Opioid-induced potentiation of the exercise pressor reflex via acid-sensing ion channels (ASIC3) in health and simulated peripheral artery disease

阿片类药物通过酸敏感离子通道 (ASIC3) 在健康和模拟外周动脉疾病中诱导运动升压反射增强

基本信息

项目摘要

PROJECT SUMMARY Chronic ischemia in muscle (skeletal or cardiac) leads to accumulation of lactic acid and other inflammatory metabolites with subsequent drop in interstitial pH. The ensuing tissue acidosis plays a major role in triggering claudication (walking-induced pain) and chest pain. The high-affinity and selective mu opioid receptor (MOR) agonists, endomorphins, are also released under ischemic and inflammatory conditions. Acid-sensing ion channels (ASIC) are key players in the perception of pH changes associated with tissue acidosis, inflammation and pain. ASIC are expressed highly in sensory (i.e. dorsal root ganglion, DRG) and central neurons and are voltage-insensitive, depolarizing cationic channels. Endomorphin-1 (E-1) and -2 (E-2) are tetrapeptides known to activate MOR and exert analgesic effects. However, our recent findings indicate that E- 1 and E-2 significantly potentiated the acid-induced ASIC3 currents in transfected fibroblast L-cells and in acutely isolated DRG neurons independent of MOR activation. The potentiation by both opioids was significantly greater in DRG neurons isolated from rats with ligated femoral arteries (peripheral artery disease model). Importantly, our in vivo data demonstrated that E-2 significantly enhanced the lactic acid-induced increase in mean arterial pressure in rats. The E-2-mediated enhancement was significantly attenuated by the ASIC3 blocker, APETx2, but was insensitive to naloxone. Our long-term goal is to understand the mechanisms by which endomorphins and clinically employed opiates (oxycodone, fentanyl, remifentanil) modulate ASIC3 currents, the interacting site on the channel, and how they regulate the exercise pressor reflex (EPR) which is evoked by muscle contraction. Our overall hypothesis is that chronic muscle ischemia—accompanied by an acidified and inflamed environment, and enhanced ASIC3 expression— elevates endomorphin release, leading to enhanced ASIC3 currents. The overall effect is hyperexcitability of primary afferents that produces an exaggerated EPR. This hypothesis will be tested using complementary in vitro and in vivo approaches. We will determine the biophysical and pharmacological effects of endomorphins and prescription opiates on heterologously expressed ASIC3 in L-cells. We will identify ASIC3 channel residues that functionally negate the actions of E-1 and E-2, but leave the basic physiology of the channel intact. We also will compare the opioid agonist pharmacological profiles on ASIC channel currents in DRG neurons from rats with “freely perfused” or “ligated” femoral arteries. We will examine the effects of E-1, E-2 and prescription opiates on the EPR evoked in both wild-type and ASIC3 knockout rats in which the femoral arteries are “freely perfused” or “ligated”. Overall, these experiments will provide novel information about how opioid peptides potentiate ASIC currents under ischemic conditions, thereby enhancing pressor responses to exercise and possibly worsening pain associated with chronic use of prescription opiates (i.e., opioid-induced hyperalgesia).
项目概要 肌肉(骨骼或心脏)的慢性缺血导致乳酸和其他炎症的积累 代谢物随后间质 pH 值下降。随后发生的组织酸中毒在引发 跛行(行走引起的疼痛)和胸痛。高亲和力和选择性 mu 阿片受体 (MOR) 激动剂内吗啡也会在缺血和炎症条件下释放。酸敏离子 通道 (ASIC) 是感知与组织酸中毒相关的 pH 变化的关键角色, 炎症和疼痛。 ASIC 在感觉神经节(即背根神经节,DRG)和中枢神经节中高度表达 神经元并且是电压不敏感的去极化阳离子通道。内吗啡肽-1 (E-1) 和-2 (E-2) 是 已知可激活 MOR 并发挥镇痛作用的四肽。然而,我们最近的研究结果表明,E- 1 和 E-2 显着增强了转染的成纤维细胞 L 细胞和 急性分离的 DRG 神经元独立于 MOR 激活。两种阿片类药物的增强作用为 从结扎股动脉的大鼠(外周动脉疾病)中分离出的 DRG 神经元显着增加 模型)。重要的是,我们的体内数据表明,E-2 显着增强了乳酸诱导的 大鼠平均动脉压增加。 E-2介导的增强被显着减弱 ASIC3 阻断剂 APETx2,但对纳洛酮不敏感。我们的长期目标是了解 内啡肽和临床使用的阿片类药物(羟考酮、芬太尼、瑞芬太尼)的作用机制 调节 ASIC3 电流、通道上的相互作用位点以及它们如何调节运动加压源 由肌肉收缩引起的反射(EPR)。我们的总体假设是慢性肌肉 缺血——伴随着酸化和发炎的环境,以及增强的 ASIC3 表达—— 提高内吗啡释放,导致 ASIC3 电流增强。总体效果是过度兴奋 产生夸大 EPR 的初级传入神经。该假设将使用互补的方法进行检验 体外和体内方法。我们将确定内吗啡的生物物理和药理作用 以及处方阿片类药物对 L 细胞中异源表达的 ASIC3 的影响。我们将识别 ASIC3 通道 功能上否定 E-1 和 E-2 作用但保留通道基本生理学的残基 完好无损的。我们还将比较 DRG 中 ASIC 通道电流的阿片类激动剂药理学特征 来自具有“自由灌注”或“结扎”股动脉的大鼠的神经元。我们将检查E-1、E-2的效果 和处方阿片类药物对野生型和 ASIC3 敲除大鼠 EPR 的影响,其中股骨 动脉是“自由灌注”或“结扎”的。总的来说,这些实验将提供关于如何 阿片肽在缺血条件下增强 ASIC 电流,从而增强升压反应 运动和可能与长期使用处方阿片类药物(即阿片类药物引起的 痛觉过敏)。

