Acid-sensing ion channels (ASICs): pharmacology and implication in pain.

The perception of fatigue is common in many disease states, however, the mechanisms of sensory muscle fatigue are not understood. In mice, rats and cats, muscle afferents signal metabolite production in skeletal muscle using a complex of ASIC, P2X and TRPV1 receptors. Endogenous muscle agonists for these receptors are combinations of protons, lactate, and ATP. Here we applied physiological concentrations of these agonists to muscle interstitium in human subjects to determine if this combination could activate sensations, and if so determined how these subjects described these sensations. Ten volunteers received infusions (0.2 ml over 30-s) containing protons, lactate and ATP under the fascia of a thumb muscle, abductor pollicis brevis (APB). Infusion of individual metabolites at maximum amounts evoked no fatigue or pain. Metabolite combinations found in resting muscles (pH 7.4+300nM ATP+1mM lactate) also evoked no sensation. The infusion of a metabolite-combination found in muscle during moderate endurance-exercise (pH 7.3+400nM ATP+5 mM lactate) produced significant fatigue sensations. Infusion of a metabolite-combination associated with vigorous exercise (pH 7.2+500nM ATP+10mM lactate) produced stronger sensations of fatigue and some ache. Higher levels of metabolites (as found with ischemic exercise) caused more ache but no additional fatigue-sensation. Thus, in a dose-dependent manner, intramuscular infusion of combinations of protons, lactate, and ATP leads to fatigue-sensation and eventually pain, probably through activation of ASIC, P2X, and TRPV1 receptors. This is the first demonstration in humans that metabolites normally produced by exercise act in combination to activate sensory neurons that signal sensations of fatigue and muscle pain.

/pdf/exogenously-applied-muscle-metabolites-synergistically-evoke-464kula4hf.pdf

Exogenously Applied Muscle Metabolites Synergistically Evoke Sensations of Muscle Fatigue and Pain in Human Subjects

Acid-Sensing Ion Channels and nociception in the peripheral and central nervous systems.

ASIC1 and ASIC3 Play Different Roles in the Development of Hyperalgesia After Inflammatory Muscle Injury

Pharmacology of acid-sensing ion channels - Physiological and therapeutical perspectives.

Angina, the prototypic vasoocclusive pain, is a radiating chest pain that occurs when heart muscle gets insufficient blood because of coronary artery disease. Other examples of vasoocclusive pain include the acute pain of heart attack and the intermittent pains that accompany sickle cell anemia and peripheral artery disease. All these conditions cause ischemia - insufficient oxygen delivery for local metabolic demand - and this releases lactic acid as cells switch to anaerobic metabolism. Recent discoveries demonstrate that sensory neurons innervating the heart are richly endowed with an ion channel that is opened by, and perfectly tuned for, the lactic acid released by muscle ischemia.

https://downloads.hindawi.com/journals/tswj/2001/580242.pdf

D.C. Immke

Papers

ASIC3: A Lactic Acid Sensor for Cardiac Pain