Coates Matthew D, Walter Vonn, Stuart August, Small Jeffrey, Dalessio Shannon, Carkaci-Salli Nurgul, Ouyang Ann, Clarke Kofi, Tinsley Andrew, Williams Emmanuelle D, Janicki Piotr, Ruiz-Velasco Victor, Vrana Kent E
Department of Medicine, Division of Gastroenterology & Hepatology, Penn State Hershey Medical Center, Hershey, Pennsylvania, USA.
Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, USA.
Clin Transl Gastroenterol. 2024 Dec 1;15(12):e00778. doi: 10.14309/ctg.0000000000000778.
Hypoalgesic inflammatory bowel disease (IBD) may provide critical insights into human abdominal pain. This condition was previously associated with homozygosity for a polymorphism (rs6795970, A1073V; 1073 val/val ) related to Na v 1.8, a voltage-gated sodium channel preferentially expressed on nociceptors. It was unclear whether this relationship existed for both Crohn's disease (CD) and ulcerative colitis (UC). This study evaluated a larger, carefully phenotyped IBD cohort to investigate this question.
Allelic and genotypic frequencies of rs6795970 were compared among study cohorts characterized by concomitant assessment of intestinal inflammatory status and abdominal pain experience. Visceral sensory perception was performed in healthy individuals using rectal balloon distension.
We analyzed 416 patients with IBD (261CD:155UC) and 142 healthy controls. In the IBD cohort, 84 individuals (43CD:41UC) were determined to have hypoalgesic disease. The allelic frequency of rs6795970 was significantly higher in patients with hypoalgesic IBD when compared with other patients with IBD and healthy controls. Patients with hypoalgesic IBD were also more likely to be homozygous for this polymorphism when compared with other patients with IBD and healthy controls. Hypoalgesic CD (30% vs 12%, P = 0.004) and hypoalgesic UC (32% vs 15%, P = 0.036) were each significantly more likely to be associated with homozygosity for the rs6795970 polymorphism. In a cohort of healthy individuals (n = 50), rs6795970 homozygotes (n = 11) also demonstrated reduced abdominal discomfort to rectal balloon distension.
These findings indicate that Na v 1.8 plays a key role in human visceral pain perception, and could serve as a novel diagnostic target in the management of hypoalgesic CD and UC, and potential therapeutic target for conditions associated with chronic abdominal pain.
痛觉减退型炎症性肠病（IBD）可能为人类腹痛提供重要见解。这种情况以前与一种与Nav1.8相关的多态性（rs6795970，A1073V；1073缬氨酸/缬氨酸）的纯合性有关，Nav1.8是一种在伤害感受器上优先表达的电压门控钠通道。尚不清楚这种关系在克罗恩病（CD）和溃疡性结肠炎（UC）中是否都存在。本研究评估了一个更大的、经过仔细表型分析的IBD队列来研究这个问题。
在以肠道炎症状态和腹痛经历的同步评估为特征的研究队列中比较rs6795970的等位基因和基因型频率。在健康个体中使用直肠气囊扩张进行内脏感觉知觉测试。
我们分析了416例IBD患者（261例CD：155例UC）和142例健康对照。在IBD队列中，84人（43例CD：41例UC）被确定患有痛觉减退型疾病。与其他IBD患者和健康对照相比，痛觉减退型IBD患者中rs6795970的等位基因频率显著更高。与其他IBD患者和健康对照相比，痛觉减退型IBD患者也更有可能是这种多态性的纯合子。痛觉减退型CD（30%对12%，P = 0.004）和痛觉减退型UC（32%对15%，P = 0.036）各自与rs6795970多态性的纯合性显著更相关。在一组健康个体（n = 50）中，rs6795970纯合子（n = 11）对直肠气囊扩张的腹部不适也有所减轻。
这些发现表明Nav1.8在人类内脏痛觉感知中起关键作用，并且可作为痛觉减退型CD和UC管理中的一个新的诊断靶点，以及与慢性腹痛相关病症的潜在治疗靶点。
