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

摘要和项目总结 许多影响颅面区域的慢性疼痛状况，如颞下颌关节紊乱病（TMD）， 不成比例地影响女性。越来越多的研究表明，与性别有关的差异 在条件性疼痛调制（CPM），内源性疼痛抑制的心理物理指标，是一种机制 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功能障碍和慢性口面之间的因果关系 疼痛状况，在很大程度上是未知的。我们先前的工作表明，在下降过程中存在性别差异。 有害抑制控制（DNIC），一种类似于临床前环境中CPM的测量方法，并且DNIC是 以睾酮（TS）依赖性方式调节。DNIC的效率在男性中较强， 对女性来说。雄激素受体的药理学阻断可减弱男性的DNIC，TS替代 增强雌性大鼠的DNIC。我们还提供了令人信服的证据，证明男性的有效DNIC是 与喙侧前扣带皮层（rACC）之间更强的静息功能连接相关 和中脑导水管周围灰质（PAG）。这些观察结果为调查影响提供了强有力的理由 TS对中枢疼痛调节的作用，它们对疼痛管理也有重要的临床意义， 接受激素治疗的变性人和顺性人。在这个项目中，我们将调查 TS在维持有效的DNIC中的作用，以及功能失调的DNIC、TMD样 疼痛和TMD相关的共病疼痛状况。具体地说，我们假设rACC到PAG回路 以TS依赖的方式介导DNIC效率的性别差异， 减弱TMD相关的原发性和共病性疼痛反应。在具体目标（SA）1中，我们将确定 使用行为范例和化学遗传学，研究了rACC至PAG回路在DNIC效率中的作用， 实验性地操纵回路的强度，在男性中有和没有抗雄激素治疗， 而在雌性中未进行TS治疗。在SA 2中，我们将研究DNIC和TMD样 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- 诱导脑网络的变化，并证实TS治疗和加强rACC到PAG 在雄性和雌性大鼠的大脑网络中，神经回路纠正了疼痛引起的变化。在SA 3中，我们将确定 化学发生激活DNIC是否导致TMD相关共病疼痛反应的减少， TS处理是否进一步增强化学发生作用。该项目将大大改善我们的 了解性别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翻译意义： 为变性人和顺性人制定定制的治疗策略。

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.