Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Jul 1;100(1):142–148. doi: 10.1172/JCI119506

Immune cell-derived beta-endorphin. Production, release, and control of inflammatory pain in rats.

P J Cabot 1, L Carter 1, C Gaiddon 1, Q Zhang 1, M Schäfer 1, J P Loeffler 1, C Stein 1
PMCID: PMC508174  PMID: 9202066

Abstract

Localized inflammation of a rat's hindpaw elicits an accumulation of beta-endorphin-(END) containing immune cells. We investigated the production, release, and antinociceptive effects of lymphocyte-derived END in relation to cell trafficking. In normal animals, END and proopiomelanocortin mRNA were less abundant in circulating lymphocytes than in those residing in lymph nodes (LN), suggesting that a finite cell population produces END and homes to LN. Inflammation increased proopiomelanocortin mRNA in cells from noninflamed and inflamed LN. However, END content was increased only in inflamed paw tissue and noninflamed LN-immune cells. Accordingly, corticotropin-releasing factor and IL-1beta released significantly more END from noninflamed than from inflamed LN-immune cells. This secretion was receptor specific, calcium dependent, and mimicked by potassium, consistent with vesicular release. Finally, both agents, injected into the inflamed paw, induced analgesia which was blocked by the co-administration of antiserum against END. Together, these findings suggest that END-producing lymphocytes home to inflamed tissue where they secrete END to reduce pain. Afterwards they migrate to the regional LN, depleted of the peptide. Consistent with this notion, immunofluorescence studies of cell suspensions revealed that END is contained predominantly within memory-type T cells. Thus, the immune system is important for the control of inflammatory pain. This has implications for the understanding of pain in immunosuppressed conditions like cancer or AIDS.

