Abstract：
Acute gastrointestinal (GI) inflammation induces neuroplasticity that produces long-lasting changes in gut motor function and pain. The endocannabinoid system is an attractive target to correct pain and dysmotility, but how inflammation changes endocannabinoid control over cellular communication in enteric neurocircuits is not understood. Enteric glia modulate gut neurons that control motility and pain and express monoacylglycerol lipase (MAGL) which controls endocannabinoid availability. We used a combination of in situ calcium imaging, chemogenetics, and selective drugs to study how endocannabinoid mechanisms affect glial responses and subsequent enteric neuron activity in health and following colitis in Wnt1Cre;GCaMP5g-tdT;GFAP::hM3Dq mice. Trpv1Cre;GCaMP5gtdT mice were used to study nociceptor sensitivity and Sox10CreERT2;Mgllf/f mice were used to test the role of glial MAGL in visceral pain. The data show that endocannabinoid signaling regulates neuro-glial signaling in gut neurocircuits in a sexually dimorphic manner. Inhibiting MAGL in healthy samples decreased glial responsiveness but this effect was lost in females following colitis and converted to an excitatory effect in males. Manipulating CB1 and CB2 receptors revealed further sex differences amongst neuro-glia signaling that were impacted following inflammation. Inflammation increased gut nociceptor sensitivity in both sexes but only females exhibited visceral hypersensitivity in vivo. Blocking MAGL normalized nociceptor responses in vitro and deleting glial Mgll in vivo rescued visceral hypersensitivity in females. These results show that sex and inflammation impact endocannabinoid mechanisms that regulate intercellular enteric glia-neuron communication. Further, targeting glial MAGL could provide therapeutic benefits for visceral nociception in a sex-dependent manner.
摘要：
急性胃肠(GI)炎症诱导神经可塑性,其产生肠运动功能和疼痛的持久变化。内源性大麻素系统是纠正疼痛和运动障碍的有吸引力的目标，但是炎症如何改变内源性大麻素对肠道神经回路细胞通讯的控制尚不清楚。肠神经胶质调节控制运动和疼痛的肠神经元，并表达控制内源性大麻素可用性的单酰基甘油脂肪酶（MAGL）。我们使用了原位钙成像的组合，化学遗传学，和选择性药物，以研究内源性大麻素机制如何影响健康和Wnt1Cre结肠炎后的神经胶质反应和随后的肠神经元活性;GCaMP5g-tdT;GFAP::hM3Dq小鼠。Trpv1Cre;GCaMP5gtdT小鼠用于研究伤害性感受器敏感性和Sox10CreERT2;Mgllf/f小鼠用于测试神经胶质MAGL在内脏疼痛中的作用。数据显示内源性大麻素信号传导以性二态方式调节肠神经回路中的神经-神经胶质信号传导。在健康样品中抑制MAGL会降低神经胶质反应性，但这种作用在结肠炎后的女性中消失，并在男性中转化为兴奋作用。操纵CB1和CB2受体揭示了在炎症后受到影响的神经胶质信号之间的进一步性别差异。炎症增加了两种性别的肠道伤害感受器敏感性，但只有女性在体内表现出内脏超敏反应。阻断MAGL可在体外使伤害感受器反应正常化，并在体内删除神经胶质Mgll可挽救女性的内脏高敏感性。这些结果表明，性别和炎症影响调节细胞间肠神经胶质-神经元通讯的内源性大麻素机制。Further,靶向神经胶质细胞MAGL可以以性别依赖性方式为内脏伤害感受提供治疗益处.
