Targeting visceral pain through intestinal neuropod cell GUCY2C signaling

肠脑相互作用障碍(DGBI)的内脏高敏感性(VH)和疼痛，如便秘型应激 肠综合征(IBS-C)或慢性特发性便秘(CIC)，困扰着10%的人口随着减少 在美国，每年花费约300亿美元来提高生活质量。DBGI中VH的病因尚不清楚。VH反映招聘情况 静息背根神经节(DRG)内脏传入，降低它们的射击阈值，提高它们的放电频率。 发射，动作电位。目前的止痛药，包括非类固醇抗炎药和阿片类药物， 不足，疗效差，副作用大，突出了临床对新疗法的需求。肠道 受体鸟苷酸环化酶C(GUCY2C)与胞外结构域上的同源多肽结合，激活一种 细胞内催化结构域，将GTP转化为下游效应物环状GMP。GUCY2C是受体 对于致泻性细菌耐热肠毒素(STS)，以及小鼠的同源激素尿鸟苷 肠道及其受体的激活诱导分泌物(STS的腹泻)。这种分泌物是治疗的基础 新诺明(LINZESS™)，一种ST类似物，或普来卡那肽(Trulance™)，a 尿鸟苷类似物。除了分泌外，GUCY2C激动剂还可以缓解DBGI患者和啮齿动物的疼痛，减少 结直肠扩张(CRD)产生的内脏伤害性感觉。而通过激动剂缓解内脏疼痛是通过 在GUCY2C中，VH的机制及其在VH病理生理学中的作用尚不清楚。有趣的是，GUCY2C 激动剂的配方仅限于小肠活动。我们最近的研究表明，DBGI患者 随着VH失去尿鸟苷，GUCY2C在小肠中沉默。此外，我们发现GUCY2C是 由与控制肠道脊髓的DRG神经元突触的小肠神经足细胞过度表达 电源线信号。沉默GUCy2C产生的自发VH与炎症产生的VH相同。在……里面 非常一致的是，神经足细胞产生DRG神经元的超兴奋性，这种兴奋性被GUCY2C消除 发信号。这些数据提出了一种新的解剖学假说，在该假说中，小肠中的神经足细胞控制 传入脊髓的DRG神经元的兴奋性，进而抑制来自CRD的伤害性信号。 病理生理学假说认为，DBGI中的VH反映了尿鸟苷脂的缺失，从而沉默了GUC2C 在小肠的神经荚细胞中，扰乱了对DRG神经元兴奋性的控制，从而放大了结肠 伤害性感受。治疗假说认为GUCY2C-cGMP信号可以选择性扩增 仅在神经荚中，而不是其他肠道细胞，抑制控制内脏疼痛的神经元兴奋性，而不是 产生分泌物和腹泻，这是口服GUCY2C激动剂的主要治疗限制。建议的研究 将定义一种新的肠道-脊髓轴的关键要素，在该轴中，GUCY2C通过神经荚驱动神经传递 小肠细胞调节神经元兴奋性，控制结肠直肠内脏痛。潜在的 将这些见解转化为VH靶向神经足细胞以最大限度地发挥止痛作用的新治疗范例， 但最大限度地减少腹泻，突出表现在口服GUCY2C激动剂可用于治疗便秘。

Visceral hypersensitivity (VH) and pain in disorders of gut-brain interaction (DGBI), like constipation-type irritable bowel syndrome (IBS-C) or chronic idiopathic constipation (CIC), afflicts >10% of the population with reducing quality of life at a cost of ~$30B/y in the U.S. The etiology of VH in DBGI is not known. VH reflects recruitment of silent dorsal root ganglia (DRG) visceral afferents, reducing their threshold to fire, and increasing their rate of firing, action potentials. Current analgesics, including non-steroidal anti-inflammatory drugs and opiates, are inadequate, with poor efficacy and side effects, highlighting the clinical need for novel therapeutics. The intestinal receptor guanylyl cyclase C (GUCY2C) binds cognate peptides at the extracellular domain that activate an intracellular catalytic domain, converting GTP to cyclic GMP, the downstream effector. GUCY2C is the receptor for diarrheagenic bacterial heat-stable enterotoxins (STs), and the homologous hormone uroguanylin in small intestine and their receptor activation induces secretion (diarrhea for STs). This secretion is the basis for treating DBGI constipation syndromes with linaclotide (Linzess™), an ST analog, or plecanatide (Trulance™), a uroguanylin analog. Beyond secretion, GUCY2C agonists relieve pain in DBGI patients and rodents, reducing visceral nociception produced by colorectal distension (CRD). While visceral pain relief by agonists is mediated by GUCY2C, mechanisms, and their role in the pathophysiology of VH, are unknown. Interestingly, GUCY2C agonists are formulated for activity confined to small intestine. Our recent studies revealed that DBGI patients with VH lose uroguanylin, silencing GUCY2C in small intestine. Additionally, we discovered that GUCY2C is over-expressed by small intestine neuropod cells, which synapse with DRG neurons controlling gut-spinal cord signaling. Silencing GUCY2C produced spontaneous VH identical to that produced by inflammation. In close agreement, neuropod cells produce DRG neuron hyperexcitability which is eliminated by GUCY2C signaling. These data suggest a novel Anatomical Hypothesis in which neuropod cells in small intestine control the excitability of DRG neurons afferent to the spinal cord which, in turn, inhibit nociceptive signaling from CRD. The Pathophysiological Hypothesis suggests that VH in DBGI reflects uroguanylin loss, silencing GUCY2C in neuropod cells in small intestine, disrupting the control of DRG neuron excitability which amplifies colorectal nociception. The Therapeutic Hypothesis suggests that GUCY2C-cGMP signaling can be selectively amplified only in neuropod, but not other intestinal, cells to suppress neuron excitability controlling visceral pain without producing secretion and diarrhea, the major therapeutic limitation to oral GUCY2C agonists. Proposed studies will define key elements of a new gut-spinal cord axis in which GUCY2C drives neurotransmission by neuropod cells in small intestine to regulate neuron excitability controlling visceral pain in the colorectum. The potential to translate these insights into new therapeutic paradigms for VH targeting neuropod cells to maximize analgesia, but minimize diarrhea, is highlighted by the availability of oral GUCY2C agonists to treat constipation.