Département de Physiologie, Institut de Génomique Fonctionnelle, 34094 Montpellier, France.
Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11268-73. doi: 10.1073/pnas.1100869108. Epub 2011 Jun 20.
The symptoms of irritable bowel syndrome (IBS) include significant abdominal pain and bloating. Current treatments are empirical and often poorly efficacious, and there is a need for the development of new and efficient analgesics aimed at IBS patients. T-type calcium channels have previously been validated as a potential target to treat certain neuropathic pain pathologies. Here we report that T-type calcium channels encoded by the Ca(V)3.2 isoform are expressed in colonic nociceptive primary afferent neurons and that they contribute to the exaggerated pain perception in a butyrate-mediated rodent model of IBS. Both the selective genetic inhibition of Ca(V)3.2 channels and pharmacological blockade with calcium channel antagonists attenuates IBS-like painful symptoms. Mechanistically, butyrate acts to promote the increased insertion of Ca(V)3.2 channels into primary sensory neuron membranes, likely via a posttranslational effect. The butyrate-mediated regulation can be recapitulated with recombinant Ca(V)3.2 channels expressed in HEK cells and may provide a convenient in vitro screening system for the identification of T-type channel blockers relevant to visceral pain. These results implicate T-type calcium channels in the pathophysiology of chronic visceral pain and suggest Ca(V)3.2 as a promising target for the development of efficient analgesics for the visceral discomfort and pain associated with IBS.
肠易激综合征(IBS)的症状包括明显的腹痛和腹胀。目前的治疗方法是经验性的,往往效果不佳,因此需要开发针对 IBS 患者的新型有效镇痛药。T 型钙通道以前被验证为治疗某些神经性疼痛病理的潜在靶点。在这里,我们报告 Ca(V)3.2 异构体编码的 T 型钙通道在结肠伤害性初级传入神经元中表达,并且它们有助于丁酸介导的 IBS 啮齿动物模型中过度的疼痛感知。选择性 Ca(V)3.2 通道遗传抑制和钙通道拮抗剂的药理学阻断均可减轻 IBS 样疼痛症状。从机制上讲,丁酸通过翻译后效应促进 Ca(V)3.2 通道向初级感觉神经元膜的插入增加。丁酸介导的调节可以用在 HEK 细胞中表达的重组 Ca(V)3.2 通道再现,并且可能为鉴定与内脏疼痛相关的 T 型通道阻滞剂提供方便的体外筛选系统。这些结果表明 T 型钙通道参与慢性内脏疼痛的病理生理学,并表明 Ca(V)3.2 是开发针对与 IBS 相关的内脏不适和疼痛的有效镇痛药的有前途的靶标。