Mu and delta opioid receptor knockout mice show increased colonic sensitivity

Reiss, D.; Ceredig, Rhian Alice; Sécher, Thomas; Boué, Jérôme; Barreau, Frédérick; Dietrich, Gilles; Gavériaux‐Ruff, Claire

doi:10.1002/ejp.965

Cited by 19 publications

(16 citation statements)

References 59 publications

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“…Opioid peptides are constitutively produced by mucosal immune cells in steady-state conditions but their production is not sufficient to inhibit abdominal pain upon acute colitis. 18,21,[27][28][29][30] By contrast, chronic F I G U R E 5 CD4 + T lymphocytes from IL-10 −/− mice activated under nonpolarizing conditions produce lesser amounts of PENK mRNA than those from wild-type. Naïve CD4 + T lymphocytes isolated from either wild-type (IL-10 +/+ ) or IL-10 −/− mice were activated with a cocktail of anti-CD3 and anti-CD28 antibodies for 6 d. Proliferation was monitored by analyzing CellTrace Violet dispersion in live CD4 + T cells before (A) and on days 3 (B) and 6 (C) following activation (left panels).…”

Section: Discussionmentioning

confidence: 94%

Endogenous control of inflammatory visceral pain by T cell‐derived opioids in IL‐10‐deficient mice

Basso

Benamar

Mas-Orea

et al. 2019

Neurogastroenterology Motil

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Background The opioid‐mediated analgesic activity of mucosal CD4+ T lymphocytes in colitis has been reported in immunocompetent mice so far. Here, we investigated whether CD4+ T lymphocytes alleviate from inflammation‐induced abdominal pain in mice with defective immune regulation. Methods Endogenous control of visceral pain by opioids locally produced in inflamed mucosa was assessed in IL‐10‐deficient mice. Key Results CD4+ T lymphocytes but not F4/80+ macrophages isolated from the lamina propria of IL‐10‐deficient mice with colitis express enkephalin‐containing opioid peptides as assessed by cytofluorometry. Colitis in IL‐10−/− mice was not associated with abdominal pain. Intraperitoneal injection of naloxone‐methiodide, a peripheral opioid receptor antagonist, induced abdominal hypersensitivity in IL‐10−/− mice with colitis. Conclusion and inferences Opioid‐mediated analgesic activity of mucosal T lymphocytes remains operating in IL‐10−/− mice with impaired immune regulation. The data suggest that endogenous T cell‐derived opioids might reduce inflammation‐induced abdominal pain in inflammatory bowel diseases associated with homozygous “loss of function mutations” in interleukin‐10.

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Section: Discussionmentioning

confidence: 94%

Endogenous control of inflammatory visceral pain by T cell‐derived opioids in IL‐10‐deficient mice

Basso

Benamar

Mas-Orea

et al. 2019

Neurogastroenterology Motil

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“…[21] Even though the mechanisms underlying visceral pain share some homology with somatic pain, both are still not fully elucidated yet. According to the study performed by Reiss et al, [25] mice deficient in MOP and DOP are more prone to pressure stimulus compared with their wild-type littermates in the mouse model of CRD. Overall quality of life in IBS patients is diminished, and the inefficiency of drugs could further decrease it.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, Larsson et al [24] demonstrated that the selective KOP-agonists U-69593 (5 and 25 mg/kg, s.c.) and asimadoline (25 mg/kg, s.c.) significantly decreased the VMR in mice lacking KOP, while having no effect in control mice. According to the study performed by Reiss et al, [25] mice deficient in MOP and DOP are more prone to pressure stimulus compared with their wild-type littermates in the mouse model of CRD. This, along with our results, strengthens the importance of opioid receptors in colon sensitivity and paves the way for development of future treatment options in IBS.…”

Section: Resultsmentioning

confidence: 99%

Antinociceptive potency of enkephalins and enkephalinase inhibitors in the mouse model of colorectal distension—proof‐of‐concept

et al. 2018

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Irritable bowel syndrome (IBS) is a chronic disease characterized by abdominal pain and changes in bowel habits. Patients with IBS comprise a significant portion of attendants at the outpatient clinics. Targeting intestinal opioid receptors was found successful in alleviating pain and diarrhea-two major symptoms of IBS. In this study, we aimed to evaluate a novel potential pharmacological option: the use of enkephalinase inhibitors in therapy of visceral pain occurring in the course of IBS. We thus assessed the antinociceptive efficacy of enkephalins: Leu-enkephalin and Met-enkephalin, and enkephalinase inhibitors: opiorphin and sialorphin in the mouse model of visceral pain induced by colorectal distension. Leu-enkephalin, Met-enkephalin, and sialorphin, but not opiorphin, at the dose of 1 mg/kg injected subcutaneously potently decreased the visceromotor response to colon distension as compared to control. To conclude, enkephalinase inhibitors are worth being considered as potential therapeutics in patients with chronic abdominal pain and/or changed bowel habits, that is, suffering from IBS.

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“…33,34 This inhibits the release of proinflammatory and algesic neuropeptides in the periphery and at the dorsal horn of the spinal cord, reducing neurogenic inflammation and nociception, respectively. Chronic inflammation is associated with the peripheral release of opioids from mucosal CD4+ T cells.…”

Section: Enkephalinase Inhibitionmentioning

confidence: 99%

“…These opioids activate mu and delta opioid receptors expressed on sensory afferent terminals, activation of which leads to a suppression of action potential firing and to reduced sensitivity. 33,34 This inhibits the release of proinflammatory and algesic neuropeptides in the periphery and at the dorsal horn of the spinal cord, reducing neurogenic inflammation and nociception, respectively. 1.…”

Section: F I G U R Ementioning

confidence: 99%

Inflammation without pain: Immune‐derived opioids hold the key

Carbone

Poole

2020

Neurogastroenterology Motil

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Visceral pain is commonly associated with acute or remitting inflammatory bowel disease (IBD). In marked contrast, chronic IBD is often painless, even in the presence of active inflammation. This suggests that inflammation in itself is insufficient to sustain altered nociceptive signaling and raises the possibility that there is an endogenous analgesic system in effect in chronic disease. A new study by Basso et al. published in this issue of Neurogastroenterology & Motility provides additional support for an immune‐mediated mechanism that suppresses visceral hypersensitivity. The authors examined visceral pain in the IL‐10‐piroxicam model of chronic colitis, which differs from other experimental IBD models in that it involves immune suppression. During active inflammation, responses by these mice to graded increases in colorectal distension were equivalent to healthy controls, consistent with normal afferent signaling. However, treatment with a peripherally restricted opioid receptor antagonist resulted in marked visceral hypersensitivity to the same stimuli. This effect was attributed to the production of endogenous opioids by colitogenic CD4+ T cells present in the mucosa. This mini‐review provides a brief overview of analgesia by immune‐derived opioids under inflammatory conditions and highlights how the work of Basso et al. contributes to this area of research. Potential pharmacological approaches to harness or mimic this system are provided. These strategies may prove to be an effective means through which targeted and sustained relief of IBD pain may be achieved.

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Mu and delta opioid receptor knockout mice show increased colonic sensitivity

Abstract: Knockout mice for mu and delta opioid receptor have augmented colon sensitivity in the CRD assay. It shows endogenous mu and delta opioid analgesia that may be explored as potential targets for alleviating chronic intestinal pain.

Cited by 19 publications

References 59 publications

Endogenous control of inflammatory visceral pain by T cell‐derived opioids in IL‐10‐deficient mice

Endogenous control of inflammatory visceral pain by T cell‐derived opioids in IL‐10‐deficient mice

Antinociceptive potency of enkephalins and enkephalinase inhibitors in the mouse model of colorectal distension—proof‐of‐concept

Inflammation without pain: Immune‐derived opioids hold the key

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