Muscle Fatigue Increases the Probability of Developing Hyperalgesia in Mice

Abstract

Chronic muscle pain is a major clinical problem that is often associated with fatigue. Conversely, chronic fatigue conditions are commonly associated with muscle pain. We tested the hypothesis that muscle fatigue enhances hyperalgesia associated with injection of acidic saline into muscle. We evaluated mechanical sensitivity of the paw (von Frey) in mice after 2 intramuscular injections of saline (20 µL; pH 4, pH 5, pH 6, pH 7.2) in a fatigue and a control group. To induce fatigue, mice were run for 2 h/day for 2 days prior to the first injection and 2 h/day for 2 days prior to the second injection. Muscle lactate, pCO 2 , pO 2 , creatinine kinase, phosphate, and histology were examined after the fatigue task and compared to a control group. Grip force was significantly decreased after 2 h of running indicating fatigue. The fatigue task did not induce muscle damage as there was no difference in muscle lactate, pCO 2 , pO 2 , creatinine kinase, phosphate, or histology. The fatigue task altered the dose-response relationship to intramuscular acidic saline injections. Mechanical hyperalgesia was observed in both fatigue and control groups after intramuscular injection of pH 4.0, but only the fatigue group after injection of pH 5. Neither the fatigue nor the control group developed hyperalgesia in response to intramuscular injection of pH 6 or pH 7.2. In conclusion, fatigue modified the susceptibility of mice to acid injection of pH 5.0 to result in mechanical hyperalgesia after 2 injections of pH 5.0. The fatigue task did not produce measurable changes in the muscle tissue suggesting a central mechanism mediating the enhancement of hyperalgesia.Perspective-These data therefore show that muscle fatigue can enhance the likelihood that one develops pain to a mild insult. Clinically, this could relate to the development of pain from such conditions as repetitive strain injury, and may relate to the interrelationship between chronic pain and fatigue. KeywordsFatigue; exercise; acid; protons; low-pH saline Pain arising from musculoskeletal disorders is a major clinical problem globally, 58 and fibromyalgia affects 2% of population in the United States. 57 As high as 76% of people with chronic widespread musculoskeletal pain conditions, such as fibromyalgia and arthritis, also report fatigue. 26 Conversely, as high as 94% of people with chronic fatigue syndrome report musculoskeletal pain and approximately half of the population has chronic widespread musculoskeletal pain. 56,60 Pain is increased during and after exercise in people with fibromyalgia and chronic fatigue syndrome. 20,48,54,55 Similarly, muscle fatigue is increased in people with chronic fatigue syndrome. 3,10,23 To assess mechanisms of chronic widespread pain, we developed an animal model that mimics the clinical symptoms. Two injections of acidic saline (pH 4.0), 5 days apart, into 1 muscle results in bilateral long-lasting hyperalgesia of the paw, 41 muscle,59 and the viscera28 without muscle tissue damage.41 The intramuscular pH decreases to a p...

Enhanced muscle fatigue occurs in male but not female ASIC3−/− mice

“…During exercise, there is increased pain in people with chronic fatigue syndrome and in people with fibromyalgia (36,64,67,70). In an animal model of pain, induced by intramuscular injections of acidic saline, exercise increases nociceptive responses in mice during a long-duration fatigue task (72). These data suggest an overlap between fatigue and pain such that fatigue plays a significant role in the development of pain, and that pain is enhanced in response to fatigue.…”

“…Together, our data suggest that there was no difference in the ability to perform the fatigue tasks between male and female mice, regardless of genotype, despite different levels of fatigue. The long-duration fatigue tasks on the Rota-Rod used in the current study are uniquely different from previously published fatigue protocols in animals, which typically involve spontaneous wheel running (72), treadmill running (9, 49), or electrical stimulation of isolated muscles (2, 49).…”

Regular physical activity prevents development of chronic pain and activation of central neurons

“…We have developed a model where a single bout of exercise enhances the nociceptive response to a low-dose muscle insult. A single bout of exercise was induced by placing mice in an activity wheel for 2 h at a self-selected speed prior to injection of carrageenan (55); mice typically run 2.16 Ϯ 0.52 km during the 2 h (a speed of ϳ1 km/h) (55,64). Immediately following the exercise task, a mild muscle inflammation was produced by a single injection of 0.03% carrageenan into one gastrocnemius muscle while the mouse was anesthetized with 4% isoflurane (55).…”

“…Further, a single bout of exercise in people with existing acute inflammatory and chronic noninflammatory pain conditions enhances ongoing pain and hyperalgesia (27,59,61). Animal models of muscle pain have been developed to mimic acute inflammatory pain, chronic noninflammatory pain, and exercise-enhanced pain (45,46,54,55,64). These models involve assessing pain sensitivity at 1) the site of injury (muscle), termed primary hyperalgesia, which is thought to be mediated by hypersensitivity in the peripheral nervous system; and 2) outside the site of injury (paw), termed secondary hyperalgesia, and is thought to be mediated by hypersensitivity in the central nervous system.…”

Aerobic Exercise Alters Analgesia and Neurotrophin-3 Synthesis in an Animal Model of Chronic Widespread Pain

“…The acid model used in the present study is a noninflammatory muscle pain model and is considered to mirror some aspects of human fibromyalgia and other related syndromes that display referred hypersensitivity to mechanical stimuli. Acidic saline produces mechanical hypersensitivity of cutaneous, 4 -9 visceral, 10 and muscular tissue 11,12 that lasts up to 3 to 4 weeks. It is suggested that the influx of acid stimulates the acidsensing ion channel-3 (ASIC3) receptors expressed by muscle afferent sensory fibers, resulting in increased nociceptive input to the spinal cord.…”