Female-specific role of trigeminal dynorphin in temporomandibular disorder and its comorbidity

三叉神经强啡肽在颞下颌疾病及其合并症中的女性特异性作用

• 批准号: 10657801
• 负责人: Feng Tao
• 金额: $ 35.98万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657801
• 关键词: Address; Animal Model; Binding; Bradykinin; Bradykinin B2 Receptor; Bradykinin Receptor; Development; Dose; Dynorphins; Female; Genes; Genetic; Goals; Injections; Investigation; Knowledge; Ligation; Masseter Muscle; Mediating; Migraine; Molecular; Mus; Neurons; Nitric Oxide; Nitric Oxide Synthase Type I; Nitroglycerin; Nociception; Pain; Pathway interactions; Patients; Peptides; Play; Prevalence; Production; Publishing; Receptor Inhibition; Regulation; Research; Role; Sex Differences; Signal Transduction; Structure of trigeminal nerve spinal tract nucleus; System; Temporomandibular Joint Disorders; Temporomandibular joint disorder pain; Tendon structure; Testing; Time; Trigeminal Pain; Trigeminal System; Up-Regulation; Woman; Work; animal pain; antagonist; comorbidity; dynorphin receptor; epidemiologic data; epidemiology study; innovation; interdisciplinary approach; kappa opioid receptors; knock-down; non-opioid analgesic; novel therapeutics; pain model; prodynorphin; receptor; sex; sexual dimorphism; small hairpin RNA; therapeutic target; transcriptome sequencing

Project Summary: Epidemiological studies have shown that temporomandibular disorders (TMDs) pain and migraine headache are closely associated. Specifically, migraine headache appears to be more prevalent in women with myogenic TMD. However, the molecular mechanisms for TMD pain and its comorbidity with migraine as well as their sex differences remain poorly understood. Our long-term goal is to identify potential targets for developing a novel therapy for TMD and migraine overlapping pain. In our preliminary studies, we have developed an animal model to study TMD pain and its comorbidity with migraine by combining masseter muscle tendon ligation (MMTL)- produced myogenic TMD with systemic injection of nitroglycerin (NTG)-induced migraine-like pain, and this work has been published recently. Using RNA sequencing followed by qPCR confirmation, we identified trigeminal dynorphin as a potential female-specific therapeutic target for this overlapping pain condition. We observed for the first time that blockade of dynorphin in the spinal trigeminal nucleus caudalis (Sp5C) of female mice significantly inhibits myogenic TMD pain and diminishes TMD-enhanced migraine-like pain, and that Sp5C injection of dynorphin enables a non-sensitizing dose of NTG to produce persistent migraine-like pain in female mice, but not male mice. We further found that Sp5C antagonism of bradykinin receptor, but not kappa opioid receptor, inhibits such overlapping pain in female mice. Moreover, bradykinin receptor B2 (BKRB2), but not BKRB1, is expressed in the Sp5C, and MMTL plus NTG treatment decreases the binding of BKRB2 with neuronal nitric oxide synthase (nNOS) and increases NOS activity in the Sp5C, which will increase nitric oxide production and then promote migraine pain development. These results suggest that Sp5C dynorphin could play a female- specific role in TMD pain and its comorbidity with migraine through a non-opioid receptor mechanism. In this project, we will determine the central mechanisms by which trigeminal dynorphin contributes to TMD and migraine overlapping pain condition. Our hypothesis is that trigeminal dynorphin enhances TMD and migraine comorbidity in female mice by activating bradykinin receptor BKRB2 and then inhibiting its binding with nNOS to increase nitric oxide production in the Sp5C, thereby promoting TMD and migraine overlapping pain. To test this central hypothesis, we will use multidisciplinary approaches to characterize female-specific role of trigeminal dynorphin in TMD and migraine overlapping pain (Aim 1), determine the receptor mechanism for dynorphin in trigeminal pain regulation (Aim 2), and define the downstream pathway of dynorphin signaling in trigeminal nociceptive system (Aim 3). Collectively, we expect to reveal the central mechanisms by which trigeminal dynorphin specifically contributes to TMD and migraine comorbidity in females. The proposed research is significant since it will advance our understanding of TMD pain and its comorbidity. The proposed studies are innovative since these studies will identify a previously unrecognized female-specific role for dynorphin in trigeminal overlapping pain condition.

项目摘要： 流行病学研究表明，颞下颌疾病（TMD）疼痛和偏头痛是 密切相关。具体而言，肌脱源性TMD女性的偏头痛似乎更为普遍。 但是，TMD疼痛的分子机制及其与偏头痛的合并症及其性别 差异仍然很少理解。我们的长期目标是确定发展新颖的潜在目标 TMD和偏头痛的治疗重叠疼痛。在我们的初步研究中，我们开发了一个动物模型 通过结合咬肌肌腱连接（MMTL）来研究TMD疼痛及其与偏头痛的合并症 - 通过全身注入硝酸甘油（NTG）诱导的偏头痛疼痛产生肌源性TMD，这项工作 最近出版了。使用RNA测序，然后进行qPCR确认，我们确定了三叉神经 Dynorphin是这种重叠疼痛状况的潜在女性特异性治疗靶标。我们观察到 雌性小鼠的脊柱三叉神经核（SP5C）中第一次封锁动力啉 显着抑制肌源性TMD疼痛并减轻TMD增强的偏头痛样疼痛，而SP5C 注射dynorphin使得不敏化剂量的NTG能够在女性中产生持续的偏头痛疼痛 老鼠，但不是雄性小鼠。我们进一步发现，sp5c拮抗激发素受体的拮抗作用，而不是卡帕阿片类药物 受体，抑制雌性小鼠的这种重叠疼痛。此外，Bradykinin受体B2（BKRB2），但没有 BKRB1在SP5C中表达，MMTL加NTG处理降低了BKRB2与神经元的结合 一氧化氮合酶（NNOS）并增加SP5C的NOS活性，这将增加一氧化氮的产生 然后促进偏头痛疼痛的发展。这些结果表明，SP5C Dynorphin可以玩女性 通过非阿片类受体机制，在TMD疼痛及其与偏头痛的合并症中的特定作用。在这个 项目，我们将确定三角球对TMD和TMD和 偏头痛重叠疼痛状况。我们的假设是三叉苯甲苯强化可增强TMD和偏头痛 雌性小鼠的合并症通过激活心动激肽受体BKRB2，然后抑制其与NNOS的结合 增加SP5C中一氧化氮的产生，从而促进TMD和偏头痛重叠疼痛。测试这个 中心假设，我们将使用多学科的方法来表征三叉神经的特定女性角色 TMD中的Dynorphin和偏头痛重叠的疼痛（AIM 1），确定Dynorphin的受体机制 三叉神经疼痛调节（AIM 2），并定义三角态信号的下游途径 伤害性系统（AIM 3）。总体而言，我们期望揭示三叉神经的中心机制 Dynorphin特别有助于女性的TMD和偏头痛合并症。拟议的研究是 意义重大，因为它将提高我们对TMD疼痛及其合并症的理解。拟议的研究是 创新性，因为这些研究将确定先前未识别的女性特异性角色在Dynorphin中 三叉神经重叠的疼痛状况。