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).
项目摘要 肌肉(骨骼肌或心肌)中的慢性缺血导致乳酸和其他炎性物质的积聚, 随后的组织酸中毒在触发细胞凋亡中起着重要作用。 跛行(步行引起的疼痛)和胸痛。高亲和力和选择性μ阿片受体(莫尔) 激动剂内吗啡肽也在缺血和炎症条件下释放。酸敏感离子 通道(ASIC)是感知与组织酸中毒相关的pH变化的关键参与者, 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(即背根神经节,DRG)中高度表达。 神经元和电压不敏感,去极化阳离子通道。内吗啡肽-1(E-1)和内吗啡肽-2(E-2)是 已知激活莫尔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显著增强了转染的成纤维细胞L-细胞中酸诱导的ASIC 3电流, 急性分离的DRG神经元不依赖于莫尔激活。两种阿片类药物的增强作用均为 在从结扎股动脉(外周动脉疾病)的大鼠分离的DRG神经元中, 模型)。重要的是,我们的体内数据表明,E-2显着增强乳酸诱导的 大鼠平均动脉压升高。E-2介导的增强作用明显减弱, ASIC 3阻断剂APETx 2,但对纳洛酮不敏感。我们的长期目标是了解 内吗啡肽和临床使用的阿片类药物(羟考酮、芬太尼、瑞芬太尼) 调节ASIC 3电流,通道上的相互作用位点,以及它们如何调节运动升压 肌肉收缩引起的EPR反射。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ASIC 3表达- 提高内吗啡肽释放,导致增强的ASIC 3电流。总体效果是过度兴奋, 产生夸大的EPR的初级传入。这一假设将被测试使用互补的 体外和体内方法。我们将确定内吗啡肽的生物物理和药理作用 和处方阿片类药物对L细胞中异源表达的ASIC 3的影响。我们将识别ASIC 3通道 在功能上否定E-1和E-2的作用,但留下通道的基本生理学的残基 完整我们还将比较阿片受体激动剂对背根神经节ASIC通道电流的药理作用 来自具有“自由灌注”或“结扎”股动脉的大鼠的神经元。我们将研究E-1、E-2 和处方阿片类药物对野生型和ASIC 3基因敲除大鼠诱发的EPR的影响, 动脉被“自由灌注”或“结扎”。总的来说,这些实验将提供新的信息, 阿片肽在缺血条件下增强ASIC电流,从而增强对 运动和可能恶化的与长期使用处方阿片类药物相关的疼痛(即,阿片诱导 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:
    10395569
  • 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:
    6815786
  • 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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