Methionine-enkephalin-and Dynorphin A-release from immune cells and control of inflammatory pain.
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.
Cabot
Peter J
PJ
Behavioral Pharmacology and Genetics Section, Intramural Research Program, NIDA/NIH, Baltimore, MD 21224, USA Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD 21287-8711, USA Klinik für Anaesthesiologie und Operative Intensivmedizin, Klinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, D12200 Berlin, Germany School of Pharmacy, The University of Queensland, St Lucia, Queensland, Australia 4072.
Carter
Laurenda
L
Schäfer
Michael
M
Stein
Christoph
C
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000276:immunology / Q000378:metabolism*; D004744:Enkephalin, Methionine / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D010146:Pain / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D000906:Antibodies; D007376:Interleukin-2; D004744:Enkephalin, Methionine; D004399:Dynorphins; D003346:Corticotropin-Releasing Hormone