Fatigue-enhanced hyperalgesia in response to muscle insult: Induction and development occur in a sex-dependent manner

Abstract

Chronic muscle pain affects 20–50% of the population, is more common in women than men, and is associated with increased pain during physical activity and exercise. Muscle fatigue is common in people with chronic muscle pain, occurs in response to exercise and is associated with release of fatigue metabolites. Fatigue metabolites can sensitize muscle nociceptors which could enhance pain with exercise. Using a mouse model we tested whether fatigue of a single muscle, induced by electrical stimulation, resulted in enhanced muscle hyperalgesia and if the enhanced hyperalgesia was more pronounced in female mice. Muscle fatigue was induced in combination with a sub-threshold muscle insult (2 injections of pH 5.0 saline) in male and female mice. We show that male and female mice, fatigued immediately prior to muscle insult in the same muscle, develop similar muscle hyperalgesia 24h later. However, female mice also develop hyperalgesia when muscle fatigue and muscle insult occur in different muscles, and when muscle insult is administered 24 hours after fatigue in the same muscle. Further, hyperalgesia lasts significantly longer in females. Finally, muscle insult with or without muscle fatigue results in minimal inflammatory changes in the muscle itself, and sex differences are not related to estradiol (ovariectomy) or changes in brainstem activity (pNR1). Thus, the current model mimics muscle fatigue-induced enhancement of pain observed in chronic muscle pain conditions in the human population. Interactions between fatigue and muscle insult may underlie the development of chronic widespread pain with an associated female predominance observed in human subjects.

ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia

“…As previously shown [13], wild type mice showed a significant decrease in the muscle withdrawal threshold. ASIC3−/− mice showed no decrease and were significantly different from both wildtype mice (Fig.…”

“…The unbuffered pH 5 saline injections reduce muscle pH to approximately 6.9 [18], which is comparable to decreases seen after intense exercise [35, 36]. Previous studies show that the combination of pH 5.0 saline with muscle fatigue is critical for the development of mechanical hyperalgesia, as neither 2 injections of pH 5.0 alone nor 2 injections of pH 7.2 saline combined with fatigue produce hyperalgesia [11–13]. On the other hand two injections of pH 4.0 produce decreases in muscle pH to an average of pH 6.5 and results in long-lasting hyperalgesia [18].…”

“…Muscle fatigue was induced using a modified Burke protocol that produces rapidly recovering single muscle fatigue as previously described [13, 33, 34]. Briefly, mice were deeply anesthetized using 2–4% isoflurane.…”

“…The enhanced pain response occurs with levels of activity that do not typically produce tissue damage or pain in healthy subjects [9, 10]. Animal studies similarly show an enhanced hyperalgesia when combining fatiguing, non-damaging exercise with a non-painful low-dose muscle insult [11–13] We previously show that whole-body fatiguing exercise enhances hyperalgesia to muscle insult and is associated with increased activity in brainstem neurons without significant changes in the muscle metabolites [11, 14,15]. On the other hand, enhanced hyperalgesia to muscle insult after fatiguing a single muscle was not associated with changes in brainstem neurons [13].…”

The dichotomized role for acid sensing ion channels in musculoskeletal pain and inflammation

“…Muscle fatigue decreases pH, increases lactate [39], enhances hyperalgesia to muscle insult [40]. Application of fatigue metabolites to muscle produces pain in human subjects [41].…”