Pain and Endometriosis: Effects on Ectopic Cyst Innervation and Axons

疼痛和子宫内膜异位症：对异位囊肿神经支配和轴突的影响

• 批准号: 8008959
• 负责人: GEOFFREY M BOVE
• 金额: $ 14.93万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8008959
• 关键词: Axon; Cyst; Pain; endometriosis; nerve supply

DESCRIPTION (provided by applicant): Women with endometriosis often have significant pain. Modern studies have implicated the neo-innervation of endometrial cysts as a primary source of this pain. However, the presence of nerve fibers does not necessarily specify their function and cannot determine whether, or in which situations, they are active. There has been no investigation to functionally characterize the effect of endometrial lesions on nerves or on axons. Our laboratory has focused on the effects of inflammation on axons. We have shown that nerve inflammation induces ectopic mechanical sensitivity of nociceptor axons, which are not normally sensitive. Our data also indicate that nerve inflammation induces ongoing activity that arises from both the inflamed site and / or the cell body, and that sympathetic neuronal activity is decreased during nerve inflammation. Recently we adapted the model of rat endometriosis to involve the sciatic nerve. This model is very similar to the rat endometriosis model where a section of uterus is transplanted to a intraperitoneal site. In preliminary data, a uterine section was transplanted to the sciatic nerve. Three complimentary electrophysiological methods are proposed to determine the characteristics of the effect of uterus, endometrium, and myometrium on the sciatic nerve. First, the proportion of through-conducting axons will be determined. Then, teased fiber recordings will be made from the dorsal roots in some experiments and from the distal end of peripheral nerves in other experiments. This combination of methods offers the advantage that sensory and sympathetic axons that pass through the cyst, as well as those innervating the cyst, can be studied. We will determine if the axons passing in close proximity to the cyst or directly innervating the cyst develop ongoing activity and / or mechanical sensitivity. Recordings will be made 3 months post surgically, after the cysts become stable, and the results compared to myometrium or fat transplant, and unoperated nerves. Because preliminary results revealed the presence of intraneural immune cells, we will determine whether the lesions of endometriosis damage axons. Importantly, we will use not only full thickness uterus, but also isolated endometrium and myometrium, and evaluate the viability of these specific tissues to form cysts. Using immunohistological methods, we will determine the extent of neutrophil and macrophage invasion of the nerve-uterus complex. We will also determine if axons are damaged using ninjurin and fluoro-jade, assessing the presence in both axons and dorsal root ganglion cells. These studies will determine the function and thus the importance of the ectopic innervation of endometrial cysts, as well as the effects of the lesions on through-conducting axons. The results of this study will impacts the understanding of endometriosis pain and seed further research into the pain mechanisms of endometriosis. PUBLIC HEALTH RELEVANCE: In these studies we plan to develop our recently developed model of sciatic endometriosis to make novel inquiries regarding the etiology of endometriosis-related pain. The information that this study will yield stands to improve diagnostic awareness and mechanistic understanding, and thus therapeutic approaches, of the treatment of the symptoms of endometriosis. As a result of this research, consideration and specific examination of nerves within the pelvis during ablative laparoscopic techniques may become an important additional diagnostic procedure for women with endometriosis.

描述（由申请人提供）：子宫内膜异位症的妇女通常会出现明显的疼痛。现代研究暗示了子宫内膜囊肿的新作用是这种疼痛的主要来源。但是，神经纤维的存在并不一定指定其功能，无法确定它们是否处于活动状态。尚无研究在功能上表征子宫内膜病变对神经或轴突的影响。我们的实验室专注于炎症对轴突的影响。我们已经表明，神经炎症会诱导不敏感的伤害感受器轴突的异位机械灵敏度。我们的数据还表明，神经炎症会引起持续的活性，这是由发炎的部位和 /或细胞体引起的，并且在神经炎症过程中这种交感神经活性降低。最近，我们调整了大鼠子宫内膜异位症的模型，以涉及坐骨神经。该模型与大鼠子宫内膜异位症模型非常相似，其中子宫的一部分被移植到腹膜内部位。在初步数据中，子宫截面被移植到坐骨神经。 提出了三种免费电生理方法来确定子宫，子宫内膜和子宫肌对坐骨神经的影响的特征。首先，将确定通过传导轴突的比例。然后，在某些实验中，在其他实验中，将从背根和外周神经的远端进行嘲笑的纤维记录。这种方法的组合提供了一个优势，即可以研究通过囊肿的感觉和交感轴突以及工具支配囊肿的轴突。我们将确定轴突是否靠近囊肿或直接支配囊肿会发展出持续的活性和 /或机械灵敏度。在囊肿稳定后，手术后3个月将进行记录，并且与肌层或脂肪移植和未经手术的神经相比结果。由于初步结果揭示了内部免疫细胞的存在，因此我们将确定子宫内膜异位症损伤轴突的病变。重要的是，我们不仅将使用全厚子宫，还使用孤立的子宫内膜和子宫骨值，评估这些特定组织的生存能力以形成囊肿。使用免疫组织学方法，我们将确定神经 - 乌特鲁斯复合物的中性粒细胞和巨噬细胞侵袭的程度。我们还将确定轴突是否使用忍者和氟jade损坏了轴突，以评估轴突和背根神经节细胞中的存在。这些研究将确定子宫内膜囊肿异位神经支配的功能和重要性，以及病变对通过导电轴突的影响。这项研究的结果将影响对子宫内膜异位症疼痛的理解，并进一步研究子宫内膜异位症的疼痛机制。 公共卫生相关性：在这些研究中，我们计划开发我们最近开发的坐骨神病子宫内膜异位症模型，以对与子宫内膜异位相关疼痛的病因进行新的询问。这项研究将产生的信息旨在提高对子宫内膜异位症症状治疗的诊断意识和机械理解，从而提高治疗方法。由于这项研究，在消融腹腔镜技术期间对骨盆内神经内神经的考虑和特定检查可能成为子宫内膜异位症女性的重要额外诊断程序。