Characterization Of Endogenous Opioids In The Immune System

Originally, the endogenous opioids enkephalin, dynorphin, and endorphin were considered to be specific products of the nervous system, but cells of the immune system have recently been shown to express these peptides. These mediators stem from three different prohormones: proenkephalin, proopiomelanocortin (POMC), and prodynorphin, encoded by three separate genes. All opioids start with the same sequence, Tyr-Gly-Gly-Phe, followed by methionine or leucine. Transcription of the POMC gene has been demonstrated in stimulated macrophages and lymphocytes. Proenkephalin A mRNA has been expressed in thymocytes, bone marrow cells, and spleno-cytes. Localized inflammation of a rat's hindpaw elicits an accumulation of h-endorphin-releasing lymphocytes, suggesting the immune system is a key factor of inflammatory pain management [45]. A secreted peptidase from activated murine CD4+ and CD8+ cells metabolizes endorphin into biologically active and possibly immunoregulatory peptides [30]. Endorphin binds to Jurkat potassium channel proteins, displacing channel inhibitors charybdotoxin and tetraethylammonium, relieving the cell of calcium ion flux inhibition [46]. Endorphin levels are positively correlated to NK- and T-cell activity in mistletoe lectin treated breast carcinoma patients [47]. Increases in immunocyte-derived endorphin were seen in rats injected intracerebroven-tricularly with IL-1 or stress induced by foot intermittent foot shock. These increases led to decreased NK cell activity and lymphocyte proliferation, which were blocked by a corticosteroid releasing hormone antagonist, despite elevated corticosteroid levels [48]. Aging is associated with the increase in intracellular endorphin concentrations in resting and fresh cultured peripheral blood mononuclear cells (PBMCs), the intracellular decrease, and the increased release of the endogenous opioid from mitogen induced PBMCs from young and old subjects. These data suggest that changes in Ca2 + homeostasis modulation may be involved in these cells [49]. It is shown that synthesis of the endogenous opioid precursor proenkephalin A in human peripheral T cells and monocytes is induced through stimulation of CD2/ CD28 receptors and LPS treatment, respectively. Lack of enkephalin production resulted in inhibition of monocytic IL-6 production acting via membrane opioid receptors [50]. Signal transduction pathways involving calcium seem to be mediated by met-enkephalin in human T-cells [35]. Endogenous enkephalins are expressed in fetal but not newborn murine thymocytes, suggesting their possible role in T-cell differentiation and maturation [51]. The endopeptidase carboxypeptidase M, with numerous immu-nological substrates including enkephalin, serves as a marker for macrophage maturation [52].

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