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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.

项目总结

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