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Dissecting the Parabrachial Nucleus’s Role in the Development and Maintenance of Neuropathic Pain

剖析臂旁核在神经病理性疼痛的发生和维持中的作用

基本信息

批准号：
10710096
负责人：
Tyler Scott Nelson
金额：
$ 8.64万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10710096
关键词：
Ablation Absence of pain sensation Address Affect Afferent Neurons Agonist Amygdaloid structure Analgesics Behavior Behavioral Behavioral Symptoms Brain Brain region Cells Complex Coupled Data Data Set Development Disease Educational process of instructing Electrophysiology (science)Equilibrium Family Fellowship Fluorescent in Situ Hybridization Frequencies General Population Genes Genetic Genetic Techniques Glutamates Goals Immediate-Early Genes Injury Institution Interneurons Knock-out Label Laboratories Learning Lesion Maintenance Measures Mediating Mentors Mentorship Messenger RNA Methods Mus National Research Service Awards Neurobiology Neurons Neuropeptide Y Receptor Neuropeptides Neurosciences Nociception Nociceptors Nucleosomes Opioid Output Pain Pathologic Patients Peripheral Peripheral nerve injury Pharmacology Phase Physiological Population Positioning Attribute Postdoctoral Fellow Principal Investigator Proteins Quality of life Reporting Research Research Personnel Role Signal Transduction Slice Societies Spinal Spinal Cord Spinal cord posterior horn Stimulus System Techniques Technology Testing Therapeutic Tissues Training United States Universities Vertebral column Work Writing aspirate behavior test behavioral pharmacology chronic pain chronic painful condition dorsal horn experience healing improved in vivo in vivo calcium imaging inflammatory pain mouse model nerve injury neural neuropeptide Y neuropeptide Y-Y1 receptor neurotransmission novel strategies optogenetics pain perception painful neuropathy parabrachial nucleus patch clamp postsynaptic presynaptic receptor segregation sham surgery single-cell RNA sequencing skills somatosensory temporal measurement tenure track transcriptome sequencing transcriptomics voltage clamp wireless

项目摘要

Project Summary Chronic pain conditions place significant burdens on patients, their families, and society by reducing quality of life and creating enormous financial consequences that total more than 630 billion USD annually for the United States of America alone. Neuropathic pain is a debilitating type of chronic pain that arises from a lesion or disease affecting the somatosensory system. Neuropathic pain affects 7-8% of the general population yet is poorly responsive to analgesic drugs, including opioids, thus, alternative therapeutics for treatment are desperately needed. However, the underlying mechanisms of the development and maintenance of neuropathic pain are poorly understood. It is hypothesized that neuropathic pain results from a loss of spinal cord dorsal horn inhibition and/or a gain in dorsal horn excitation that allows the propagation of low threshold innocuous inputs to be perceived as painful. Exactly how nerve injury disrupts this balance to generate a net pronociceptive tone, however, remains unclear. Specific Aim 1 describes promising preliminary data within our laboratory that implicates glutamatergic dorsal horn interneurons expressing the neuropeptide Y (NPY) Y1 receptor in both the development and maintenance of neuropathic pain. First, selective ablation of neuropeptide Y1 receptor- expressing interneurons (Y1-INs) with intrathecal NPY-saporin reduced the development of behavioral signs of neuropathic pain. Second, intrathecal pharmacology and intraspinal chemogenetic techniques indicate that Y1- INs are both necessary and sufficient for the behavioral manifestations of neuropathic pain. Lastly, both single cell RNA-sequencing and fluorescence in situ hybridization data indicate that Y1-INs segregate into three distinct dorsal horn interneuron subpopulations. Together, these observations form the premise for my central hypothesis that nerve injury increases the excitability of Y1-INs, and this makes one or more subpopulations of Y1-INs necessary for the behavioral symptoms of neuropathic pain. Specific Aim 2 will explore this hypothesis via intraspinal pharmacology, behavioral testing, in vivo wireless optogenetics, intersectional Cre-lox transgenics, and patch clamp electrophysiology. Together these methods will test which Y1-IN subpopulation(s) is/are necessary for the behavioral signs of neuropathic pain. Further, these methods will assess changes in pre- or postsynaptic excitatory and inhibitory activity to Y1-INs following nerve injury to uncover mechanistic changes in the circuit that might lead to the development of neuropathic pain. Specific Aim 3 details a plan to identify and pursue a neuroscience focused postdoctoral fellowship following the completion of the dissertation work described in Specific Aim 2. The overarching goals of this study are to increase our understanding of how nerve injury increases the excitability of Y1-IN subpopulations, and provide rationale for targeting spinal Y1-INs as a novel approach to treat neuropathic pain.

