Singh Prashant, Sayuk Gregory S, Rosenbaum David P, Edelstein Susan, Kozuka Kenji, Chang Lin
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
Clin Exp Gastroenterol. 2024 Apr 10;17:87-96. doi: 10.2147/CEG.S454526. eCollection 2024.
Patients with irritable bowel syndrome with constipation (IBS-C) experience persistent abdominal pain, a common symptom leading to greater healthcare utilization and reports of treatment non-response. Clinically significant improvements in abdominal pain were observed in clinical trials of tenapanor, a first-in-class inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3), for the treatment of IBS-C in adults.
This narrative review reports the current knowledge about visceral hypersensitivity as a mechanism for abdominal pain in patients with IBS-C and explores the published evidence for hypothesized mechanisms by which tenapanor may reduce visceral hypersensitivity leading to the observed clinical response of decreased abdominal pain.
Abdominal pain is experienced through activation and signaling of nociceptive dorsal root ganglia that innervate the gut. These sensory afferent neurons may become hypersensitized through signaling of transient receptor potential cation channel subfamily V member 1 (TRPV1), resulting in reduced action potential thresholds. TRPV1 signaling is also a key component of the proinflammatory cascade involving mast cell responses to macromolecule exposure following permeation through the intestinal epithelium. Indirect evidence of this pathway is supported by observations of higher pain in association with increased intestinal permeability in patients with IBS. Tenapanor reduces intestinal sodium absorption, leading to increased water retention in the intestinal lumen, thereby improving gastrointestinal motility. In animal models of visceral hypersensitivity, tenapanor normalized visceromotor responses and normalized TRPV1-mediated nociceptive signaling.
By improving gastrointestinal motility, decreasing intestinal permeability and inflammation, and normalizing nociception through decreased TRPV1 signaling, tenapanor may reduce visceral hypersensitivity, leading to less abdominal pain in patients with IBS-C. Therapies that have demonstrated effects on visceral hypersensitivity may be the future direction for meaningful abdominal pain relief for patients with IBS-C.
便秘型肠易激综合征（IBS-C）患者会经历持续性腹痛，这是一种常见症状，会导致更高的医疗利用率以及治疗无反应的报告。在一项针对成人IBS-C治疗的临床试验中，一流的钠/氢交换蛋白3（NHE3）抑制剂替那帕诺在腹痛方面显示出具有临床意义的改善。
本叙述性综述报告了关于内脏超敏反应作为IBS-C患者腹痛机制的当前知识，并探讨了已发表的证据，以证明替那帕诺可能通过何种假设机制降低内脏超敏反应，从而导致观察到的腹痛减轻的临床反应。
腹痛是通过支配肠道的伤害性背根神经节的激活和信号传导来感受的。这些感觉传入神经元可能通过瞬时受体电位阳离子通道亚家族V成员1（TRPV1）的信号传导而变得超敏，导致动作电位阈值降低。TRPV1信号传导也是促炎级联反应的关键组成部分，涉及肥大细胞在通过肠上皮渗透后对大分子暴露的反应。IBS患者中与肠道通透性增加相关的更高疼痛观察结果支持了该途径的间接证据。替那帕诺减少肠道钠吸收，导致肠腔内水分潴留增加，从而改善胃肠动力。在内脏超敏反应的动物模型中，替那帕诺使内脏运动反应正常化，并使TRPV1介导的伤害性信号传导正常化。
通过改善胃肠动力、降低肠道通透性和炎症，并通过降低TRPV1信号传导使伤害感受正常化，替那帕诺可能降低内脏超敏反应，从而减轻IBS-C患者的腹痛。已证明对内脏超敏反应有影响的疗法可能是为IBS-C患者缓解有意义的腹痛的未来方向。
