小胶质细胞
TRPV1型
嘌呤能受体
内脏痛
医学
嘌呤能信号
瞬时受体电位通道
脊髓
慢性疼痛
结肠炎
受体
炎症性肠病
神经科学
伤害感受器
炎症
免疫学
腺苷受体
病理
伤害
内科学
生物
兴奋剂
疾病
精神科
作者
Manon Defaye,Nasser Abdullah,Mircea Iftinca,Ahmed M. Hassan,Francina Agosti,Zizhen Zhang,Mélissa Cuménal,Gerald W. Zamponi,Christophe Altier
标识
DOI:10.1016/j.jcmgh.2021.12.012
摘要
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.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.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.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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