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

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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Published inCellular and molecular gastroenterology and hepatology Vol. 13; no. 4; pp. 977 - 999
Main Authors Manon Defaye, Nasser S. Abdullah, Mircea Iftinca, Ahmed Hassan, Francina Agosti, Zizhen Zhang, Melissa Cumenal, Gerald W. Zamponi, Christophe Altier
Format Journal Article
LanguageEnglish
Published Elsevier 01.01.2022
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Abstract 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.
AbstractList 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.
Author Zizhen Zhang
Melissa Cumenal
Francina Agosti
Mircea Iftinca
Christophe Altier
Nasser S. Abdullah
Manon Defaye
Ahmed Hassan
Gerald W. Zamponi
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  fullname: Manon Defaye
  organization: Department of Physiology and Pharmacology, Calgary, Alberta, Canada; Inflammation Research Network-Snyder Institute for Chronic Diseases, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, Calgary, Alberta, Canada
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  fullname: Nasser S. Abdullah
  organization: Department of Physiology and Pharmacology, Calgary, Alberta, Canada; Inflammation Research Network-Snyder Institute for Chronic Diseases, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, Calgary, Alberta, Canada
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  fullname: Mircea Iftinca
  organization: Department of Physiology and Pharmacology, Calgary, Alberta, Canada; Inflammation Research Network-Snyder Institute for Chronic Diseases, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, Calgary, Alberta, Canada
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  fullname: Ahmed Hassan
  organization: Department of Physiology and Pharmacology, Calgary, Alberta, Canada; Inflammation Research Network-Snyder Institute for Chronic Diseases, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, Calgary, Alberta, Canada
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  fullname: Francina Agosti
  organization: Department of Physiology and Pharmacology, Calgary, Alberta, Canada; Inflammation Research Network-Snyder Institute for Chronic Diseases, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, Calgary, Alberta, Canada
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  fullname: Zizhen Zhang
  organization: Department of Physiology and Pharmacology, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, Calgary, Alberta, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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  fullname: Melissa Cumenal
  organization: Department of Physiology and Pharmacology, Calgary, Alberta, Canada; Inflammation Research Network-Snyder Institute for Chronic Diseases, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, Calgary, Alberta, Canada
– sequence: 8
  fullname: Gerald W. Zamponi
  organization: Department of Physiology and Pharmacology, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, Calgary, Alberta, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
– sequence: 9
  fullname: Christophe Altier
  organization: Department of Physiology and Pharmacology, Calgary, Alberta, Canada; Inflammation Research Network-Snyder Institute for Chronic Diseases, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, Calgary, Alberta, Canada; Correspondence Address correspondence to: Christophe Altier, PhD, Associate Professor, Canada Research Chair in Inflammatory Pain, Department of Physiology & Pharmacology, Inflammation Research Network, Snyder Institute for Chronic Diseases, University of Calgary, HS 1665, 3330 Hospital Dr NW, Calgary, AB, T2N4N1 Canada. tel: 220-7549
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Snippet Background & Aims: Chronic abdominal pain is a common symptom of inflammatory bowel diseases (IBDs). Peripheral and central mechanisms contribute to the...
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SubjectTerms Microglia
P2RY12
TRPV1 Neurons
Visceral Pain
Title Gut-innervating TRPV1+ Neurons Drive Chronic Visceral Pain via Microglial P2Y12 ReceptorSummary
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