Endogenous Regulation of Visceral Pain via Production of Opioids by Colitogenic CD4+ T Cells in Mice

Boué, Jérôme; Basso, Lilian; Cenac, Nicolas; Blanpied, Catherine; Rolli–Derkinderen, Malvyne; Neunlist, Michel; Vergnolle, Nathalie; Dietrich, Gilles

doi:10.1053/j.gastro.2013.09.020

Cited by 89 publications

(110 citation statements)

References 14 publications

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“…MOR are also significantly enhanced by pro-inflammatory cytokines and repressed by NF-κB inhibitors in myeloid and lymphocytic cell lines [66]. Increased numbers of β-endorphin immunoreactive CD4 + T cells and CD11b + macrophages are found in murine colonic lamina propria in chronic dextran sodium sulphate (DSS)-induced colitis, where the release of endogenous opioids decreases nociceptive signalling through the activation of μ-opioid receptors [67]. Therefore, it is speculated that the anti-nociceptive actions of peripheral opioids in colitis may indirectly result from a reduction of the neurogenic 'pro-nociceptive' components of inflammation, by decreasing CGRP and Substance P (SP) release that could counteract the pro-nociceptive effects of inflammatory mediators such as TNF-α during inflammation [68].…”

Section: The Intestinal Opioid Systemmentioning

confidence: 99%

Microbial Neuro-Immune Interactions and the Pathophysiology of IBD

Aguilera¹,

Melgar²

2016

New Insights Into Inflammatory Bowel Disease

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Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a group of debilitating disorders affecting patient's quality of life and with unknown aetiology. The collected evidence indicates that individuals can develop IBD as a result of genetic susceptibility, a dysregulated immune response and the influence of certain environmental factors. Common symptomatology includes abdominal pain, fever and bowel diarrhoea with blood and/or mucus excretion. The location and extent of disease differ between UC and CD, affecting the mucosal layer in the colon in UC patients, whereas in CD patients, a transmural inflammation is found anywhere in the gastrointestinal tract. Factors associated with IBD pathophysiology include alterations in immune responses, characterized by an atypically T helper (Th)-2 profile in UC, and a Th1/Th17 profile in CD, modifications in epithelial barrier function and alterations in the commensal microbiota composition with blooming of specific pathobionts, for example, adherent-invasive Escherichia coli (AIEC), and with diet. Recent research has uncovered that inflammation, per se, can activate the enteric nervous system inducing neurogenic inflammation and increasing visceral sensitivity, leading to pain. Similarly, alterations in the commensal microbiota composition/ligands have also led to modifications in intestinal nociceptive markers and in visceral pain. In this chapter, we aim to review the mechanisms implicated in microbial neuroimmune axis and its potential contribution to IBD pathophysiology and symptomatology. We focus on the findings identified in animal models and in IBD patients and on the prospective translation of targeting the microbial neuro-immune axis as future therapeutic treatment for intestinal inflammatory conditions.

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Section: The Intestinal Opioid Systemmentioning

confidence: 99%

Microbial Neuro-Immune Interactions and the Pathophysiology of IBD

Aguilera¹,

Melgar²

2016

New Insights Into Inflammatory Bowel Disease

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“…The ability to produce opioids is however irrespective of the phenotype Th1, Th2, or Th17 of effector CD4 + T cells. 38,39 Then, effector CD4 + T lymphocytes leave draining lymph nodes to enter the circulation and move back to the site of inflammation. The recognition of the antigen for which they are specific presented by resident antigenpresenting cells within the inflamed tissue triggers the release of their opioid content 38 (Fig.…”

Section: Endogenous Regulation Of Inflammatory Pain By Cd4 + T Lymphomentioning

confidence: 99%

“…These colitogenic effector CD4 + T lymphocytes, which initiate and perpetuate inflammation, also produce opioids and prevent abdominal pain despite intestinal injury. 39 The analgesic properties of colitogenic CD4 + T lymphocytes are also manifest in dextran sodium sulfate (DSS)-induced colitis model. In this model, disruption of intestinal epithelial integrity by DSS allows the entry of luminal microbiota, which activates innate immune cells.…”

Section: Endogenous Regulation Of Inflamma-tory Pain: the Janus Face mentioning

confidence: 99%

“…Then, the specific adaptive immune response against luminal antigens takes place, resulting in an accumulation of T lymphocytes within the inflamed mucosa, most of which express Met-enkephalin-containing peptides. 39,71 According to the analgesic effect of effector CD4 + T lymphocytes, the abdominal pain arises in the early phase of the DSS-induced colitis (on day 5) but disappears 5 days later (on day 10), although inflammation increases 39,72 (Fig. 2).…”

Section: Endogenous Regulation Of Inflamma-tory Pain: the Janus Face mentioning

confidence: 99%

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Endogenous Regulation of Inflammatory Pain by T-cell-derived Opioids

Basso¹,

Boué

Bourreille

et al. 2014

Inflammatory Bowel Diseases

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Painful sensation is a hallmark of microbe-induced inflammation. This inflammatory pain is downregulated a few days after infection by opioids locally released by effector T lymphocytes generated in response to microbe-derived antigens. This review focuses on the endogenous regulation of inflammatory pain associated with adaptive T-cell response and puts in perspective the clinical consequences of the opioid-mediated analgesic activity of colitogenic T lymphocytes in inflammatory bowel disease.

