The impact of hormonal modulation on systemic inflammation and central sensitization

激素调节对全身炎症和中枢敏化的影响

• 批准号: 10584701
• 负责人: Sawsan As-Sanie
• 金额: $ 66.3万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584701
• 关键词: Affect; Aftercare; Analgesics; Attenuated; Biology; Brain; Central Nervous System; Clinical; Clinical Trials; Complex; Data; Disease; Disease model; Dose; Double-Blind Method; Economics; Estradiol; Estrogens; Evaluation; FDA approved; Fatigue; Female; Functional Magnetic Resonance Imaging; Gonadotropin-Releasing Hormone Receptor; Gynecologic; Hormonal; Hormones; Hypersensitivity; Hysterectomy; Inflammation; Inflammatory; Interstitial Cystitis; Intervention; Irritable Bowel Syndrome; Lesion; Measures; Mediating; Medical; Migraine; Neurobiology; Outcome; Pain; Pathway interactions; Patients; Pelvic Pain; Pelvis; Peripheral; Pharmaceutical Preparations; Phenotype; Placebos; Positioning Attribute; Randomized; Reproductive Biology; Research Personnel; Risk Factors; Severities; Severity of illness; Stimulus; Symptoms; Syndrome; Testing; Treatment outcome; United States; Vulnerable Populations; Woman; Work; antagonist; associated symptom; central sensitization; chronic pain; chronic pelvic pain; clinical phenotype; clinical practice; comorbidity; cost; dosage; endometriosis; experience; improved; neurobiological mechanism; pain model; pain relief; predicting response; randomized placebo-controlled clinical trial; randomized, clinical trials; recruit; response; systemic inflammatory response; treatment effect; treatment strategy

Abstract. Chronic pelvic pain remains a challenging condition to treat, in large part because underlying disease mechanisms are poorly understood. Endometriosis-associated pelvic pain (EAPP) is a common form of CPP wherein the severity of disease is only weakly associated with the degree of pain experienced. While pelvic inflammation is a well-established contributing factor to EAPP, we propose that low-grade systemic inflammation also contributes to the disease state by promoting central nervous system (CNS) sensitization. Emerging evidence from our group and others suggests that low-grade systemic inflammation can promote multiple aspects of CNS sensitization including clinical manifestations (comorbid pain conditions, widespread pain), hypersensitivity to experimental stimuli, and altered brain functional connectivity in pelvic pain. While hormonal suppression is effective for many women, and acts in part by dampening estradiol-dependent pelvic inflammation, little is known about the relative contributions of low-grade systemic inflammation and CNS sensitization to EAPP. We propose to use the FDA-approved, gonadotropin releasing hormone receptor antagonist, elagolix, available in two dosages, as a mechanistic probe to assess the effects of pelvic and systemic inflammation on EAPP. The presence of robust dose-dependent effects on EAPP and its comorbid symptoms suggests to us that the higher dose also reduces CNS sensitization, possibly due to reduced systemic inflammation. To investigate this hypothesis, we will conduct a double-blind, placebo controlled randomized clinical trial in which 200 women with EAPP will be randomly assigned to low-dose (150mg daily) or high-dose (400mg daily) elagolix or placebo with evaluation of pain mechanism outcomes prior to and after treatment. We will focus on two common patient phenotypes – those with EAPP only and those with EAPP and widespread pain (1:1 recruitment). In Aim 1, we will first define the relationship between pelvic inflammation, systemic inflammation, and CNS sensitization using well-vetted neurobiological measures of CNS sensitization. We anticipate that systemic inflammation will be associated with CNS sensitization, while pelvic inflammation will not be. In Aim 2, we will identify dose-dependent changes in CNS sensitization as well as systemic and pelvic inflammation during hormonal suppression for EAPP through the above-described clinical trial. We anticipate that both dosages will improve pelvic inflammation, but that systemic inflammation and CNS sensitization will be improved on high-dose elagolix. We furthermore anticipate that those with widespread pain will be more likely to respond to high-dose elagolix. In an exploratory Aim 3, we will determine if baseline levels of pelvic and/or systemic inflammatory activity, as well as CNS sensitization, predict the response to elagolix. These studies are critical to develop alternative mechanistic models of pain promotion and relief in this vulnerable group of patients and will have implications for understanding hormonal contributions to the female preponderance of chronic pain syndromes.

抽象的。慢性骨盆疼痛仍然是治疗的挑战条件，在很大程度上是因为基础 疾病机制知之甚少。子宫内膜异位相关的骨盆疼痛（EAPP）是一种常见形式 CPP的疾病严重程度仅与经历的疼痛程度微弱相关。尽管 骨盆炎症是EAPP的一个完善的促成因素，我们建议低级系统性 炎症还通过促进中枢神经系统（CNS）敏感性来促进疾病状态。 来自我们小组和其他人的新兴证据表明，低度的系统性炎症可以促进 中枢神经系统敏感性的多个方面包括临床表现（合并症条件，宽度 疼痛），对实验刺激的超敏反应以及骨盆疼痛中大脑功能连通性的改变。 马抑制对许多女性有效，并且部分作用是通过使雌二醇依赖性骨盆染色 炎症，对低度全身注射和CNS的相对贡献知之甚少 对EAPP的敏感。我们建议使用FDA批准的，促性腺激素释放的马赛酮接收器 拮抗剂，Elagolix，有两次剂量，作为一种机械探针，以评估骨盆和 EAPP上的系统性炎症。对EAPP及其合并症的剂量依赖性作用有强大的效果 症状向我们表明，较高剂量还会降低中枢神经系统的敏感性，这可能会降低 系统性保险。为了研究这一假设，我们将进行双盲，安慰剂控制 随机临床试验，其中200名EAPP女性将随机分配给低剂量（每天150mg） 或高剂量（每天400毫克）Elagolix或安慰剂，并在疼痛机制结局之前和之后评估 治疗。我们将专注于两种常见的患者表型 - 仅具有EAPP的患者和EAPP的表型 和宽度疼痛（1：1招募）。在AIM 1中，我们将首先定义骨盆之间的关系 使用精心看见的神经生物学测度的炎症，全身炎症和中枢神经系统敏感 CNS灵敏度。我们预计系统性炎症将与中枢神经系统的敏感性有关，而 骨盆炎症不会。在AIM 2中，我们还将确定CNS灵敏度的剂量依赖性变化 作为在EAPP的激素抑制期间的全身和骨盆注射。 临床试验。我们预计这两种剂量都会改善骨盆注射，但是全身注射 高剂量elagolix将提高CNS敏感性。我们还期望那些与 宽度疼痛将更有可能对高剂量的eelagolix做出反应。在探索性目标3中，我们将 确定骨盆和/或全身性炎症活性的基线水平以及CNS敏感性， 预测对Elagolix的反应。这些研究对于开发疼痛的替代机械模型至关重要 在这一脆弱的患者组中促进和缓解，将对理解马有影响 对慢性疼痛综合征的女性优势的贡献。