The Role of Habenular Hyperactivity in the Action of Tianeptine, a Novel Treatment for Neuropathic Pain

缰核过度活跃在噻奈普汀（一种治疗神经性疼痛的新疗法）作用中的作用

• 批准号: 10618202
• 负责人: Elizabeth Pekarskaya
• 金额: $ 3.18万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618202
• 关键词: Acute; Address; Affective; Affective Symptoms; Analgesics; Anhedonia; Animals; Antidepressive Agents; Area; Aversive Stimulus; Behavior; Behavioral; Biological; Biological Assay; Brain; Brain region; Calcium; Cells; Chronic; Chronic Disease; Clinical; Collaborations; Data; Disease; Disparity; Dopamine; Dose; Euphoria; Exhibits; Exposure to; Female; Fiber; Fire - disasters; Future; G-Protein-Coupled Receptors; Gene Expression; Genetic Transcription; Habenula; Hour; Human; Hyperactivity; Hyperalgesia; Injury; Intervention; Label; Ligation; Major Depressive Disorder; Measurement; Measures; Mental Depression; Microarray Analysis; Modeling; Molecular; Morphine; Mus; Nervous System; Neurobiology; Neurons; Norepinephrine; Opioid; Opioid agonist; Output; Pain; Painless; Pathologic; Pathway interactions; Patients; Pattern; Photometry; Population; Proteins; Publishing; Quinine; Receptor Inhibition; Regulation; Reporting; Rewards; Risk Factors; Role; Second-Generation Antidepressive Agents; Serotonin; Shock; Site; Slice; Stimulus; Sucrose; Symptoms; System; Tactile; Testing; Therapeutic; Tissues; Withdrawal; Work; allodynia; antidepressant effect; calcium indicator; chronic neuropathic pain; chronic pain; chronic painful condition; common symptom; depressive symptoms; differential expression; disability; endogenous opioids; experience; in vivo; male; monoamine; mouse model; mu opioid receptors; nerve injury; neural; novel; novel therapeutics; pain behavior; pain sensitivity; pain symptom; painful neuropathy; pharmacologic; physical symptom; preference; protein expression; receptor expression; receptor function; reduce symptoms; response; sham surgery; somatosensory; spared nerve; stem; tianeptine; treatment comparison

Project Summary/Abstract Neuropathic pain (NP) is defined as chronic pain following injury or disease in the somatosensory nervous system resulting in pain and affective symptoms. The primary treatments are monoamine targeting antidepressants, which roughly half of patients do not respond to. An atypical antidepressant called tianeptine (TIA) was discovered by our lab to be an MOR agonist, but differs from other opioids by lacking euphoric quality, metabolizing rapidly out of the body, and not showing tolerance/withdrawal effects all at clinical doses. Preliminary data indicates that TIA reduces allodynia from NP, without rapid tolerance as observed in morphine. How and where TIA is acting to relieve these symptoms is unclear. One candidate region is the habenula (Hb), which is dysregulated in chronic pain, and has inhibitory outputs to several monoamine regulating regions. Typically, neurons in the Hb fire in response to aversive stimuli, inhibiting those downstream reward pathways. Under chronic pain, the region becomes hyperactive. One option for how this happens relates to the habenula having the densest MOR expressing in the brain. MORs are typically inhibitory, and activated by the release of endogenous opioids. However, during chronic pain this system becomes dysregulated and, in many regions, MORs decrease in expression or availability. I hypothesize that pathological hyperactivity in the Hb, which is associated with an increase in allodynia and anhedonia, is at least partially due to a decrease in MOR expression or availability under conditions of chronic pain, and that chronic TIA administration will normalize activity in the region, correlating with decreased NP behaviors. In order to address this, I will use the spared nerve injury model (SNI) of NP, which induces both painful and affective symptoms, including allodynia and anhedonia. In Aim 1, I will test the hypothesis that habenula hyperactivity is related to changes in MOR activity, and that tianeptine normalizes habenular activity in NP. In 1.A, I will perform fiber photometry in SNI and sham control male and female MOR-Cre mice. I will measure calcium activity in both global and MOR expressing cells in the Hb, during measures of allodynia and anhedonia. In 1.B, I will chronically treat animals with TIA, and observe if this results in reversal of neural and/or behavioral disparities between SNI and control mice. In Aim 2, I will examine the molecular and transcriptional changes caused by NP and following chronic TIA treatment by comparing habenular tissue from sham/vehicle, SNI/vehicle, sham/TIA, and SNI/TIA mice. In 2.A, I will use a protein ligation assay to examine changes in MOR expression with regional detail, and in 2.B, I will analyze scRNAseq data for both broad transcriptional changes induced by pain and tianeptine, how co-expression patterns change between conditions. This will allow me to observe if the ratio of MOR co-expression shifts, as it did in preliminary re-analysis of published data looking at the habenula following acute unavoidable shock. To date, no studies have looked at habenular MORs during neuropathic pain.

