Parabrachial role in chronic pain

臂旁在慢性疼痛中的作用

• 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
• 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

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.

项目摘要/摘要 慢性疼痛是患者最常见的抱怨，影响了超过1亿美国人，并使 国家/年的医疗治疗超过650亿美元，生产力降低了。大多数慢性疼痛患者是 对药物或手术疗法的抗性，在很大程度上是因为其潜在的病理生理学 慢性疼痛状况未知。该研究计划的最终目标是纠正这种缺陷。 大多数与脊髓疼痛相关的传入剂的目标是副核复合体（PB），然后投影到 多个与疼痛相关的皮质和皮质下靶标。新的初步数据表明抑制性输入 在啮齿动物神经性疼痛模型中，杏仁核（CEA）的中央核（CEA）降低到PB：慢性 胸神经（CCI）的收缩。这两个赞助商都大大减少了抑制作用 并引起PB神经元活性。结果，几种与疼痛相关的核的PB兴奋性增加， 包括腹腹髓质（RVM），这是下降疼痛调节系统的关键节点。基于 我们假设这一令人兴奋的新证据是慢性疼痛是由于病理的发展而引起的 正反馈网络：减少CEA到PB的抑制作用 - >放大的PB活动 - >增加 RVM神经元的激活 - >脊髓中伤害感受神经元的激活增加。使用 来自完整啮齿动物和大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，我们将直接检验这一总体假设。具体来说， 我们将（1）检验该假设CCI导致抑制输入的进行性逐渐降低至 对RVM投射的伤害性PB神经元，并大大增加了点火； （2）检验假设 扩增的PB活性是由于CEA的抑制作用降低。 （3）检验降低CEAI的假设 对PB的抑制与CCI-PAIN的发展意外有关。预期的发现将 揭示了慢性疼痛发展的新型机制，并可能导致新疗法的发展 改善甚至可以防止这种毁灭性的状况。

项目成果

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
• 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.)
• 作者: Ji,Yadong;Rizk,Alexandra;Voulalas,Pamela;Aljohani,Hanan;Akerman,Simon;Dussor,Gregory;Keller,Asaf;Masri,Radi
• 通讯作者: Masri,Radi

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
• 作者: Keller A;Akintola T;Colloca L
• 通讯作者: Colloca L

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.)
• 作者: Uddin,Olivia;Studlack,Paige;Akintola,Titilola;Raver,Charles;Castro,Alberto;Masri,Radi;Keller,Asaf
• 通讯作者: Keller,Asaf

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
• 作者: Smith,JesseA;Ji,Yadong;Lorsung,Rebecca;Breault,MacauleyS;Koenig,Jeffrey;Cramer,Nathan;Masri,Radi;Keller,Asaf
• 通讯作者: Keller,Asaf