Neuropeptide Y1 Receptor-Expressing Neurons in the Lateral Parabrachial Nucleus in Neuropathic Pain

神经性疼痛中臂旁核外侧核表达神经肽 Y1 受体的神经元

基本信息

批准号：
10635473
负责人：
Heather Noel Allen
金额：
$ 8.08万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10635473
关键词：
Acetone Acute Pain Affect Affective Agonist Amygdaloid structure Analgesics Anatomy Animals Behavior Behavioral Behavioral Symptoms Bilateral Brain Brain Stem Brain region Calcium Cannulas Cell Nucleus Chronic Clozapine Complex Cues Data Development Disease Emotional Family Fiber Fluorescence Fluorescent in Situ Hybridization Formalin Future General Population Genetic Glutamates Gossypium Hypersensitivity Implant In Situ In Situ Hybridization Infusion procedures Injury Laboratories Lateral Lesion Light Maintenance Mechanics Mentors Molecular Motor Mus Neurons Neuropathy Neuropeptide Y Receptor Neuropeptides Nociception Nociceptors Opioid Oxides Pain Pathologic Patients Pattern Peripheral Peripheral nerve injury Persistent pain Photometry Pontine structure Publications Publishing Quality of life Research Research Personnel Rodent Model Role Sensory Slice Societies Stimulus Structure Structure of terminal stria nuclei of preoptic region Surgical Injuries Swab System Taste aversion Testing Thalamic structure Therapeutic Tissues United States Veins Viral Virus Withdrawal Writing anatomical tracing awake career cell type chronic pain chronic painful condition conditioned place preference excitatory neuron experimental study healing heat stimulus in vivo insight midbrain central gray substance mouse model nerve injury neuropeptide Y neuropeptide Y-Y1 receptor pain signal painful neuropathy parabrachial nucleus peripheral nerve damage pharmacologic pre-clinical receptor response sensory stimulus skills somatosensory spared nerve zona incerta

项目摘要

Project Summary Pain is a complex phenomenon that elicits somatosensory and motor reflexive responses together with marked and long-lasting changes in emotional and autonomic states. While acute pain provides protection from tissue damage, chronic or long-lasting pain, provides no protective function and is often incapacitating. Chronic pain conditions are debilitating to 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 type of chronic pain that arises from a lesion or disease affecting the somatosensory system and affects 7-8% of the general population. However, neuropathic pain is poorly responsive to analgesic drugs, including opioids, and alternative therapeutics for treatment are desperately needed. The underlying mechanisms of the development and maintenance of neuropathic pain are poorly understood. A recent wave of high-profile publications implicates the parabrachial nucleus (PBN) as a sensory hub for pain and aversion. The PBN is, a small, bilateral, pontine brain structure that has long been known to receive alarming, noxious, or threatening homeostatic information such as taste aversion, nociception, or danger cues. Promising preliminary data within the Taylor (UPitt) and Betley (UPenn) laboratories implicate glutamatergic PBN neurons expressing the neuropeptide Y (NPY) Y1 receptor (Npy1r-expressing) in the maintenance of neuropathic pain. First, application of a cool (acetone droplet) or light rub (cotton swab) stimulus to the hindpaw of a mouse following peripheral nerve injury produces significant Fos activation within Npy1r-expressing PBN neurons. Second, pharmacological inhibition of PBNNpy1r-expressing neurons via a selective agonist for the NPY Y1 Gi receptor reduces behavioral symptoms of neuropathic pain, whereas chemogenetic activation of Npy1r-expressing neurons produces conditioned place aversion. Third, application of a heat stimulus produces calcium transients in PBNNpy1r-expressing neurons assessed via in vivo fiber photometry. These observations provide the premise for my central hypothesis that the Npy1r-expressing subset of PBN neurons are necessary for neuropathic pain-like behaviors. Specific Aim 1 will utilize in vivo fiber photometry and in situ hybridization to assess the activation of PBN Npy1r-expressing neurons in both sham and neuropathic animals. Specific Aim 2 will apply in vivo chemogenetics to inhibit PBN Npy1r-expressing neurons in sham and neuropathic animals to assess their necessity for the behavioral reflexive (mechanical and cold) and affective (conditioned place preference) components of pain. Specific Aim 3 will examine both the anatomy (anatomical tracing) and functional role (inhibitory chemogenetics) of the supraspinal targets of PBNNpy1r-expressing efferent projections to uncover the specific ciruits responsible for both the reflexive and affective components of neuropathic pain.

项目概要疼痛是一种复杂的现象，会引起体感和运动反射反应，并伴有明显的反应。以及情绪和自主状态的持久变化。虽然急性疼痛可以提供组织保护损伤、慢性或持久疼痛不提供保护功能并且常常导致丧失能力。慢性疼痛这些状况降低了生活质量并造成患者及其家人和社会的衰弱。每年给美国造成的巨大财务后果总计超过 6300 亿美元唯有美国。神经性疼痛是一种慢性疼痛，由影响神经的病变或疾病引起体感系统，影响 7-8% 的普通人群。但神经性疼痛的治疗效果较差对镇痛药物（包括阿片类药物）和替代疗法的反应非常迫切需要。神经性疼痛发生和维持的潜在机制尚不清楚明白了。最近一波备受瞩目的出版物表明臂旁核（PBN）是一种感觉器官痛苦和厌恶的中心。 PBN 是一种小型的双侧桥脑结构，长期以来一直被认为是接收令人震惊的、有害的或威胁性的稳态信息，例如味觉厌恶、伤害感受或危险提示。泰勒（UPitt）和贝特利（UPenn）实验室内有希望的初步数据表明表达神经肽 Y (NPY) Y1 受体（表达 Npy1r）的谷氨酸 PBN 神经元维持神经性疼痛。首先，冷敷（丙酮滴）或轻擦（棉签）周围神经损伤后对小鼠后爪的刺激会产生显着的 Fos 激活表达 Npy1r 的 PBN 神经元。其次，通过药物抑制表达 PBNNpy1r 的神经元 NPY Y1 Gi 受体的选择性激动剂可减轻神经性疼痛的行为症状，而表达 Npy1r 的神经元的化学遗传学激活会产生条件性位置厌恶。三、应用通过体内纤维评估热刺激在表达 PBNNpy1r 的神经元中产生钙瞬变光度测定。这些观察结果为我的中心假设提供了前提：Npy1r 表达 PBN 神经元的子集对于神经性疼痛样行为是必需的。具体目标 1 将利用体内光纤光度测定和原位杂交来评估 PBN 的激活假手术动物和神经病动物中表达 Npy1r 的神经元。具体目标 2 将应用体内化学遗传学来抑制假手术和假手术中表达 PBN Npy1r 的神经元。神经病动物评估其行为反射（机械和冷）和情感的必要性（条件性位置偏好）疼痛的组成部分。具体目标 3 将检查解剖学（解剖追踪）和功能作用（抑制 PBNNpy1r 表达传出投射的脊髓上目标的化学遗传学），以揭示特定的负责神经性疼痛的反射性和情感性成分的神经回路。