项目摘要/摘要 神经病理性疼痛(NP)被定义为躯体感觉损伤或疾病后的慢性疼痛。 神经系统导致疼痛和情感症状。主要的治疗方法是单胺靶向。 抗抑郁药，大约一半的患者对此没有反应。一种名为替尼普汀的非典型抗抑郁药 (TIA)是我们实验室发现的一种MOR激动剂，但与其他阿片类药物不同的是缺乏快感 高质量，在体外迅速代谢，在临床剂量下均不表现出耐受性/停药效应。 初步数据表明，短暂性脑缺血发作可减少NP引起的痛觉超敏，但不会像在 吗啡。TIA如何以及在哪里采取行动缓解这些症状尚不清楚。一个候选地区是 缰核(Hb)，在慢性疼痛中调节失调，对几种单胺类物质有抑制作用 管理区域。通常情况下，Hb中的神经元对厌恶刺激做出反应，抑制那些 下游的奖励路径。在慢性疼痛下，该区域会变得过度活跃。如何做到这一点的一个选择 发生与缰核在大脑中表达最密集有关。MORS通常是 抑制，并被内源性阿片类药物的释放激活。然而，在慢性疼痛期间，这个系统 在许多地区，MORS的表达或可获得性降低。我假设 Hb的病理性多动，与痛觉异常和快感缺乏的增加有关，至少是 部分原因是慢性疼痛条件下MOR的表达或可获得性减少，而慢性疼痛 TIA管理将使该地区的活动正常化，与NP行为的减少相关。为了 为了解决这个问题，我将使用NP的备用神经损伤模型(SNI)，它既会引起疼痛，又会产生情感 症状包括痛觉过敏症和快感减退。在目标1中，我将检验缰核过度活动是 与MOR活性的变化有关，而噻奈普汀使NP的缰核活动正常化。在1.A中，我将 对SNI和Sham对照的雄性和雌性MOR-CRE小鼠进行纤维光度测定。我来量一量钙 在痛觉异常和快感缺乏的测量过程中，Hb中的全局细胞和MOR表达细胞的活性。在……里面 1.B，我会长期用TIA治疗动物，观察这是否会导致神经和/或行为的逆转 SNI和对照小鼠之间的差异。在目标2中，我将研究分子和转录的变化 通过比较Sham/Vehicle的缰核组织， SNI/Vehicle、Sham/TIA和SNI/TIA小鼠。在2.A中，我将使用蛋白质连接分析来检查 MOR表达与区域细节，在2.B中，我将分析scRNAseq数据，以获得广泛的转录 疼痛和替尼普汀引起的变化，共表达模式在不同条件下如何变化。这将是 请允许我观察MOR共表达的比例是否发生了变化，就像它在对已发表的 在急性不可避免的休克后观察缰骨的数据。到目前为止，还没有关于缰核的研究 神经病理性疼痛时的MORS。