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 许多影响颅面部的慢性疼痛状况，如颞下颌关节紊乱病(TMD)， 对女性的影响不成比例。越来越多的研究表明，强有力的证据表明，与性别有关的差异 在条件性疼痛调制(CPM)中，内源性疼痛抑制的心理物理指标是其中一种机制 这使女性患慢性疼痛的风险增加。然而，中央机制 CPM的潜在性别差异以及CPM功能障碍与慢性口腔颌面部疾病之间的因果联系 疼痛状况，在很大程度上是未知的。我们之前的工作表明，在下降过程中存在性别差异 有害抑制控制(DNIC)，这是一种类似于临床前环境中CPM的措施，DNIC是 以睾酮(TS)依赖的方式调节。与男性相比，DNIC的效率更高 对女性来说。雄激素受体的药物阻断可减轻男性DNIC，并替代TS 增强雌性大鼠的DNIC。我们还提供了令人信服的证据，表明男性的有效DNIC是 与吻侧前扣带回皮质(RACC)之间更强的静息功能连接有关 中脑导水管周围灰质(PAG)。这些观察结果为研究影响提供了强有力的理由。 TS对中枢痛觉调制的影响，对临床疼痛控制也有重要意义。 变性人和顺性人都在接受激素治疗。在这个项目中，我们将调查 TS在维持有效的DNIC以及功能障碍的DNIC、TMD样之间的机械联系中的作用 疼痛，以及与TMD相关的并存疼痛状况。具体来说，我们假设rACC到PAG电路 以TS依赖的方式调节DNIC效率的性别差异，并有效地加强DNIC 减轻与TMD相关的原发和共病疼痛反应。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对rACC到PAG电路的DNIC效率进行研究，这将 在男性和男性接受和不接受抗雄激素治疗的情况下，实验操纵电路的强度 女性不接受TS治疗。在SA2中，我们将研究DNIC和类似TMD的关系 疼痛反应。我们将同时进行功能性磁共振成像(FMRI)来评估疼痛- 诱导脑网络改变，证实TS治疗和增强rACC对PAG均有作用 环路纠正疼痛引起的雄性和雌性大鼠脑网络的改变。在SA3中，我们将确定 化学激活DNIC是否导致TMD相关的共病疼痛反应减少和 TS治疗是否进一步增强了趋化作用。该项目将显著改善我们的 了解性行为对中枢神经系统痛觉调制的影响，这应该对 为变性人和顺性人制定定制的治疗策略。