Evidence for opioid receptors on cells involved in host defense and the immune system.
ABSTRACT Although the role of opiates and opioids in the physiological and pathological function of the immune system is only beginning to be unraveled, converging lines of evidence indicate that the opioid receptors expressed by immune cells are often the same or similar to the neuronal subtypes, particularly delta and kappa. Recent studies also point to the existence of novel opioid receptors and/or binding sites on immune cells that are selective for morphine. Opioids and their receptors, particularly those with high affinity for delta agonists, appear to function in an autocrine/paracrine manner. Thus, opioid peptides generated from immune-derived proenkephalin A act as cytokines, capable of regulating myriad functions of both granulocytes and mononuclear cells. Further identification and characterization of receptors and signal transduction pathways that account for some of the unique properties of opiate binding and immunomodulation (e.g., dose-dependent effects of morphine that occur at exceptionally low concentrations relative to the Kd's of the neuronal mu receptor or the morphine binding site reported on activated human T-cells) represents one of the major research challenges ahead. Elucidating mechanisms, such as these, may provide unique therapeutic opportunities through the application of opioid immunopharmacology to disorders involving immune responses in peripheral organs and the central nervous system.
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ABSTRACT: Opioid peptides function as immunomodulatory molecules. Reports have linked the opioid growth factor (OGF), [Met(5)]-enkephalin, and its receptor OGFr to autoimmune diseases. OGF repressed the incidence and magnitude of myelin oligodendrocyte-induced experimental autoimmune encephalomyelitis in mice. Given the extensive connection between the immune system and autoimmune diseases, the present study was conducted to examine the relationship of the OGF-OGFr axis and T lymphocyte proliferation. Splenic-derived mouse lymphocytes were stimulated with phytohemagglutin (PHA). All non-stimulated and PHA-stimulated T lymphocytes had immunoreactivity for OGF-like enkephalin and OGFr. OGF markedly suppressed T lymphocyte number in a dose-dependent manner. However, PHA-stimulated T lymphocytes were not altered in cell number by a variety of natural and synthetic opioid-related compounds, some specific for μ, δ, and κ opioid receptors. Persistent blockade of opioid receptors with the general opioid antagonist naltrexone (NTX), as well as antibody neutralization of OGF-like peptides, had no effect on cell number. Non-stimulated T lymphocytes exhibited no change in cell number when subjected to OGF or NTX. Treatment of T lymphocytes with siRNAs for μ, δ, or κ opioid receptors did not affect cell number, and the addition of OGF to these siRNA-exposed cultures depressed the population of cells. T lymphocytes treated with OGFr siRNA also had a comparable number of cells to control cultures, but the addition of OGF did not alter cell number. DNA synthesis in PHA-stimulated T lymphocytes exposed to OGF was markedly decreased from PHA-stimulated cultures receiving vehicle, but the number of cells undergoing apoptosis or necrosis in these cultures was similar to control levels. T lymphocytes subjected to siRNA for p16 and/or p21 had a comparable number of cells compared to controls, and treatment with OGF did not depress cell number in preparations transfected with both p16 and p21 siRNA. These data reveal that the OGF-OGFr axis is present in T lymphocytes and is capable of suppressing cell proliferation. However, T lymphocytes are not dependent on the regulation of cell proliferation by this system. The results showing that the OGF-OGFr axis is an immunosuppressant, offers explanation for reports that autoimmune diseases can be modulated by this system.Immunobiology 09/2010; 216(5):579-90. DOI:10.1016/j.imbio.2010.09.014 · 3.18 Impact Factor
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ABSTRACT: Endogenous opioids are known to repress the incidence and progression of autoimmune diseases. One native opioid peptide, [Met⁵]-enkephalin, termed the opioid gowth factor (OGF), interacts with the OGF receptor (OGFr) to suppress the expression of experimental autoimmune encephalomyelitis. The present study examined the role of the OGF-OGFr axis in the regulation of B lymphocyte proliferation. Murine B lymphocytes were stimulated with lipopolysaccharide. Both OGF and OGFr were present in all B lymphocytes. OGF had a dose-dependent effect on growth, with cell number inhibited by up to 43% at 72 h; no other synthetic or native opioid altered cell proliferation. Exogenous OGF depressed cell number in cultures treated with siRNAs for the classical opioid receptors, MOR (μ), DOR (δ), and KOR (κ), however this peptide had no effect in preparations exposed to siRNA for OGFr. The decrease in cell number by exogenous OGF was dependent on p16 or p21 cyclin-dependent inhibitory kinase pathways. Exposure to the opioid antagonist, naltrexone, did not change cell number from control levels. These results suggest that the OGF-OGFr axis is present and functional in B lymphocytes, but this system is not an autocrine regulator of cell proliferation. Thus, at least exogenous OGF and perhaps endogenous OGF by paracrine/endocrine sources, can be an immunosuppressant. Modulation of the OGF-OGFr axis may be a novel paradigm for the treatment of autoimmune diseases.Immunobiology 01/2010; 216(1-2):173-83. DOI:10.1016/j.imbio.2010.06.001 · 3.18 Impact Factor
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ABSTRACT: In this report, we show that affinity purified human anti-delta opioid receptor (DOR) autoantibodies from IVIG are specific to DOR and possess agonistic properties displayed by their ability to dramatically decrease forskolin stimulated cAMP accumulation. Anti-DOR autoantibody also caused phosphorylation of the opioid receptor. Anti-DOR autoantibody treatment showed a significant reduction in CXCR4 gene expression as well as surface protein expression. In contrast, anti-DOR autoantibody treatment significantly upregulated CCR5 gene and protein expression. The presence of anti-DOR autoantibodies in IVIG and their potent immunomodulatory activity is further evidence to support the cross-talk between the neuroendocrine and immune systems.Journal of neuroimmunology 10/2009; 217(1-2):65-73. DOI:10.1016/j.jneuroim.2009.10.007 · 2.79 Impact Factor