Effect of Intramuscular Protons, Lactate, and ATP on Muscle Hyperalgesia in Rats

Abstract

Chronic muscle pain is a significant health problem leading to disability[1]. Muscle fatigue can exacerbate muscle pain. Metabolites, including ATP, lactate, and protons, are released during fatiguing exercise and produce pain in humans. These substances directly activate purinergic (P2X) and acid sensing ion channels (ASICs) on muscle nociceptors, and when combined, produce a greater increase in neuron firing than when given alone. Whether the enhanced effect of combining protons, lactate, and ATP is the sum of individual effects (additive) or more than the sum of individual effects (synergistic) is unknown. Using a rat model of muscle nociceptive behavior, we tested each of these compounds individually over a range of physiologic and supra-physiologic concentrations. Further, we combined all three compounds in a series of dilutions and tested their effect on muscle nociceptive behavior. We also tested a non-hydrolyzable form of ATP (α,β-meATP) alone and in combination with lactate and acidic pH. Surprisingly, we found no dose-dependent effect on muscle nociceptive behavior for protons, lactate, or ATP when given alone. We similarly found no effect after application of each two-metabolite combination. Only pH 4 saline and α,β-meATP produced hyperalgesia when given alone. When all 3 substances were combined, however, ATP (2.4μm), lactate (10mM), and acidic pH (pH 6.0) produced an enhanced effect greater than the sum of the effects of the individual components, i.e. synergism. α,β me ATP (3nmol), on the other hand, showed no enhanced effects when combined with lactate (10mM) or acidic pH (pH 6.0), i.e. additive. These data suggest that combining fatigue metabolites in muscle produces a synergistic effect on muscle nociception.

Peripheral Mechanisms of Ischemic Myalgia

“…ATP at very high concentrations could activate neurons independently, but not at physiological concentrations. This point is supported by behavioral experiments where stimulating the muscles with ATP, lactate or low pH by themselves are unable to induce painful responses (Gregory et al, 2015 ). Interestingly the enhanced responses obtained by combining the metabolites in a way that it resembled physiological conditions provided effective neuronal activation that was more than additive in up to 30% of the observed neurons.…”

“…Interestingly the enhanced responses obtained by combining the metabolites in a way that it resembled physiological conditions provided effective neuronal activation that was more than additive in up to 30% of the observed neurons. Only this combination of ATP, lactate and protons was able to induce mechanical hyperalgesia (Gregory et al, 2015 ).…”

Thin‐fibre receptors expressing acid‐sensing ion channel 3 contribute to muscular mechanical hypersensitivity after exercise

“…In rats, the expression of ASIC3 is more abundant in small sensory neurons innervating the muscle than those innervating the skin (Fujii et al, 2008;Molliver et al, 2005). Chemical mediators such as protons, lactic acid and adenosine 5'-triphosphate (ATP), that are liberated by muscle contraction, combine to produce a synergistic effect on pain amplification (Gregory, Whitley, & Sluka, 2015;Light et al, 2008). The activation of ASIC3 by these chemical mediators may be associated with the onset of DOMS.…”

Macrophage polarization contributes to local inflammation and structural change in the multifidus muscle after intervertebral disc injury

“…One possibility is the muscle fiber type transformation from slow (oxidative) to fast (glycolytic) that is significant by six months after IVD lesion [8,7], with a non-significant tendency at three months (19.8% lower slow fibers proportion than controls) [8,14]. Altered skeletal muscle microenvironment secondary to slow muscle fiber loss could affect the macrophage population and hyperalgesia [23,33,34]. Slow fiber loss reduces oxidative metabolism and fatigue resistance (as observed in humans [35]), leading to increased glycolytic metabolism and lactic acid production.…”