Parabrachial role in chronic pain

臂旁在慢性疼痛中的作用

基本信息

批准号：
10183341
负责人：
ASAF KELLER
金额：
$ 33.8万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183341
关键词：
Affect American Amygdaloid structure Animals Behavioral Brain Cell Nucleus Chronic Complex Data Development Diabetes Mellitus Electrophysiology (science)Emotions Esthesia Feedback Functional disorder Glutamate Decarboxylase Goals Heart Diseases In Vitro Intractable Pain Lead Malignant Neoplasms Medical Nerve Nerve Pain Neurons Nociception Nuclear Operative Surgical Procedures Pain Pain Clinics Painless Pathologic Pathway interactions Patients Peripheral nerve injury Persistent pain Pharmacogenetics Pharmacologic Substance Pharmacology Play Pontine structure Productivity Proteins Regulation Research Research Project Grants Resistance Rodent Role Serotonin Slice Spinal Cord Stimulus Structure System Testing animal pain awake base chronic constriction injury chronic neuropathic pain chronic pain chronic pain patient chronic painful condition constriction cost gamma-Aminobutyric Acid in vivo insight nerve injury neuronal circuitry novel novel therapeutics optogenetics pain model pain processing pain relief pain symptom painful neuropathy parabrachial nucleus patch clamp postsynaptic prevent programs relating to nervous system side effect synthetic enzyme therapeutically effective

项目摘要

Project Summary/Abstract Chronic pain is the most common complaint of patients, affecting over 100 million Americans, and costing the nation more than $650 billion/year in medical treatment and lost productivity. Most chronic pain patients are resistant to pharmaceutical or surgical therapies, in large part because the underlying pathophysiology of their chronic pain condition is unknown. The ultimate goal of this research program is to rectify this deficiency. Most spinal cord pain-related afferents target the parabrachial nuclear complex (PB), which then projects to multiple pain-related cortical and subcortical targets. New preliminary data indicate that inhibitory inputs from the central nucleus of the amygdala (CeA) to PB are reduced in a rodent neuropathic pain model: chronic constriction of the infraorbital nerve (CCI). This reduced inhibition dramatically `amplifies' both spontaneous and evoked PB neural activity. As a consequence, there is increased PB excitation of several pain-related nuclei, including the rostral ventral medulla (RVM), a key node of the descending pain modulation system. Based on this exciting new evidence we hypothesize that chronic pain results from the development of a pathologic positive feedback network: Reduced inhibition from CeA to PB –> amplified PB activity –> increased activation of RVM neurons –> increased activation of nociceptive neurons in the spinal cord. With the use of electrophysiological recordings from intact rodents and from brain slices, and taking advantage of behavioral approaches, optogenetics and pharmacogenetics, we will directly test this overarching hypothesis. Specifically, we will (1) Test the hypothesis CCI causes a progressive and significant reduction of inhibitory inputs to nociceptive PB neurons that project to RVM, and dramatically increases their firing; (2) Test the hypothesis that amplified PB activity is due to reduced inhibition from CeA.; (3) Test the hypothesis that reduced CeAI inhibition to PB is causally related to the development of CCI-Pain. The anticipated findings are expected to reveal novel mechanisms for the development of chronic pain, and may lead to development of novel therapies to ameliorate, and perhaps even prevent, this devastating condition.

项目概要/摘要慢性疼痛是患者最常见的主诉，影响着超过 1 亿美国人，并造成了巨大的经济损失。国家每年花费超过 6500 亿美元的医疗费用并导致大多数慢性疼痛患者丧失生产力。对药物或手术治疗产生耐药性，很大程度上是因为其潜在的病理生理学慢性疼痛状况尚不清楚，该研究计划的最终目标是纠正这一缺陷。大多数与脊髓疼痛相关的传入神经以臂旁核复合体 (PB) 为目标，然后该复合体投射到新的初步数据表明，多个与疼痛相关的皮质和皮质下目标。在啮齿动物神经病理性疼痛模型中，从杏仁核中央核 (CeA) 到 PB 的信号减少：慢性眶下神经（CCI）的收缩显着“增强”了自发性抑制。并诱发 PB 神经活动，结果是，几个与疼痛相关的核团的 PB 兴奋增加，包括延髓头端腹侧（RVM），它是下行疼痛调节系统的关键节点。我们追求的这一令人兴奋的新证据表明，慢性疼痛是由病理学发展引起的正反馈网络：CeA 对 PB 的抑制减少 –> PB 活性放大 –> 增加 RVM 神经元的激活 –> 脊髓中伤害性神经元的激活增加。来自完整啮齿动物和脑切片的电生理记录，并利用行为方法、光遗传学和药物遗传学，我们将直接测试这个总体假设。我们将 (1) 检验假设 CCI 会导致抑制性输入逐渐显着减少 (2) 检验假设 PB 活性增强是由于 CeA 的抑制作用减少。 (3) 检验 CeAI 减少的假设对 PB 的抑制与 CCI 疼痛的发展存在因果关系。揭示慢性疼痛发展的新机制，并可能导致新疗法的开发改善，甚至可能预防这种毁灭性的状况。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Divergent profiles of fentanyl withdrawal and associated pain in mice and rats.

DOI：
10.1016/j.pbb.2020.173077
发表时间：
2021-01
期刊：
Pharmacology, biochemistry, and behavior
影响因子：
0
作者：
Uddin O;Jenne C;Fox ME;Arakawa K;Keller A;Cramer N
通讯作者：
Cramer N

Sex differences in the expression of calcitonin gene-related peptide receptor components in the spinal trigeminal nucleus.

三叉神经脊髓核中降钙素基因相关肽受体成分表达的性别差异。

DOI：
10.1016/j.ynpai.2019.100031
发表时间：
2019
期刊：
Neurobiology of pain (Cambridge, Mass.)
影响因子：
0
作者：
Ji,Yadong;Rizk,Alexandra;Voulalas,Pamela;Aljohani,Hanan;Akerman,Simon;Dussor,Gregory;Keller,Asaf;Masri,Radi
通讯作者：
Masri,Radi

Amplified parabrachial nucleus activity in a rat model of trigeminal neuropathic pain.

三叉神经病理性疼痛大鼠模型中臂旁核活动增强。

DOI：
10.1016/j.ynpai.2018.02.002
发表时间：
2018
期刊：
Neurobiology of pain (Cambridge, Mass.)
影响因子：
0
作者：
Uddin,Olivia;Studlack,Paige;Akintola,Titilola;Raver,Charles;Castro,Alberto;Masri,Radi;Keller,Asaf
通讯作者：
Keller,Asaf

Placebo Analgesia in Rodents: Current and Future Research.

DOI：
10.1016/bs.irn.2018.02.001
发表时间：
2018
期刊：
International review of neurobiology
影响因子：
0
作者：
Keller A;Akintola T;Colloca L
通讯作者：
Colloca L

Parabrachial Nucleus Activity in Nociception and Pain in Awake Mice.

清醒小鼠伤害感受和疼痛中的臂旁核活动。

DOI：
10.1523/jneurosci.0587-23.2023
发表时间：
2023
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Smith,JesseA;Ji,Yadong;Lorsung,Rebecca;Breault,MacauleyS;Koenig,Jeffrey;Cramer,Nathan;Masri,Radi;Keller,Asaf
通讯作者：
Keller,Asaf