Document Type


Date of Degree

Spring 2015

Degree Name

PhD (Doctor of Philosophy)

Degree In


First Advisor

Kathleen A. Sluka

First Committee Member

Christopher Benson

Second Committee Member

Tim Brennan

Third Committee Member

Laura Frey-Law

Fourth Committee Member

Donna Hammond


Exercise has numerous health benefits. Yet, exercise can exacerbate pain for individuals with chronic musculoskeletal pain conditions such as myofascial pain syndrome (MPS) and fibromyalgia (FM). The exacerbation is out of proportion to the activity performed and lasts for long periods of time even after the cessation of activity. This pain acts as a barrier to healthy exercise and physical rehabilitation, which, when applied consistently, are effective treatments for MPS and FM--two diseases that produce substantial suffering and disability. The goal of the proposed studies is to determine the underlying peripheral mechanisms that contribute to enhanced pain following exercise. A better understanding of these mechanisms will lead to better pain management and prevention for these diseases.

Previous data show that two hours of running wheel activity lowers the threshold necessary to induce muscle pain by acidic saline injection, producing robust pain behaviors to normally innocuous stimuli. Muscle activity that produces fatigue is associated with extracellular increases in protons, lactate, and ATP. These fatigue metabolites can directly activate muscle nociceptors and, when combined, produce a potentiated effect.

Acid sensing ion channels (ASICs) are non-selective cation channels that open in response to increased proton concentrations, a response that is enhanced when lactate binds at a separate location. Ionotropic purinergic receptors (P2X) similarly produce an inward current in response to elevated ATP. Evidence suggests certain ASIC and P2X subtypes are capable of a physical interaction that allows ASIC activation at lower proton concentrations in the presence of ATP. This suggests that ATP, lactate, and protons released during exercise could activate ASIC and P2X receptors on muscle nociceptors, exciting the nociceptors and sensitizing them to subsequent muscle insult.

However, the limitations of these experiments leave several gaps. First, the running wheel task fails to produce measurable increases in fatigue metabolites, possibly due to the fact that there was minimal fatigue (10%) or that their levels quickly return to baseline. Further, the running wheel task depends on central nervous system (CNS) activity and volitional running, which may introduce confounding factors upstream of muscle activation and result in large variation in the rate and duration of running. Second, it is unclear whether ASICs are necessary for the development of mechanical hyperalgesia induced by muscle activity, nor is it understood which ASIC subtypes might be required for such an effect. Finally, the molecules necessary for the induction of mechanical hyperalgesia after exercise are not known. Protons, lactate, and ATP have been suggested, but it is not known if these compounds are themselves sufficient or if they interact in an additive or synergistic manner. We address these concerns by developing an electrically-stimulated muscle fatigue paradigm that reliably fatigues a single muscle independent of the CNS, allowing for metabolite measurement during muscle activity and in vivo study of molecular mechanisms of muscle pain in the peripheral tissue. We then use genetic and pharmacologic approaches to test the role of ASIC subtypes in the development of mechanical hyperalgesia after exercise. Finally, we test the effectiveness of by-products of muscle activity in recapitulating the effects of the exercise-enhanced pain model.

Public Abstract

Exercise has numerous health benefits. Yet, exercise can be unpleasant, which may prevent adherence to a fitness program. Further, for people with certain chronic conditions, exercise can make some of their symptoms worse. In these chronic conditions, which include myofascial pain syndrome and fibromyalgia, exercise results in unexpectedly severe muscle pain and fatigue. The goal of this research is to better understand how exercise produces muscle pain so that such pain can be treated or prevented. Treating this pain may, in turn, result in better adherence to fitness programs among people who find exercise-related pain intolerable.

Exercise consists of repeated muscle contractions, which results in accumulation of substances in the fluid around muscle. These substances include ATP, lactate, and acid. When these substances reach high enough levels in the fluid around muscle, they can cause pain by activating specialized pain receptors on nerves. In fact, the combination of ATP, lactate, and acid produces enhanced pain that is greater than the sum of the effects of each individual molecule.

This research has three main objectives. The first is to develop an animal model of muscle pain produced by exercise. The second is to identify receptors responsible for muscle pain after exercise. Finally, the research looks at the interaction between ATP, lactate, and acid to determine the levels of each compound, alone or in combination, that are necessary for the development of muscle pain.


publicabstract, ASIC, Fatigue, Ion Channels, Muscle, Pain, Sex Differences


xii, 133 pages


Includes bibliographical references (pages 110-133).


Copyright 2015 Nicholas S Gregory