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Gut-innervating TRPV1+ Neurons Drive Chronic Visceral Pain via Microglial P2Y12 Receptor

BACKGROUND & AIMS: Chronic abdominal pain is a common symptom of inflammatory bowel diseases (IBDs). Peripheral and central mechanisms contribute to the transition from acute to chronic pain during active disease and clinical remission. Lower mechanical threshold and hyperexcitability of viscera...

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Autores principales: Defaye, Manon, Abdullah, Nasser S., Iftinca, Mircea, Hassan, Ahmed, Agosti, Francina, Zhang, Zizhen, Cumenal, Melissa, Zamponi, Gerald W., Altier, Christophe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8867057/
https://www.ncbi.nlm.nih.gov/pubmed/34954381
http://dx.doi.org/10.1016/j.jcmgh.2021.12.012
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author Defaye, Manon
Abdullah, Nasser S.
Iftinca, Mircea
Hassan, Ahmed
Agosti, Francina
Zhang, Zizhen
Cumenal, Melissa
Zamponi, Gerald W.
Altier, Christophe
author_facet Defaye, Manon
Abdullah, Nasser S.
Iftinca, Mircea
Hassan, Ahmed
Agosti, Francina
Zhang, Zizhen
Cumenal, Melissa
Zamponi, Gerald W.
Altier, Christophe
author_sort Defaye, Manon
collection PubMed
description BACKGROUND & AIMS: Chronic abdominal pain is a common symptom of inflammatory bowel diseases (IBDs). Peripheral and central mechanisms contribute to the transition from acute to chronic pain during active disease and clinical remission. Lower mechanical threshold and hyperexcitability of visceral afferents induce gliosis in central pain circuits, leading to persistent visceral hypersensitivity (VHS). In the spinal cord, microglia, the immune sentinels of the central nervous system, undergo activation in multiple models of VHS. Here, we investigated the mechanisms of microglia activation to identify centrally acting analgesics for chronic IBD pain. METHODS: Using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) expressed in transient receptor potential vanilloid member 1-expressing visceral neurons that sense colonic inflammation, we tested whether neuronal activity was indispensable to control microglia activation and VHS. We then investigated the neuron-microglia signaling system involved in visceral pain chronification. RESULTS: We found that chemogenetic inhibition of transient receptor potential vanilloid member 1(+) visceral afferents prevents microglial activation in the spinal cord and subsequent VHS in colitis mice. In contrast, chemogenetic activation, in the absence of colitis, enhanced microglial activation associated with VHS. We identified a purinergic signaling mechanism mediated by neuronal adenosine triphosphate (ATP) and microglial P2Y12 receptor, triggering VHS in colitis. Inhibition of P2RY12 prevented microglial reactivity and chronic VHS post-colitis. CONCLUSIONS: Overall, these data provide novel insights into the central mechanisms of chronic visceral pain and suggest that targeting microglial P2RY12 signaling could be harnessed to relieve pain in patients with IBD who are in remission.
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spelling pubmed-88670572022-03-02 Gut-innervating TRPV1+ Neurons Drive Chronic Visceral Pain via Microglial P2Y12 Receptor Defaye, Manon Abdullah, Nasser S. Iftinca, Mircea Hassan, Ahmed Agosti, Francina Zhang, Zizhen Cumenal, Melissa Zamponi, Gerald W. Altier, Christophe Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: Chronic abdominal pain is a common symptom of inflammatory bowel diseases (IBDs). Peripheral and central mechanisms contribute to the transition from acute to chronic pain during active disease and clinical remission. Lower mechanical threshold and hyperexcitability of visceral afferents induce gliosis in central pain circuits, leading to persistent visceral hypersensitivity (VHS). In the spinal cord, microglia, the immune sentinels of the central nervous system, undergo activation in multiple models of VHS. Here, we investigated the mechanisms of microglia activation to identify centrally acting analgesics for chronic IBD pain. METHODS: Using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) expressed in transient receptor potential vanilloid member 1-expressing visceral neurons that sense colonic inflammation, we tested whether neuronal activity was indispensable to control microglia activation and VHS. We then investigated the neuron-microglia signaling system involved in visceral pain chronification. RESULTS: We found that chemogenetic inhibition of transient receptor potential vanilloid member 1(+) visceral afferents prevents microglial activation in the spinal cord and subsequent VHS in colitis mice. In contrast, chemogenetic activation, in the absence of colitis, enhanced microglial activation associated with VHS. We identified a purinergic signaling mechanism mediated by neuronal adenosine triphosphate (ATP) and microglial P2Y12 receptor, triggering VHS in colitis. Inhibition of P2RY12 prevented microglial reactivity and chronic VHS post-colitis. CONCLUSIONS: Overall, these data provide novel insights into the central mechanisms of chronic visceral pain and suggest that targeting microglial P2RY12 signaling could be harnessed to relieve pain in patients with IBD who are in remission. Elsevier 2021-12-24 /pmc/articles/PMC8867057/ /pubmed/34954381 http://dx.doi.org/10.1016/j.jcmgh.2021.12.012 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Research
Defaye, Manon
Abdullah, Nasser S.
Iftinca, Mircea
Hassan, Ahmed
Agosti, Francina
Zhang, Zizhen
Cumenal, Melissa
Zamponi, Gerald W.
Altier, Christophe
Gut-innervating TRPV1+ Neurons Drive Chronic Visceral Pain via Microglial P2Y12 Receptor
title Gut-innervating TRPV1+ Neurons Drive Chronic Visceral Pain via Microglial P2Y12 Receptor
title_full Gut-innervating TRPV1+ Neurons Drive Chronic Visceral Pain via Microglial P2Y12 Receptor
title_fullStr Gut-innervating TRPV1+ Neurons Drive Chronic Visceral Pain via Microglial P2Y12 Receptor
title_full_unstemmed Gut-innervating TRPV1+ Neurons Drive Chronic Visceral Pain via Microglial P2Y12 Receptor
title_short Gut-innervating TRPV1+ Neurons Drive Chronic Visceral Pain via Microglial P2Y12 Receptor
title_sort gut-innervating trpv1+ neurons drive chronic visceral pain via microglial p2y12 receptor
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8867057/
https://www.ncbi.nlm.nih.gov/pubmed/34954381
http://dx.doi.org/10.1016/j.jcmgh.2021.12.012
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