Sexually dimorphic pain signaling mechanisms

摘要 尽管许多人都熟悉一个惊人的统计数据，高达30%的美国人患有慢性病 疼痛，一个鲜为人知的事实是，大多数慢性疼痛患者都患有不止一种并存的疼痛 条件。经常共同聚集的疼痛状况被称为慢性重叠疼痛 条件(COPC)。多种慢性疼痛情况的共同聚集经常会导致负面影响 除疼痛外的影响，包括疲劳、睡眠不足、认知障碍、功能障碍和 精神健康状况，如抑郁、焦虑，甚至有自杀念头。鉴于……的复杂性 这些副作用及其对患者福祉的影响，COPC的健康结果比 有单一慢性疼痛状况的患者。此外，大多数独立的COPC，如 颞下颌关节紊乱病(TMD)、纤维肌痛(FM)和偏头痛在 生物雌性比生物雄性高，它们的共聚性在雌性中也更高。因此，它是 必须进行更多的研究调查，以探索机械性决定因素 在患有多种并存疾病的患者中检测COPC，并对潜在的 生理上的男性和女性的机制。我们已经开发出使用临床、生物学和 将COPC患者分组为不同的患者群的心理患者变量：(1)“适应性” 没有过敏性和心理困扰的集群；(2)具有 增加疼痛对疼痛刺激的敏感性，但缺乏与疼痛相关的合并症；以及(3)“全球症状” 患者对疼痛的敏感度增加，并伴有多种抑郁症状和 焦虑，以及其他普遍的症状。通过分离表型不同的COPC患者并分析 这些队列作为单独的实体存在于男性和女性中，我们相信我们可以更好地理解 并创建更个性化的患者护理方法，这最终将改善我们的 能够治疗患有多种慢性疼痛的患者。我们的总体假设是，每个患者 与患者相比，集群在细胞和分子组成上显示出更大的相似性 其他集群，我们可以利用这些集群相关的差异来识别生物标记和治疗 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，我们将使用蛋白质组学， 转录学和临床前筛选方法确定疼痛的分子和细胞介质 不同性别的个体患者聚集在一起。在这样做的过程中，这个项目将产生对 引起男性和女性疼痛及其相关并存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.