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 许多影响颅面部区域的慢性疼痛，例如颞下颌关节紊乱病 (TMD)、 对女性的影响尤为严重。越来越多的研究表明强有力的证据表明性别相关的差异 条件性疼痛调节（CPM）是一种内源性疼痛抑制的心理物理指标，是一种机制 这使得女性患慢性疼痛的风险增加。然而，中央机制 CPM 中潜在的性别差异，以及功能失调的 CPM 与慢性口面部之间的因果关系 疼痛状况很大程度上是未知的。我们之前的工作表明，降序存在性别差异 有害抑制控制 (DNIC)，一种类似于临床前设置中的 CPM 的措施，并且 DNIC 是 以睾酮（TS）依赖性方式进行调节。与男性相比，DNIC 的效率更强 对女性。雄激素受体的药理学阻断可减弱男性的 DNIC 和 TS 替代 增强雌性大鼠的 DNIC。我们还提供了令人信服的证据，表明 DNIC 对男性的有效作用是 与头侧前扣带皮层 (rACC) 之间更强的静息功能连接相关 和导水管周围灰质（PAG）。这些观察结果为调查影响提供了强有力的理由 TS 对中枢疼痛调节的影响，并且它们对于疼痛管理也具有重要的临床意义 接受激素治疗的跨性别者和顺性别者。在这个项目中，我们将调查 TS 在维持高效 DNIC 中的作用，以及功能失调的 DNIC、TMD 类之间的机制联系 疼痛以及 TMD 相关的共病疼痛状况。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，并有效强化 DNIC 减轻 TMD 相关的原发性和共病疼痛反应。在具体目标（SA）1中，我们将确定角色 使用行为范式和化学遗传学研究 rACC 到 PAG 电路在 DNIC 效率中的作用，这将 通过实验操纵男性中接受和不接受抗雄激素治疗以及接受抗雄激素治疗的电路的强度 且女性未接受 TS 治疗。在SA2中，我们将研究DNIC和TMD-like之间的关系 疼痛反应。我们将进行同步功能磁共振成像（fMRI）来评估疼痛 诱导大脑网络的变化，并证实 TS 治疗和强化 rACC 至 PAG 电路纠正雄性和雌性大鼠大脑网络中疼痛引起的变化。在 SA3 中，我们将确定 化学遗传学激活 DNIC 是否会导致 TMD 相关共病疼痛反应减少以及 TS治疗是否进一步增强化学遗传学效应。该项目将显着改善我们的 了解性对中枢神经系统疼痛调节的影响，这应该对以下方面具有广泛的转化意义： 为跨性别者和顺性别者制定定制的治疗策略。