Interaction of sex effects and intervertebral disc degeneration in a rat model of chronic back pain pathogenesis

椎间盘退行性变是一种衰弱的疾病，与慢性低血压的发病机制有关。 背痛是全球残疾的主要原因，也是美国阿片类药物危机的原因之一。然而， IVD变性与导致慢性腰痛的神经系统之间的相互作用不是很好 明白了。此外，尽管脊柱损伤和慢性疼痛在女性中更常见， 几乎没有研究检验性行为对IVD之间关系的可能影响 慢性腰背痛的背景是退行性变和神经系统的改变。该计划的总体目标 拟议的研究是为了确定IVD退变、跨感觉方式的疼痛和神经系统 基因表达变化在慢性下腰痛发病机制中的相互作用，以及这些变化是如何复杂的 男性和女性之间的关系可能不同。拟议的研究应用了一种独特的老鼠模型来识别 慢性下腰痛非阿片类药物治疗的新靶点，可能使更精确的治疗 针对慢性下腰痛的病理变化，没有阿片类药物使用的风险。目标1将 确定性别和IVD损伤如何在结构、形态和生物力学诱导中相互作用 退行性变中IVD的变化。目标2通过测试在行为水平上测量疼痛的性别差异 用于多种感觉方式下疼痛敏感性的变化。目标3评估转录水平 神经系统的变化，这些变化可能在AIM 2中测量的疼痛敏感性中发挥重要作用 以确定可能的治疗靶点。这个项目意义重大，因为它具有翻译的潜力 具有高度临床意义的间盘源性背痛问题。这种方法是创新的，因为它 探讨性别对腰间盘源性慢性腰痛发病机制的影响 损伤和退化。提高了对性别对椎间结构影响的理解， 形态学和生物力学，以及它们可能通过什么分子途径诱导慢性疼痛状态 神经系统可能会有更好的靶向治疗，以取代阿片类止痛剂治疗慢性低血压 背部疼痛。这些知识将对骨科、神经科学和 医学，因为澄清这些相互作用可能会改进目前的治疗方法，减少全球因 慢性背部疼痛。这项奖学金申请还将资助一位非常有前途的临床医生的医学/博士研究- 致力于应用补充和综合卫生战略进行管理的科学家 慢性腰背痛。

Intervertebral disc (IVD) degeneration is a debilitating disorder implicated in the pathogenesis of chronic low back pain, a leading cause of global disability and a contributor to the opioid crisis in the USA. However, the interaction between IVD degeneration and the nervous system that leads to chronic low back pain is not well understood. Further, while both spine impairments and chronic pain conditions are more common in women, there are almost no studies examining the possible effects of sex on the relationship between IVD degeneration and nervous system changes in the setting of chronic low back pain. The overall goal of the proposed research is to determine how IVD degeneration, pain across sensory modalities, and nervous system gene expression changes interact in the pathogenesis of chronic low back pain, and how these complicated relationships may differ between males and females. The proposed studies apply a unique rat model to identify novel targets for non-opioid therapies for chronic low back pain, that may enable more precise therapeutic targeting of the pathologic changes in chronic low back pain, without the risks of opioid usage. Aim 1 will determine how sex and IVD injury interact in the induction of structural, morphological, and biomechanical changes in the IVD in degeneration. Aim 2 measures sex differences in pain at the behavioral level by testing for changes in pain sensitivity across multiple sensory modalities. Aim 3 evaluates the transcription-level changes in the nervous system that likely play a significant role in the pain sensitivity measured in Aim 2, in order to identify possible therapeutic targets. This project is significant because of the translational potential to the highly clinically significant problem of discogenic back pain. The approach is innovative because it investigates the influence of sex on the pathogenesis of chronic back pain originating from intervertebral disc injury and degeneration. Improved understanding of the influence of sex on intervertebral structure, morphology, and biomechanics, and via what molecular pathways they may induce a chronic pain state in the nervous system may enable better-targeted therapies to replace the use of opioid analgesics for chronic low back pain. Such knowledge would be highly significant to the fields of orthopaedics, neuroscience, and medicine, as clarifying these interactions may improve current treatments and reduce the global suffering from chronic back pain. This fellowship application will also fund MD/PhD studies of a highly promising clinician- scientist with commitment to the application of complementary and integrative health strategies to manage chronic low back pain.