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

• Published in: Cellular 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
• Language: English
• Published: Elsevier 01.01.2022
• Subjects: Microglia; P2RY12; TRPV1 Neurons; Visceral Pain
• ISSN: 2352-345X; 2352-345X

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.