The Role of Testosterone on Mediating Sex and Gender Influences on Chronic Orofacial Pain Conditions

睾酮在调节性别和性别对慢性口面部疼痛的影响中的作用

• 批准号: 10755148
• 负责人: Joyce Teixeira Da Silva
• 金额: $ 47.14万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755148
• 关键词: Affect; Androgen Receptor; Animals; Anterior; Antiandrogen Therapy; Attenuated; Behavioral Paradigm; Biological Assay; Brain; Brain region; Burning Mouth Syndrome; Chronic; Clinical; Combined Modality Therapy; Data; Development; Disease; Evidence based treatment; Female; Functional Magnetic Resonance Imaging; Functional disorder; Gender; Genetic; High Prevalence; Human; Hypersensitivity; Incidence; Individual; Irritable Bowel Syndrome; Knowledge; Link; Measures; Mediating; Migraine; Modeling; Neurobiology; Neurons; Orofacial Pain; Outcome; Pain; Pain Disorder; Pain Measurement; Pain management; Play; Pre-Clinical Model; Prevalence; Property; Psychophysics; Rattus; Rest; Risk; Risk Factors; Role; Severities; Sex Differences; System; TMD treatment; Temporomandibular Joint Disorders; Testing; Testosterone; Therapeutic; Visceral; Woman; Work; antinociception; central pain; chronic painful condition; cingulate cortex; cisgender; clinical pain; comorbidity; conditioned pain modulation; craniofacial; diffuse noxious inhibitory control; evidence base; gender difference; gender transition; genetic manipulation; hormone therapy; improved; indexing; insight; male; men; midbrain central gray substance; neural circuit; novel; pain inhibition; pain outcome; pain processing; pharmacologic; pre-clinical; response; scale up; sex; transgender; treatment response; treatment strategy

ABSTRACT AND PROJECT SUMMARY Many chronic pain conditions that affect craniofacial regions, such as temporomandibular disorders (TMD), disproportionately affect females. A growing number of studies show strong evidence that sex-related differences in conditioned pain modulation (CPM), a psychophysical index of endogenous pain inhibition, is one mechanism that predisposes women to an increased risk of chronic pain conditions. However, the central mechanisms underlying gender differences in CPM, as well as causal links between dysfunctional CPM and chronic orofacial pain conditions, are largely unknown. Our prior work has shown that there are sex differences in descending noxious inhibitory control (DNIC), a measure that is similar to CPM in preclinical settings, and that DNIC is modulated in a testosterone (TS)-dependent manner. The efficiency of DNIC was stronger in males compared to females. A pharmacological blockade of androgen receptors attenuated DNIC in males, and TS replacement enhanced DNIC in female rats. We also provided compelling evidence that the efficient DNIC in males is associated with a stronger resting functional connectivity between the rostral anterior cingulate cortex (rACC) and the periaqueductal gray (PAG). These observations provide a strong rationale for investigating the impact of TS on central pain modulation, and they also have significant clinical implications for pain management for both transgender and cisgender individuals undergoing hormone therapy. In this project, we will investigate the role of TS in maintaining efficient DNIC, as well as the mechanistic links between dysfunctional DNIC, TMD-like pain, and TMD-related comorbid pain conditions. Specifically, we hypothesize that the rACC to PAG circuit mediates sex differences in DNIC efficiency in a TS-dependent manner and that strengthening DNIC effectively attenuates TMD-related primary and comorbid pain responses. In specific aim (SA) 1, we will determine the role of the rACC to PAG circuit in DNIC efficiency using a behavioral paradigm and chemogenetics, which will experimentally manipulate the strength of the circuit with and without anti-androgen treatment in males and with and without TS treatment in females. In SA2, we will investigate the relationship between DNIC and TMD-like pain responses. We will conduct a concurrent functional magnetic resonance imaging (fMRI) to assess pain- induced changes in brain networks and confirm that both TS treatment and strengthening the rACC to PAG circuit rectify the pain-induced changes in the brain networks in male and female rats. In SA3, we will determine whether chemogenetically activating DNIC leads to a reduction in TMD-related comorbid pain responses and whether TS treatment further enhances the chemogenetic effects. The project will significantly improve our knowledge of the impact of sex on CNS pain modulation, which should have broad translational implications for the development of customized therapeutic strategies for both transgender and cisgender individuals.

摘要和项目摘要 许多影响颅面区域的慢性疼痛状况，例如颞下颌疾病（TMD）， 不成比例地影响女性。越来越多的研究表明，与性别相关的差异的有力证据 在条件疼痛调节（CPM）中，内源性疼痛抑制的心理物理指数是一种机制 这使妇女容易增加慢性疼痛状况的风险。但是，中心机制 CPM中的性别差异以及功能失调的CPM与慢性口面相之间的因果关系 疼痛状况在很大程度上未知。我们先前的工作表明，下降存在性别差异 有害抑制性控制（DNIC），该度量与临床前环境中的CPM相似，并且DNIC是 以睾丸激素（TS）依赖性方式调节。与男性相比，DNIC的效率更强 给女性。雄激素受体的药理学阻断雄性DNIC和TS置换 雌性大鼠增强的DNIC。我们还提供了令人信服的证据，表明男性的有效性是 与前扣带回皮层（RACC）之间的更强的静息功能连接有关 和围栏灰色（PAG）。这些观察结果为研究影响提供了有力的理由 中枢疼痛调节的TS，它们对疼痛管理具有重大临床意义 跨性别者和顺式人都接受激素治疗。在这个项目中，我们将调查 TS在维持有效的DNIC以及功能失调的DNIC，TMD样之间的机理联系中的作用 疼痛和与TMD相关的合并症疼痛状况。具体来说，我们假设RACC到PAG电路 以TS依赖性方式介导DNIC效率的性别差异，并有效增强DNIC 减弱与TMD相关的原发性和合并症疼痛反应。在特定目标（SA）1中，我们将确定角色 使用行为范式和化学遗传学的RACC到DNIC效率的PAG电路，这将 在男性和没有抗雄激素治疗的情况下，通过实验操纵电路的强度 并且没有女性的TS治疗。在SA2中，我们将调查DNIC与TMD的关系 疼痛反应。我们将进行并发的功能磁共振成像（fMRI），以评估疼痛 诱导大脑网络的变化，并确认TS治疗和加强RACC的PAG 电路纠正了雄性和雌性大鼠大脑网络的疼痛引起的变化。在SA3中，我们将确定 化学遗传激活DNIC是否会导致TMD相关的合并疼痛反应减少和 TS处理是否进一步增强了化学作用。该项目将大大改善我们的 了解性别对CNS疼痛调节的影响，这应该对 针对跨性别者和派人士的定制治疗策略的制定。