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.

In this large series of outpatients treated with CPNB, there were surprisingly few interventions requiring an anesthesiologist. Likewise, patients were able to manage and remove their catheters at home without additional follow-up. This suggests that with adequate instruction and telephone access to health care providers, patients are comfortable with managing and removing CPNB catheters at home.

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