项目成果

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Marc Peter Kaufman其他文献

Marc Peter Kaufman的其他文献

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{{ truncateString('Marc Peter Kaufman', 18)}}的其他基金

Opioid-induced potentiation of the exercise pressor reflex via acid-sensing ion channels (ASIC3) in health and simulated peripheral artery disease
阿片类药物通过酸敏感离子通道 (ASIC3) 在健康和模拟外周动脉疾病中诱导运动升压反射增强
  • 批准号:
    10593184
  • 财政年份:
    2021
  • 资助金额:
    $ 61.35万
  • 项目类别:
Opioid-induced potentiation of the exercise pressor reflex via acid-sensing ion channels (ASIC3) in health and simulated peripheral artery disease
阿片类药物通过酸敏感离子通道 (ASIC3) 在健康和模拟外周动脉疾病中诱导运动升压反射增强
  • 批准号:
    10230430
  • 财政年份:
    2021
  • 资助金额:
    $ 61.35万
  • 项目类别:
Role played by Acid Ion Sensing Channels in Peripheral Artery Disease
酸离子传感通道在外周动脉疾病中的作用
  • 批准号:
    10531228
  • 财政年份:
    2020
  • 资助金额:
    $ 61.35万
  • 项目类别:
Role played by Acid Ion Sensing Channels in Peripheral Artery Disease
酸离子传感通道在外周动脉疾病中的作用
  • 批准号:
    10153286
  • 财政年份:
    2020
  • 资助金额:
    $ 61.35万
  • 项目类别:
Role played by Acid Ion Sensing Channels in Peripheral Artery Disease
酸离子传感通道在外周动脉疾病中的作用
  • 批准号:
    10318665
  • 财政年份:
    2020
  • 资助金额:
    $ 61.35万
  • 项目类别:
Project 3: Role Played by ASIC, P2X and EP4 Receptors in the Exercise Pressor Reflex in Health and Simulated PAD
项目 3:ASIC、P2X 和 EP4 受体在健康和模拟 PAD 运动加压反射中的作用
  • 批准号:
    10117112
  • 财政年份:
    2017
  • 资助金额:
    $ 61.35万
  • 项目类别:
Acute and Chronic Afferent Engagement: Sympathetic and End Organ Responses
急性和慢性传入参与:交感神经和终末器官反应
  • 批准号:
    10117087
  • 财政年份:
    2017
  • 资助金额:
    $ 61.35万
  • 项目类别:
Effects of arterial occlusion on the respon of thin fib. afferents to contraction
动脉闭塞对细纤维反应的影响。
  • 批准号:
    8001279
  • 财政年份:
    2010
  • 资助金额:
    $ 61.35万
  • 项目类别:
Differential sympathetic reflex control in excerise
运动中交感神经反射的差异控制
  • 批准号:
    6915186
  • 财政年份:
    2004
  • 资助金额:
    $ 61.35万
  • 项目类别:
Differential sympathetic reflex control in excerise
运动中交感神经反射的差异控制
  • 批准号:
    7049592
  • 财政年份:
    2004
  • 资助金额:
    $ 61.35万
  • 项目类别:

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肿瘤微环境因子Lactic acidosis在肿瘤细胞耐受葡萄糖剥夺中的作用机制研究
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Impact of metabolic acidosis on muscle mitochondrial energetics, metabolic health and physical endurance in persons with chronic kidney disease
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