Full Text

The Full Text of this article is available as a PDF (258.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bell E. B., Sparshott S. M., Ager A. Migration pathways of CD4 T cell subsets in vivo: the CD45RC- subset enters the thymus via alpha 4 integrin-VCAM-1 interaction. Int Immunol. 1995 Nov;7(11):1861–1871. doi: 10.1093/intimm/7.11.1861. [DOI] [PubMed] [Google Scholar]
  2. Carr D. J. The role of endogenous opioids and their receptors in the immune system. Proc Soc Exp Biol Med. 1991 Nov;198(2):710–720. doi: 10.3181/00379727-198-43309b. [DOI] [PubMed] [Google Scholar]
  3. Członkowski A., Stein C., Herz A. Peripheral mechanisms of opioid antinociception in inflammation: involvement of cytokines. Eur J Pharmacol. 1993 Oct 5;242(3):229–235. doi: 10.1016/0014-2999(93)90246-e. [DOI] [PubMed] [Google Scholar]
  4. Davis T. P., Konings P. N. Peptidases in the CNS: formation of biologically active, receptor-specific peptide fragments. Crit Rev Neurobiol. 1993;7(3-4):163–174. [PubMed] [Google Scholar]
  5. Gause W. C., Urban J. F., Linsley P., Lu P. Role of B7 signaling in the differentiation of naive CD4+ T cells to effector interleukin-4-producing T helper cells. Immunol Res. 1995;14(3):176–188. doi: 10.1007/BF02918215. [DOI] [PubMed] [Google Scholar]
  6. Heijnen C. J., Kavelaars A., Ballieux R. E. Beta-endorphin: cytokine and neuropeptide. Immunol Rev. 1991 Feb;119:41–63. doi: 10.1111/j.1600-065x.1991.tb00577.x. [DOI] [PubMed] [Google Scholar]
  7. Mackay C. R. Homing of naive, memory and effector lymphocytes. Curr Opin Immunol. 1993 Jun;5(3):423–427. doi: 10.1016/0952-7915(93)90063-x. [DOI] [PubMed] [Google Scholar]
  8. Mackay C. R., Marston W., Dudler L. Altered patterns of T cell migration through lymph nodes and skin following antigen challenge. Eur J Immunol. 1992 Sep;22(9):2205–2210. doi: 10.1002/eji.1830220904. [DOI] [PubMed] [Google Scholar]
  9. Miller B. C., Thiele D. L., Rodd D., Hersh L. B., Cottam G. L. Active beta-endorphin metabolites generated by T-cell ectopeptidases. Adv Exp Med Biol. 1995;373:49–56. doi: 10.1007/978-1-4615-1951-5_8. [DOI] [PubMed] [Google Scholar]
  10. Mousa S. A., Schäfer M., Mitchell W. M., Hassan A. H., Stein C. Local upregulation of corticotropin-releasing hormone and interleukin-1 receptors in rats with painful hindlimb inflammation. Eur J Pharmacol. 1996 Sep 12;311(2-3):221–231. doi: 10.1016/0014-2999(96)00440-2. [DOI] [PubMed] [Google Scholar]
  11. Przewłocki R., Hassan A. H., Lason W., Epplen C., Herz A., Stein C. Gene expression and localization of opioid peptides in immune cells of inflamed tissue: functional role in antinociception. Neuroscience. 1992;48(2):491–500. doi: 10.1016/0306-4522(92)90509-z. [DOI] [PubMed] [Google Scholar]
  12. Schafer M., Mousa S. A., Zhang Q., Carter L., Stein C. Expression of corticotropin-releasing factor in inflamed tissue is required for intrinsic peripheral opioid analgesia. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):6096–6100. doi: 10.1073/pnas.93.12.6096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Schäfer M., Carter L., Stein C. Interleukin 1 beta and corticotropin-releasing factor inhibit pain by releasing opioids from immune cells in inflamed tissue. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4219–4223. doi: 10.1073/pnas.91.10.4219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Sharp B., Linner K. What do we know about the expression of proopiomelanocortin transcripts and related peptides in lymphoid tissue? Endocrinology. 1993 Nov;133(5):1921A–1921B. doi: 10.1210/endo.133.5.8404637. [DOI] [PubMed] [Google Scholar]
  15. Shimizu Y., Shaw S. Lymphocyte interactions with extracellular matrix. FASEB J. 1991 Jun;5(9):2292–2299. doi: 10.1096/fasebj.5.9.1860621. [DOI] [PubMed] [Google Scholar]
  16. Simon E. J. Opioid receptors and endogenous opioid peptides. Med Res Rev. 1991 Jul;11(4):357–374. doi: 10.1002/med.2610110402. [DOI] [PubMed] [Google Scholar]
  17. Stein C., Gramsch C., Herz A. Intrinsic mechanisms of antinociception in inflammation: local opioid receptors and beta-endorphin. J Neurosci. 1990 Apr;10(4):1292–1298. doi: 10.1523/JNEUROSCI.10-04-01292.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Stein C., Hassan A. H., Przewłocki R., Gramsch C., Peter K., Herz A. Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5935–5939. doi: 10.1073/pnas.87.15.5935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Stein C., Millan M. J., Herz A. Unilateral inflammation of the hindpaw in rats as a model of prolonged noxious stimulation: alterations in behavior and nociceptive thresholds. Pharmacol Biochem Behav. 1988 Oct;31(2):445–451. doi: 10.1016/0091-3057(88)90372-3. [DOI] [PubMed] [Google Scholar]
  20. Stein C., Pflüger M., Yassouridis A., Hoelzl J., Lehrberger K., Welte C., Hassan A. H. No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. J Clin Invest. 1996 Aug 1;98(3):793–799. doi: 10.1172/JCI118852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Stein C. The control of pain in peripheral tissue by opioids. N Engl J Med. 1995 Jun 22;332(25):1685–1690. doi: 10.1056/NEJM199506223322506. [DOI] [PubMed] [Google Scholar]
  22. Westermann J., Persin S., Matyas J., van der Meide P., Pabst R. Migration of so-called naive and memory T lymphocytes from blood to lymph in the rat. The influence of IFN-gamma on the circulation pattern. J Immunol. 1994 Feb 15;152(4):1744–1750. [PubMed] [Google Scholar]
  23. Westly H. J., Kleiss A. J., Kelley K. W., Wong P. K., Yuen P. H. Newcastle disease virus-infected splenocytes express the proopiomelanocortin gene. J Exp Med. 1986 Jun 1;163(6):1589–1594. doi: 10.1084/jem.163.6.1589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Yaksh T. L. Substance P release from knee joint afferent terminals: modulation by opioids. Brain Res. 1988 Aug 23;458(2):319–324. doi: 10.1016/0006-8993(88)90474-x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES