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1.
J Neuroinflammation ; 19(1): 7, 2022 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-34991641

RESUMEN

BACKGROUND: Inflammatory visceral pain is endogenously controlled by enkephalins locally released by mucosal CD4+ T lymphocytes in mice. The present study aimed at identifying opioid receptor(s) expressed on nociceptive sensory nerves involved in this peripheral opioid-mediated analgesia. METHODS: The peripheral analgesia associated with the accumulation of CD4+ T lymphocytes within the inflamed colonic mucosa was assessed in conditional knockout mice specifically deleted for either of the two opioid receptors for enkephalins (i.e., µ (MOR) and δ (DOR) receptors) in Nav1.8-expressing sensory neurons in the dextran sulfate sodium (DSS)-induced colitis model. RESULTS: Endogenous analgesia is lost in conditional knockout mice for DOR, but not MOR at the later phase of the DSS-induced colitis. The absence of either of the opioid receptors on sensory nerves had no impact on both the colitis severity and the rate of T lymphocytes infiltrating the inflamed colonic mucosa. CONCLUSION: The key role of DOR on primary afferents in relieving intestinal inflammatory pain opens new therapeutic opportunities for peripherally restricted DOR analgesics to avoid most of the side effects associated with MOR-targeting drugs used in intestinal disorders.


Asunto(s)
Colitis/metabolismo , Mucosa Intestinal/metabolismo , Nociceptores/metabolismo , Receptores Opioides delta/metabolismo , Dolor Visceral/metabolismo , Analgesia , Animales , Colitis/genética , Modelos Animales de Enfermedad , Inflamación/genética , Inflamación/metabolismo , Ratones , Ratones Noqueados , Receptores Opioides delta/genética , Dolor Visceral/genética
2.
Gut ; 70(6): 1078-1087, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33020209

RESUMEN

OBJECTIVE: The enteric nervous system (ENS) plays a key role in controlling the gut-brain axis under normal and pathological conditions, such as type 2 diabetes. The discovery of intestinal actors, such as enterosynes, able to modulate the ENS-induced duodenal contraction is considered an innovative approach. Among all the intestinal factors, the understanding of the role of gut microbes in controlling glycaemia is still developed. We studied whether the modulation of gut microbiota by prebiotics could permit the identification of novel enterosynes. DESIGN: We measured the effects of prebiotics on the production of bioactive lipids in the intestine and tested the identified lipid on ENS-induced contraction and glucose metabolism. Then, we studied the signalling pathways involved and compared the results obtained in mice to human. RESULTS: We found that modulating the gut microbiota with prebiotics modifies the actions of enteric neurons, thereby controlling duodenal contraction and subsequently attenuating hyperglycaemia in diabetic mice. We discovered that the signalling pathway involved in these effects depends on the synthesis of a bioactive lipid 12-hydroxyeicosatetraenoic acid (12-HETE) and the presence of mu-opioid receptors (MOR) on enteric neurons. Using pharmacological approaches, we demonstrated the key role of the MOR receptors and proliferator-activated receptor γ for the effects of 12-HETE. These findings are supported by human data showing a decreased expression of the proenkephalin and MOR messanger RNAs in the duodenum of patients with diabetic. CONCLUSIONS: Using a prebiotic approach, we identified enkephalin and 12-HETE as new enterosynes with potential real beneficial and safety impact in diabetic human.


Asunto(s)
Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/biosíntesis , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Duodeno/fisiología , Sistema Nervioso Entérico/fisiología , Prebióticos , Receptores Opioides mu/metabolismo , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/farmacología , Adulto , Anciano , Animales , Eje Cerebro-Intestino , Diabetes Mellitus Experimental/fisiopatología , Duodeno/inervación , Encefalinas/genética , Encefalinas/metabolismo , Sistema Nervioso Entérico/efectos de los fármacos , Microbioma Gastrointestinal , Prueba de Tolerancia a la Glucosa , Humanos , Contracción Isotónica/efectos de los fármacos , Masculino , Ratones , Persona de Mediana Edad , Músculo Liso/fisiología , Neuronas/fisiología , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo I/metabolismo , Oligosacáridos/farmacología , PPAR gamma/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , ARN Mensajero/metabolismo , Receptores Opioides mu/genética , Transducción de Señal
3.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-34299013

