Sexually dimorphic pain signaling mechanisms

摘要 尽管许多人都熟悉惊人的统计数据，高达30%的美国人患有慢性 疼痛，一个鲜为人知的事实是，大多数慢性疼痛患者患有一种以上的共病疼痛 条件疼痛的条件，经常共同聚集已被称为慢性重叠疼痛 条件（COPC）。多种慢性疼痛状况的共同聚集经常导致负面影响 除疼痛外，还包括疲劳、睡眠不足、认知障碍、功能障碍和 心理健康状况，如抑郁，焦虑，甚至自杀意念。考虑到 这些副作用及其对患者健康的影响，COPC的健康结果比 患有单一慢性疼痛病症的患者。此外，大多数个体COPC，如 颞下颌关节紊乱病（TMD）、纤维肌痛（FM）和偏头痛在美国有较高的患病率。 生物学上的女性多于生物学上的男性，并且它们的共聚集性在女性中同样更高。照经上所 迫切需要进行更多的研究调查，探索机械的决定因素 在患有多种共病的患者中， 生物学上的男性和女性。我们已经开发了使用临床，生物学和 将COPC患者分组为不同患者群的心理患者变量：（1）“适应性” 集群，这是免费的超敏反应和心理困扰;（2）一个“疼痛敏感”集群，这有 对疼痛刺激的疼痛敏感性增加，但缺乏疼痛相关的合并症;和（3）“整体症状” 一群患者对疼痛的敏感性增加，沿着多种抑郁症状， 焦虑和其他广泛的症状。通过分离表型不同的COPC患者并分析 这些群体作为单独的实体，分别在男性和女性，我们相信我们可以更好地了解 这些条件，并创造一个更个性化的方法，以病人护理，这将最终改善我们的 治疗患有多种慢性疼痛病症的患者的能力。我们的总体假设是， 集群将表现出更大程度的相似性，在他们的细胞和分子组成相比，患者在 其他集群，我们可以利用这些集群相关的差异，以确定生物标志物和治疗 为每个患者群体提供个性化的治疗方法。为了验证这一假设，我们将采用蛋白质组学， 转录组学和临床前筛选方法，以确定疼痛的分子和细胞介质， 个体患者集群和每个性别。在这样做的过程中，这个项目将产生新的机械见解， 在男性中引起疼痛及其相关合并症的不同病理生理机制， 女性

ABSTRACT Although many people are familiar with the staggering statistic that up to 30% of Americans suffer from chronic pain, a less-known fact is that most individuals with chronic pain suffer from more than one comorbid pain condition. Pain conditions which frequently co-aggregate have come to be known as chronic overlapping pain conditions (COPCs). Co-aggregation of multiple chronic pain conditions frequently results in negative side effects in addition to pain, including fatigue, sleep deficits, cognitive impairment, functional impairment, and mental health conditions such as depression, anxiety, and even suicidal ideation. Given the complexity of these side effects and their impact on patient well-being, COPCs have worse health outcomes compared to patients with a single chronic pain condition. In addition, the majority of individual COPCs such as temporomandibular joint disorders (TMD), fibromyalgia (FM), and migraines have a higher prevalence in biological females than in biological males, and their coaggregation is likewise higher in females. Thus, it is imperative that additional research investigations be undertaken which explores the mechanistic determinants of COPCs in patients with multiple comorbid conditions, and which critically evaluates the underlying mechanisms in biological males and females. We have developed methods that use clinical, biological, and psychological patient variables to group patients with COPCs into distinct patient clusters: (1) an “adaptive” cluster, which is free of hypersensitivity and psychological distress; (2) a “pain-sensitive” cluster, which has increased pain sensitivity to pain stimuli, but lacks pain-related comorbidities; and (3) a “global symptoms” cluster of patients which has increased sensitivity to pain, along with multiple symptoms of depression and anxiety, and other widespread symptoms. By separating phenotypically distinct COPC patients and analyzing these cohorts as separate entities individually in males and females, we believe we can better understand these conditions and create a more personalized approach to patient care, which will ultimately improve our ability to treat patients with multiple chronic pain conditions. Our overall hypothesis is that patients within each cluster will exhibit a greater degree of similarity in their cellular and molecular makeup compared to patients in other clusters, and we can exploit these cluster-related differences to identify biological markers and treatment approaches that are personalized for each patient group. To test this hypothesis, we will employ proteomic, transcriptomic, and preclinical screening approaches to ascertain molecular and cellular mediators of pain in individual patient clusters and in each sex. In doing so, this project will yield new mechanistic insights into the divergent pathophysiological mechanisms that give rise to pain and its associated comorbidities in males and females.