项目摘要慢性疼痛状况通过降低患者的生活质量，给患者、他们的家人和社会带来了沉重的负担生命和创造巨大的财务后果，每年为美国带来总计超过6300亿美元的仅美国一国。神经性疼痛是一种由病变或疾病引起的使人衰弱的慢性疼痛。影响到体感系统。神经病理性疼痛影响7-8%的普通人群，但并不严重对包括阿片类药物在内的止痛药的反应，因此，治疗的替代疗法迫切需要需要的。然而，神经病理性疼痛发生和维持的潜在机制是人们对此知之甚少。据推测，神经病理性疼痛是由于脊髓背角抑制丧失所致。和/或允许传播低阈值无害输入的背角激励中的增益被视为痛苦的。神经损伤究竟是如何破坏这种平衡以产生净伤害感受性音调的，然而，目前仍不清楚。具体目标1描述了我们实验室内有希望的初步数据谷氨酸能背角中间神经元表达神经肽Y(NPY)Y1受体神经病理性疼痛的发展和维持。第一，选择性消融神经肽Y1受体- 鞘内注射NPY-Saporin表达中间神经元(Y1-ins)可减少大鼠行为体征的发生神经性疼痛。其次，鞘内药理学和椎管内化学发生技术表明，Y1- INS对神经病理性疼痛的行为表现既是必要的也是充分的。最后，两人都是单身细胞RNA测序和荧光原位杂交数据表明，Y1-INS分离为三个不同的背角中间神经元亚群。总之，这些观察结果构成了我的中央假设神经损伤增加Y1-INS的兴奋性，这使得一个或多个亚群 Y1-INS对于神经病理性疼痛的行为症状是必要的。《特定目标2》将探讨这一假说。通过椎管内药理学、行为测试、体内无线光遗传学、交叉CRE-lox 转基因和膜片钳电生理学。这些方法将一起测试哪个Y1-In亚群(S) 是神经病理性疼痛的行为体征所必需的。此外，这些方法将评估前或突触后对Y1-INS的兴奋和抑制活性揭示神经损伤后的机制变化这可能会导致神经病理性疼痛的发展。具体目标3详细说明了一项确定在完成论文工作后，继续以神经科学为重点的博士后研究在具体目标中描述2.这项研究的首要目标是增加我们对神经损伤增加了Y1-IN亚群的兴奋性，并为以脊髓Y1-IN为靶点提供了理论基础治疗神经病理性疼痛的新方法。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Emerging Translational Potential of MNK Inhibitors for the Treatment of Chronic Pain.

MNK 抑制剂治疗慢性疼痛的新兴转化潜力。

DOI：
10.1016/j.neuroscience.2023.02.009
发表时间：
2023
期刊：
Neuroscience
影响因子：
3.3
作者：
Nelson,TylerS;Khanna,Rajesh
通讯作者：
Khanna,Rajesh

The spino-parabrachio-amygdaloid pathway is critical for the manifestation of chronic pain.

脊髓-旁臂肌-杏仁通路对于慢性疼痛的表现至关重要。

DOI：
10.1038/s41386-023-01745-7
发表时间：
2024
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
0
作者：
Nelson,TylerS;Allen,HeatherN
通讯作者：
Allen,HeatherN