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.

项目摘要疼痛是一种复杂的现象，引起体感和运动反射反应以及标记情感和自主状态的持久变化。而急性疼痛可防止组织损害，慢性或持久的疼痛，没有保护功能，并且常常丧失能力。慢性疼痛条件通过降低生活质量和创造而使患者，家人和社会使人衰弱美国每年总计超过6,300亿美元的财务后果独自一人。神经性疼痛是一种慢性疼痛，是由影响的病变或疾病引起的体感系统，影响7-8％的普通人群。但是，神经性疼痛很差对包括阿片类药物在内的镇痛药的反应和治疗替代治疗方法需要。神经性疼痛的发展和维持的基本机制很差理解。最近的备受瞩目的出版物浪潮将副核（PBN）视为一种感觉用于疼痛和厌恶的枢纽。 PBN是一种小的双边，蓬托脑结构，长期以来已知收到令人震惊，有害或威胁性稳态信息，例如厌恶，伤害感受或危险提示。泰勒（Upitt）和贝特利（Upenn）实验室中有希望的初步数据牵涉表达神经肽Y（NPY）Y1受体（表达NPY1R）的谷氨酸能PBN神经元维持神经性疼痛。首先，使用凉爽（丙酮液滴）或轻摩擦（棉签）外周神经损伤后，刺激小鼠的后爪刺激会在内部产生明显的FOS激活表达NPY1R的PBN神经元。其次，通过A的PBNNPY1R表达神经元的药理抑制 NPY Y1 GI受体的选择性激动剂减少了神经性疼痛的行为症状，而表达NPY1R的神经元的化学发生激活会产生条件的位置厌恶。第三，申请热刺激在通过体内纤维评估的表达PBNNPY1R的神经元中产生钙瞬变光度法。这些观察结果为我的中心假设提供了前提，即表达NPY1R 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将利用体内纤维光度法和原位杂交来评估PBN的激活在假动物和神经性动物中表达NPY1R的神经元。具体的目标2将应用体内化学遗传学来抑制假在假和神经性动物评估其行为反射性（机械和冷）和情感的必要性（条件地点偏好）疼痛的组成部分。特定的目标3将检查解剖学（解剖示踪）和功能作用（抑制作用 PBNNPY1R表达传出投影的化学遗传学）导致神经性疼痛的反射性和情感成分负责。