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
- 批准号:10395569
- 负责人:
- 金额:$ 61.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-20 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:ASIC channelAcidosisAcidsAcuteAddressAffectAfferent NeuronsAffinityAnalgesicsApplications GrantsArteriesAtherosclerosisAttentionAttenuatedBiophysicsBlood PressureCardiacCationsChemosensitizationChest PainChronicClinicalContractsCoronary ArteriosclerosisDataDisease modelDropsEnvironmentExerciseFentanylFibroblastsGoalsHealthHeart RateHyperalgesiaIn VitroInflammationInflammatoryIntermittent ClaudicationIonsIschemiaKnock-outL CellsLactic acidMechanoreceptorsMediatingMetabolicModelingMuscleMuscle ContractionMuscle FibersNaloxoneNeuronsOpioidOpioid PeptideOpioid agonistOxycodonePainPain in lower limbPatientsPerceptionPeripheral arterial diseasePharmacologyPhasePhysiologyPlayProductionProtein IsoformsRattusReceptor ActivationReflex actionReportingResistanceRestRoleSensorySiteSpinal GangliaTestingTextThinnessTissuesToxinTransfectionWalkingalkalinityattenuationblood pressure elevationclaudicationendogenous opioidsendomorphin 1experimental studyfemoral arteryin vivointerstitialion channel blockerlimb ischemiamu opioid receptorsnovelprescription opioidpressureremifentanilresponseskeletalventilationvoltage
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
随后组织酸中毒在引发间质 pH 值下降中起重要作用。
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(MOR)。
激动剂内吗啡也会在缺血和炎症条件下释放。
通道 (ASIC) 是感知与组织酸中毒相关的 pH 变化的关键角色,
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。
神经元和内啡肽-1 (E-1) 和-2 (E-2) 是电压不敏感的去极化阳离子通道。
已知四肽可激活 MOR 并发挥镇痛作用,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
两种阿片类药物的增强作用均与 MOR 激活无关。
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
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作用。
大鼠平均动脉压的增加被E-2介导的增强作用显着减弱。
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——
增加内吗啡的释放,导致 ASIC3 电流增强,总体效果是 ASIC3 的过度兴奋。
产生夸大 EPR 的初级传入神经将使用互补的方法进行检验。
我们将确定内吗啡肽的生物物理和药理学作用。
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
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 的作用。
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
总体而言,这些实验将提供有关如何“自由灌注”或“结扎”动脉的新信息。
阿片肽增强缺血条件下的 ASIC 电流,增强压力增强或对
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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:
6815786 - 财政年份:2004
- 资助金额:
$ 61.35万 - 项目类别:
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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
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