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
• 负责人: Marc Peter Kaufman
• 金额: $ 61.35万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10593184
• 关键词: ASIC channel; Acidosis; Acids; Acute; Address; Affect; Afferent Neurons; Affinity; Analgesics; Applications Grants; Arteries; Atherosclerosis; Attention; Attenuated; Biophysics; Blood Pressure; Cardiac; Chemosensitization; Chest Pain; Chronic; Clinical; Contracts; Coronary Arteriosclerosis; Data; Disease model; Drops; Environment; Exercise; Fentanyl; Fibroblasts; Goals; Health; Heart Rate; Hyperalgesia; In Vitro; Inflammation; Inflammatory; Intermittent Claudication; Ions; Ischemia; Knock-out; L Cells; Lactic acid; Ligation; Mechanoreceptors; Mediating; Metabolic; Modeling; Muscle; Muscle Contraction; Muscle Fibers; Naloxone; Neurons; Opioid; Opioid Peptide; Opioid agonist; Oxycodone; Pain; Pain in lower limb; Patients; Perception; Perfusion; Peripheral arterial disease; Phase; Physiology; Play; Production; Protein Isoforms; Rattus; Receptor Activation; Reflex action; Reporting; Resistance; Rest; Role; Sensory; Site; Spinal Ganglia; Testing; Text; Thinness; Tissues; Toxin; Transfection; Walking; attenuation; blood pressure elevation; claudication; endogenous opioids; endomorphin 1; experimental study; femoral artery; in vivo; interstitial; ion channel blocker; limb ischemia; mu opioid receptors; novel; pharmacologic; prescription opioid; pressure; remifentanil; response; skeletal; ventilation; voltage

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).

项目总结