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.

项目概要： 流行病学研究表明，颞下颌关节紊乱病 (TMD) 疼痛和偏头痛是 密切相关。具体来说，偏头痛似乎在患有肌源性 TMD 的女性中更为常见。 然而，TMD 疼痛的分子机制及其与偏头痛的合并症及其性别 差异仍然知之甚少。我们的长期目标是确定开发小说的潜在目标 治疗 TMD 和偏头痛重叠疼痛。在我们的初步研究中，我们开发了一种动物模型 通过结合咬肌腱结扎术 (MMTL) 研究 TMD 疼痛及其与偏头痛的合并症 - 通过全身注射硝酸甘油（NTG）引起的偏头痛样疼痛产生肌源性TMD，这项工作 最近已发布。通过 RNA 测序和 qPCR 确认，我们鉴定了三叉神经 强啡肽作为这种重叠疼痛病症的潜在女性特异性治疗靶点。我们观察到 首次阻断雌性小鼠三叉神经尾髓核（Sp5C）强啡肽 Sp5C 显着抑制肌源性 TMD 疼痛并减轻 TMD 增强的偏头痛样疼痛 注射强啡肽可使非致敏剂量的 NTG 使女性产生持续性偏头痛样疼痛 小鼠，但不是雄性小鼠。我们进一步发现 Sp5C 拮抗缓激肽受体，但不拮抗 kappa 阿片类药物 受体，抑制雌性小鼠的这种重叠疼痛。此外，缓激肽受体 B2 (BKRB2)，但不是 BKRB1 在 Sp5C 中表达，MMTL 加 NTG 治疗可降低 BKRB2 与神经元的结合 一氧化氮合酶 (nNOS) 并增加 Sp5C 中的 NOS 活性，从而增加一氧化氮的产生 进而促进偏头痛的发展。这些结果表明 Sp5C 强啡肽可以扮演女性角色 通过非阿片受体机制在 TMD 疼痛及其与偏头痛合并症中的特定作用。在这个 项目中，我们将确定三叉神经强啡肽促进 TMD 的中心机制 偏头痛重叠疼痛状况。我们的假设是三叉神经强啡肽会增强 TMD 和偏头痛 通过激活缓激肽受体 BKRB2，然后抑制其与 nNOS 的结合来治疗雌性小鼠的合并症 增加 Sp5C 中一氧化氮的产生，从而促进 TMD 和偏头痛的重叠疼痛。为了测试这个 中心假设，我们将使用多学科方法来描述三叉神经的女性特有作用 TMD 和偏头痛重叠疼痛中的强啡肽（目标 1），确定强啡肽在 TMD 和偏头痛中的受体机制 三叉神经疼痛调节（目标 2），并定义三叉神经中强啡肽信号传导的下游通路 伤害感受系统（目标 3）。总的来说，我们期望揭示三叉神经的中心机制 强啡肽尤其会导致女性 TMD 和偏头痛合并症。拟议的研究是 意义重大，因为它将增进我们对 TMD 疼痛及其合并症的理解。拟议的研究是 具有创新性，因为这些研究将确定强啡肽以前未被认识到的女性特有作用 三叉神经重叠疼痛状况。