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“…through the arachidonic acid cascade, they also play a role in mediating endogenous peripheral analgesia, as reflected by the increased expression of opioid receptors on the peripheral terminals of sensory neurons and heightened local production of opioid peptides at the site of inflammation (10,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). This suggests an integral role of the immune system in mediating analgesia in response to noxious stimuli.…”

Section: Study Backgroundmentioning

confidence: 99%

The immunomodulation of dynorphin 1-17 and its biotransformation fragments on inflammatory signalling pathways

Rahiman¹,

Sarah²

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Inflammation is a complex physiological process that involves host defense mechanisms in response to the intrusion of harmful external stimuli. Uncoordinated inflammatory responses, however, are the underlying pathophysiological cause of many chronic diseases. Inflammation is characterised by the burgeoning migration of leukocytes to the point of injury and subsequent release of pro-nociceptive mediators, generating inflammatory pain. Dynorphin 1-17 (DYN 1-17) is endogenously produced and released from leukocytes upon stimulation by local inflammatory factors in the inflamed area. This opioid peptide primarily binds to kappa-opioid receptor (KOR) to produce analgesia. Under inflammatory milieu, DYN 1-17 undergoes spontaneous degradation, yielding a variety of opioid and non-opioid fragments that may have significant implications in inflammation. The underlying cellular effects of these fragments remain unclear. This thesis seeks to explore potential mechanistic insights into selected major DYN 1-17 fragments, identified from a previous biotransformation study of DYN 1-17 in rodent inflamed tissue. This thesis examines the DYN 1-17 fragments modulation of intracellular signals associated with inflammation and thereby, gain an insight into novel therapeutic targets through exploring these endogenous mechanisms.Utilising THP-1 macrophages as an in vitro model of inflammation, this thesis begins with a semiquantitative assessment of nuclear factor-kappa B/p65 (NF-κB/p65) translocation, a major transcription factor that regulates genes responsible for immune and inflammatory responses. The findings presented in Chapter Three of this thesis demonstrated that DYN 1-17 and selected major fragments (DYN 1-6, 1-7, 1-9, 1-10, 1-11, 3-14, 6-12, 2-17 and 7-17) significantly attenuated NF-κB/p65 nuclear translocation induced by lipopolysaccharide (LPS), with the greatest reduction observed with DYN 1-7 at 10 nM. A selective KOR antagonist, ML-190, was used to examine KOR involvement in this inhibitory action. ML-190 significantly reversed the inhibition of NF-κB/p65 translocation produced by DYN 1-17, DYN 1-6, DYN 1-7 and DYN 1-9, but not DYN 1-10 and DYN 1-11.Cytokine production is linked as a downstream process to NF-κB activation; hence it is necessary to evaluate the ability of DYN 1-17 and selected biotransformation fragments in the modulation of IL-1β and TNF-α release in differentiated THP-1 cells, as presented in Chapter Four, to gain an insight into the effects on major pro-inflammatory cytokines. DYN 1-17 and the fragments, demonstrated differential modulatory effects on LPS-induced release of IL-1β and TNF-α. DYN 1-7 and DYN 1-6, inhibited and elevated the secretion of both cytokines, respectively, in a concentration-dependent manner (10 -11 to 10 -7 M). DYN 1-17, however, only inhibited IL-1β release from differentiated iii THP-1 cells and had no effect on TNF-α secretion. Intriguingly, DYN 3-14 at 10 -17 to 10 -11 M demonstrated significant inhibition on IL-1β release and paradoxically increased TNF-α lev...

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Endogenous Regulation of Visceral Pain via Production of Opioids by Colitogenic CD4+ T Cells in Mice

Cited by 89 publications

References 14 publications

Microbial Neuro-Immune Interactions and the Pathophysiology of IBD

Microbial Neuro-Immune Interactions and the Pathophysiology of IBD

Endogenous Regulation of Inflammatory Pain by T-cell-derived Opioids

The immunomodulation of dynorphin 1-17 and its biotransformation fragments on inflammatory signalling pathways

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