripheral blood mononuclear cell chemotaxis. J. Immunol. 1984;132:3046–3053. [PubMed] [Google Scholar]
  43. Van Epps D.E.V., Kutvirt S.L. Modulation of human neutrophil adherence by β-endorphin and met-enkephalin. J. Neuroimmunol. 1987;15:219–228. doi: 10.1016/0165-5728(87)90117-2. [DOI] [PubMed] [Google Scholar]
  44. Wang F.I., Stohlman S.A., Fleming J.O. Demyelination induced by murine hepatitis virus JHM strain (MHV-4) is immunologically mediated. J. Neuroimmunol. 1990;30:31–41. doi: 10.1016/0165-5728(90)90050-W. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wang F.I., Hinton D., Gilmore W., Trousdale M.D., Fleming J.O. Sequential infection of glial cells by the murine hepatitis virus JHM strain (MHV-4) leads to a characteristic distribution of demyelination. Lab. Invest. 1992;66:744–754. [PubMed] [Google Scholar]
  46. Wege H., Koga M., Wege H., ter Meulen V. JHM infections in rats as a model for acute and subacute demyelinating disease. Adv. Exp. Med. Biol. 1981;142:327–340. doi: 10.1007/978-1-4757-0456-3_27. [DOI] [PubMed] [Google Scholar]
  47. Wege H., Winter J., Korner H., Flory E., Zimprich F., Lassmann H. Coronavirus induced demyelinating encephalomyelitis in rats: immunopathological aspects of viral persistency. Adv. Exp. Med. Biol. 1990;276:637–645. doi: 10.1007/978-1-4684-5823-7_87. [DOI] [PubMed] [Google Scholar]
  48. Weiner L.P. Pathogenesis of demyelination induced by a mouse hepatitis virus (JHM Virus) Acta Neurol. 1973;18:298–303. doi: 10.1001/archneur.1973.00490230034003. [DOI] [PubMed] [Google Scholar]
  49. Williamson J.S.P., Stohlman S.A. Effective clearance of mouse hepatitis virus from the central nervous system requires both CD4+ and CD8+ T cells. J. Virol. 1990;64:4589–4592. doi: 10.1128/jvi.64.9.4589-4592.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Williamson J.S.P., Sykes K.C., Stohlman S.A. Characterization of brain-infiltrating mononuclear cells during infection with mouse hepatitis virus strain JHM. J. Neuroimmunol. 1991;32:199–207. doi: 10.1016/0165-5728(91)90189-E. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Williamson J.S.P. Virus-specific T cells in the central nervous system following infection with an avirulent neurotropic mouse hepatitis virus. Regional Immunol. 1992 [PubMed] [Google Scholar]
  52. Ye S., Applegren R.R., Davis J.M., Cheung H.T. Modulation of lymphocyte motility by β-endorphinorphin and met-enkephalin. Immunopharmacology. 1989;17:81–89. doi: 10.1016/0162-3109(89)90053-2. [DOI] [PubMed] [Google Scholar]
  53. Zimmer M.J., Dales S. In vivo and in vitro models of demyelinating diseases. XXIV. The infectious process in cyclosporin treated Wistar rats inoculated with JHM virus. Microb. Pathog. 1989;6:7–16. doi: 10.1016/0882-4010(89)90003-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Zimprich F., Winter J., Wege H., Lassmann H. Coronavirus induced primary demyelination: indications for the involvement of a humoral immune response. Neuropathol. Appl. Neurobiol. 1991;17:469–484. doi: 10.1111/j.1365-2990.1991.tb00750.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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