Greco Céline, Basso Lilian, Désormeaux Cléo, Fournel Audren, Demuynck Benedicte, Lafendi Leila, Chapiro Sylvie, Lemoine Antoinette, Zhu Ying-Ying, Knauf Claude, Cenac Nicolas, Boucheix Claude, Dietrich Gilles
UMR-S935, INSERM, Univ. Paris-Sud, Université Paris Saclay, Villejuif, France.
Department of Pain Management and Palliative Care, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
Front Pain Res (Lausanne). 2021 Feb 11;2:613187. doi: 10.3389/fpain.2021.613187. eCollection 2021.
Peritoneal carcinomatosis often results in alterations in intestinal peristalsis and recurrent abdominal pain. Pain management in these patients is often unsatisfactory. This study aimed to investigate whether endothelin-1 (EDN1) was involved in pain mediation in peritoneal carcinomatosis, and thus whether the EDN1 pathway could be a new therapeutic target for peritoneal carcinomatosis-associated pain. EDN1 plasma levels and abdominal pain severity were assessed in patients with abdominal tumors, with or without peritoneal carcinomatosis, and in healthy donors. The effects of EDN1 on the visceromotor response to colorectal distension, and on colonic contractions were then examined in mice, and the mechanism of action of EDN1 was then investigated by measuring the impact of EDN1 exposure on calcium mobilization in cultured neurons. Inhibition studies were also performed to determine if the effects of EDN1 exposure could be reversed by EDN1-specific receptor antagonists. A positive correlation between EDN1 plasma levels and abdominal pain was identified in patients with peritoneal carcinomatosis. EDN1 exposure increased visceral sensitivity and the amplitude of colonic contractions in mice and induced calcium mobilization by direct binding to its receptors on sensory neurons. The effects of EDN1 were inhibited by antagonists of the EDN1 receptors. This preliminary study, using data from patients with peritoneal carcinomatosis combined with data from experiments performed in mice, suggests that EDN1 may play a key role mediating pain in peritoneal carcinomatosis. Our findings suggest that antagonists of the EDN1 receptors might be beneficial in the management of pain in patients with peritoneal carcinomatosis.
腹膜癌病常导致肠道蠕动改变和反复腹痛。这些患者的疼痛管理往往不尽人意。本研究旨在调查内皮素-1（EDN1）是否参与腹膜癌病的疼痛介导，以及EDN1通路是否可能成为腹膜癌病相关疼痛的新治疗靶点。对患有腹部肿瘤、有或没有腹膜癌病的患者以及健康供体评估EDN1血浆水平和腹痛严重程度。然后在小鼠中检查EDN1对结肠扩张内脏运动反应和结肠收缩的影响，并通过测量EDN1暴露对培养神经元钙动员的影响来研究EDN1的作用机制。还进行了抑制研究，以确定EDN1特异性受体拮抗剂是否可以逆转EDN1暴露的影响。在腹膜癌病患者中发现EDN1血浆水平与腹痛之间存在正相关。EDN1暴露增加了小鼠的内脏敏感性和结肠收缩幅度，并通过直接与其感觉神经元上的受体结合诱导钙动员。EDN1的作用被EDN1受体拮抗剂抑制。这项初步研究结合腹膜癌病患者的数据和在小鼠中进行的实验数据表明，EDN1可能在腹膜癌病的疼痛介导中起关键作用。我们的研究结果表明，EDN1受体拮抗剂可能对腹膜癌病患者的疼痛管理有益。
