Immune cell-derived beta-endorphin. Production, release, and control of inflammatory pain in rats
Humans; Male; Time Factors; Analysis of Variance; Animals; Regression Analysis; Rats; Biomarkers of Pain; RNA; Genetic; Biomarkers Reference List; Inflammation/physiopathology; Freund's Adjuvant; Hindlimb; Pain/immunology/physiopathology; Corticotropin-Releasing Hormone/pharmacology; Wistar; Messenger/biosynthesis; beta-Endorphin/biosynthesis; Interleukin-1/pharmacology; Lymph Nodes/metabolism; Pro-Opiomelanocortin/biosynthesis; T-Lymphocytes/drug effects/immunology/metabolism; Transcription
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.
1997
Cabot PJ; Carter L; Gaiddon C; Zhang Q; Schafer M; Loeffler JP; Stein C
The Journal Of Clinical Investigation
1997
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1172/jci119506" target="_blank" rel="noreferrer">10.1172/jci119506</a>
Gene expression and localization of opioid peptides in immune cells of inflamed tissue: functional role in antinociception
Male; Pain Measurement; Analysis of Variance; Animals; Nucleic Acid Hybridization; Rats; Non-U.S. Gov't; Research Support; Biomarkers of Pain; RNA; Biomarkers Reference List; Inbred Strains; beta-Endorphin/genetics/metabolism; Calcitonin Gene-Related Peptide/analysis/metabolism; Endorphins/analysis/genetics/metabolism; Freund's Adjuvant; Gene Expression/radiation effects; Hindlimb; Inflammation/immunology/physiopathology; Messenger/genetics/metabolism; Nerve Fibers/physiology/ultrastructure; Oligonucleotide Probes; Pain/immunology/physiopathology; T-Lymphocytes/immunology/pathology; Whole-Body Irradiation
Our previous studies indicate that endogenous opioids (primarily beta-endorphin) released during stressful stimuli can interact with peripheral opioid receptors to inhibit nociception in inflamed tissue of rats. This study sought to localize opioid precursor mRNAs and opioid peptides deriving therefrom in inflamed tissue, identify opioid containing cells and demonstrate their functional significance in the inhibition of nociception. In rats with Freund's adjuvant-induced unilateral hindpaw inflammation we show that: (i) pro-opiomelanocortin and proenkephalin-mRNAs (but not prodynorphin mRNA) are abundant in cells of inflamed, but absent in non-inflamed tissue; (ii) numerous cells infiltrating the inflamed subcutaneous tissue are stained intensely with beta-endorphin and [Met]enkephalin (but only few scattered cells with dynorphin) antibodies; (iii) beta-endorphin is present in T- and B-lymphocytes, monocytes and macrophages; and (iv) whole-body irradiation suppresses stress-induced antinociception in the inflamed paw. Taken together, these data suggest that endogenous opioid peptides are synthesized and processed within various types of immune cells at the site of inflammation. Immunosuppression abolishes the intrinsic antinociception in inflammatory tissue confirming the functional significance of these cells.
1992
Przewlocki R; Hassan AH; Lason W; Epplen C; Herz A; Stein C
Neuroscience
1992
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1016/0306-4522(92)90509-z" target="_blank" rel="noreferrer">10.1016/0306-4522(92)90509-z</a>
Leukocytes in the regulation of pain and analgesia
Humans; Analgesia; Animals; Biomarkers of Pain; Receptors; Biomarkers Reference List; Pain/immunology/physiopathology; Inflammation Mediators/immunology; Leukocytes/immunology/secretion; Nervous System/immunology/physiopathology; Neuropeptides/immunology/pharmacology; Opioid Peptides/immunology/secretion; Opioid/immunology; Sensory/immunology/physiopathology; Signal Transduction/immunology
When tissue is destroyed or invaded by leukocytes in inflammation, numerous mediators are delivered by the circulation and/or liberated from resident and immigrated cells at the site. Proalgesic mediators include proinflammatory cytokines, chemokines, protons, nerve growth factor, and prostaglandins, which are produced by invading leukocytes or by resident cells. Less well known is that analgesic mediators, which counteract pain, are also produced in inflamed tissues. These include anti-inflammatory cytokines and opioid peptides. Interactions between leukocyte-derived opioid peptides and opioid receptors can lead to potent, clinically relevant inhibition of pain (analgesia). Opioid receptors are present on peripheral endings of sensory neurons. Opioid peptides are synthesized in circulating leukocytes, which migrate to inflamed tissues directed by chemokines and adhesion molecules. Under stressful conditions or in response to releasing agents (e.g., corticotropin-releasing factor, cytokines, noradrenaline), leukocytes can secrete opioids. They activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of excitatory neuropeptides. This review presents discoveries that led to the concepts of pain generation by mediators secreted from leukocytes and of analgesia by immune-derived opioids.
2005
Rittner HL; Machelska H; Stein C
Journal Of Leukocyte Biology
2005
Article information provided for research and reference use only. PedPalASCNET does not hold any rights over the resource listed here. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1189/jlb.0405223" target="_blank" rel="noreferrer">10.1189/jlb.0405223</a>