Methionine-enkephalin-and Dynorphin A-release from immune cells and control of inflammatory pain

Pain. 2001 Sep;93(3):207-212. doi: 10.1016/S0304-3959(01)00322-0.


We have previously shown that beta-endorphin (END) is contained and released from memory-type T-cells within inflamed tissue and that it is capable to control pain (J Clin Invest 100(1) (1997) 142). Methionine-enkephalin (MET) and Dynorphin-A (DYN) are endogenous opioids with preference for delta- and kappa-opioid receptors, respectively. Both MET and DYN are produced and contained within immune cells. The goal of this study was to determine the release characteristics of MET and DYN in a rat model of localized hindpaw inflammation and to examine the antinociceptive role of MET and DYN in a Freund's adjuvant induced model of inflammatory pain. We found that corticotropin-releasing factor (CRF) can stimulate the release of both MET and DYN from lymphocytes. This release is dose-dependent and reversible by the selective CRF antagonist alpha-helical-CRF. Furthermore, CRF (1.5 ng) produces analgesia when injected into the inflamed paw, which is reversible by direct co-administration of antibodies to MET. Lymphocyte content of MET was 7.0+/-1.4 ng/million cells, whilst DYN content was ~30-fold lower. Both END and DYN, but not MET, were released by IL-1. Consistently, IL-1 produced peripheral analgesic effects which were not reversed by antibodies to MET. These results indicate that both MET and DYN play a role in peripheral analgesia but have different characteristics of release. These studies further support a role of the immune system in the control of inflammatory pain. This may be particularly important in patients suffering from compromised immune systems as with cancer and AIDS.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Corticotropin-Releasing Hormone / antagonists & inhibitors
  • Corticotropin-Releasing Hormone / pharmacology
  • Corticotropin-Releasing Hormone / therapeutic use
  • Dose-Response Relationship, Drug
  • Dynorphins / immunology
  • Dynorphins / metabolism*
  • Enkephalin, Methionine / immunology
  • Enkephalin, Methionine / metabolism*
  • Humans
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interleukin-2 / pharmacology
  • Lymphocytes / drug effects
  • Lymphocytes / immunology
  • Lymphocytes / metabolism*
  • Male
  • Pain / drug therapy
  • Pain / immunology
  • Pain / metabolism*
  • Rats
  • Rats, Wistar


  • Antibodies
  • Interleukin-2
  • Enkephalin, Methionine
  • Dynorphins
  • Corticotropin-Releasing Hormone