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: 7797815
• 负责人: GEOFFREY M BOVE
• 金额: $ 5.37万
• 依托单位: UNIVERSITY OF SOUTHERN MAINE
• 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/7797815
• 关键词: Abdominal Cavity; Action Potentials; Address; Affect; Awareness; Axon; Cells; Characteristics; Chemicals; Complex; Cyst; Data; Development; Diagnostic; Diagnostic Procedure; Distal; Electrodes; Endometrial; Endometrial Cyst; Endometrium; Etiology; Evaluation; Fatty acid glycerol esters; Fiber; Foundations; Human; Immune; Inflammation; Intervention; Investigation; Knowledge; Laboratories; Lead; Lesion; Light; Mechanics; Mediating; Methods; Modality; Modeling; Myometrial; Nerve; Nerve Fibers; Neuritis; Neurons; Nociceptors; Outcome; Pain; Pelvis; Peripheral; Peripheral Nerves; Peritoneum; Rattus; Research; Seeds; Sensory; Side; Site; Source; Specific qualifier value; Spinal Ganglia; Stimulus; Symptoms; Techniques; Testing; Therapeutic; Thick; Tissue Harvesting; Tissue Transplantation; Tissues; Transplantation; Tyrosine 3-Monooxygenase; Uterus; Vascularization; Vasomotor; Woman; endometriosis; fluoro jade; ganglion cell; implantation; improved; intraperitoneal; macrophage; myometrium; nerve supply; neuronal cell body; neutrophil; novel; peripherin; public health relevance; research study; sciatic nerve; spinal nerve posterior root

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往往有显着的疼痛。现代研究表明，子宫内膜囊肿的神经支配是这种疼痛的主要来源。然而，神经纤维的存在并不一定说明它们的功能，也不能确定它们是否或在哪些情况下是活跃的。目前还没有研究子宫内膜病变对神经或轴突的影响的功能特征。我们的实验室专注于炎症对轴突的影响。我们已经表明，神经炎症诱导异位机械敏感性的伤害感受器轴突，这是不正常的敏感性。我们的数据还表明，神经炎症诱导正在进行的活动，所产生的发炎部位和/或细胞体，和交感神经元的活动减少在神经炎症。最近，我们调整了大鼠子宫内膜异位症模型，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，其中将子宫的一部分移植到腹膜内部位。在初步数据中，将子宫切片移植到坐骨神经。 提出了三种互补的电生理方法来确定子宫、子宫内膜和子宫肌层对坐骨神经的影响的特征。首先，将确定贯穿传导轴突的比例。然后，在一些实验中，从背根进行梳理纤维记录，在其他实验中，从周围神经的远端进行梳理纤维记录。这种方法的组合提供的优点是，可以研究穿过囊肿的感觉和交感神经轴突，以及支配囊肿的轴突。我们将确定是否在接近囊肿或直接支配囊肿的轴突发展持续的活动和/或机械敏感性。记录将在手术后3个月，囊肿变得稳定后进行，并将结果与子宫肌层或脂肪移植和未手术的神经进行比较。由于初步结果显示存在神经内免疫细胞，我们将确定子宫内膜异位症的病变是否损害轴突。重要的是，我们将不仅使用全层子宫，而且使用离体子宫内膜和子宫肌层，并评估这些特定组织形成囊肿的可行性。使用免疫组织学方法，我们将确定中性粒细胞和巨噬细胞浸润的神经子宫复合体的程度。我们还将使用ninjurin和fluoro-jade确定轴突是否受损，评估轴突和背根神经节细胞中的存在。这些研究将确定功能，从而异位神经支配的子宫内膜囊肿的重要性，以及病变的影响，通过传导轴突。本研究的结果将影响对子宫内膜异位症疼痛的理解，并为子宫内膜异位症疼痛机制的进一步研究奠定基础。 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经子宫内膜异位症模型，以进行关于子宫内膜异位症相关疼痛病因的新研究。本研究将产生的信息有助于提高对子宫内膜异位症症状的诊断意识和机制理解，从而提高治疗方法。作为这项研究的结果，考虑和具体检查盆腔内的神经在消融腹腔镜技术可能成为一个重要的额外的诊断程序的妇女子宫内膜异位症。