RESUMEN

Mucosal CD4+ T lymphocytes display a potent opioid-mediated analgesic activity in interleukin (IL)-10 knockout mouse model of inflammatory bowel diseases (IBD). Considering that endogenous opioids may also exhibit anti-inflammatory activities in the periphery, we examined the consequences of a peripheral opioid receptor blockade by naloxone-methiodide, a general opioid receptor antagonist unable to cross the blood-brain barrier, on the development of piroxicam-accelerated colitis in IL-10-deficient (IL-10-/-) mice. Here, we show that IL-10-deficient mice treated with piroxicam exhibited significant alterations of the intestinal barrier function, including permeability, inflammation-related bioactive lipid mediators, and mucosal CD4+ T lymphocyte subsets. Opioid receptor antagonization in the periphery had virtually no effect on colitis severity but significantly worsened epithelial cell apoptosis and intestinal permeability. Thus, although the endogenous opioid tone is not sufficient to reduce the severity of colitis significantly, it substantially contributes to the protection of the physical integrity of the epithelial barrier.


Asunto(s)
Colitis/metabolismo , Interleucina-10/genética , Mucosa Intestinal/efectos de los fármacos , Naloxona/análogos & derivados , Antagonistas de Narcóticos/administración & dosificación , Piroxicam/farmacología , Receptores Opioides/metabolismo , Animales , Antiinflamatorios/farmacología , Antiinflamatorios no Esteroideos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Linfocitos T CD4-Positivos/efectos de los fármacos , Colitis/inducido químicamente , Colitis/genética , Colitis/patología , Citocinas/genética , Citocinas/metabolismo , Células Epiteliales/efectos de los fármacos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Interleucina-10/metabolismo , Mucosa Intestinal/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Naloxona/farmacología , Permeabilidad/efectos de los fármacos , Compuestos de Amonio Cuaternario/farmacología , Índice de Severidad de la Enfermedad
4.
Commun Biol ; 6(1): 1168, 2023 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-37968381

RESUMEN

Opioid-dependent immune-mediated analgesic effects have been broadly reported upon inflammation. In preclinical mouse models of intestinal inflammatory diseases, the local release of enkephalins (endogenous opioids) by colitogenic T lymphocytes alleviate inflammation-induced pain by down-modulating gut-innervating nociceptor activation in periphery. In this study, we wondered whether this immune cell-derived enkephalin-mediated regulation of the nociceptor activity also operates under steady state conditions. Here, we show that chimeric mice engrafted with enkephalin-deficient bone marrow cells exhibit not only visceral hypersensitivity but also an increase in both epithelial paracellular and transcellular permeability, an alteration of the microbial topography resulting in increased bacteria-epithelium interactions and a higher frequency of IgA-producing plasma cells in Peyer's patches. All these alterations of the intestinal homeostasis are associated with an anxiety-like behavior despite the absence of an overt inflammation as observed in patients with irritable bowel syndrome. Thus, our results show that immune cell-derived enkephalins play a pivotal role in maintaining gut homeostasis and normal behavior in mice. Because a defect in the mucosal opioid system remarkably mimics some major clinical symptoms of the irritable bowel syndrome, its identification might help to stratify subgroups of patients.


Asunto(s)
Síndrome del Colon Irritable , Humanos , Animales , Ratones , Analgésicos Opioides , Encefalinas/genética , Inflamación , Dolor
5.
Neurogastroenterol Motil ; 32(2): e13743, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31588671

RESUMEN

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.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Interleucina-10/deficiencia , Mucosa Intestinal/inmunología , Péptidos Opioides/inmunología , Dolor Visceral/inmunología , Animales , Colitis/complicaciones , Colitis/inmunología , Inflamación/complicaciones , Inflamación/inmunología , Mucosa Intestinal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Dolor Visceral/etiología
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