ANALYZING MUSCULAR PAIN AND THE EFFECTS OF EXERCISE ON CHRONIC PAIN

Abstract

Most people suffering from various chronic pain syndromes report deep tissue pain. However, our knowledge about chronic musculoskeletal pain is primarily based on rodent models of cutaneous pain. Little is known about muscle nociception and its modulation with exercise training. The overall purpose of this dissertation was to assess muscle pain and determine the role of aerobic exercise in reducing chronic pain induced by acidic saline in mice. This animal model mimics a human condition, fibromyalgia and similar diseases that present with widespread hypersensitivity to mechanical stimuli. All experiments were carried out in 2 different strains of female mice, C57Bl/6 and CF-1. Widespread chronic pain was induced by injections of acidic saline into the gastrocnemius muscle, and treadmill running was chosen as a mode of aerobic exercise training. Hypersensitivity to mechanical stimulation was tested in the cutaneous and muscle tissues utilizing standard methods of von Frey monofilaments, instrumented forceps device and Fos expression of the dorsal horn spinal cells. The effect of aerobic exercise on chronic pain state was tested with behavioral and molecular measures. The results indicated that acid injections induced cutaneous and muscle hyperalgesia in female mice, yet the development of widespread pain is subjected to the variability of genetic background in both strains of mice. In C57BL/6 mice, the effect of acid injections was less robust. The CF-1 mice developed muscle hyperalgesia that lasted up to 2 weeks, suggesting chronic phase of muscle pain. This finding was confirmed with increased Fos activity in the corresponding spinal cord level. Furthermore, the central projection of nociceptors from the paw and the gastrocnemious muscle evoked different Fos activation pattern. The molecular basis for the positive actions of exercise remains poorly understood. Therefore, we tested the effects of exercise training of 2-intensivity levels (mildly-intense on C57BL/6 mice and moderately-intense on CF-1 mice) on widespread chronic pain and neurotrophin-3 (NT-3) synthesis. The results indicated that moderate exercise training reduced widespread hyperalgesia, whereas the effect of mild exercise training was less robust. Likewise, moderately-intense exercise training upregulated NT-3 synthesis in the skeletal muscle; mild exercise training had no effect of NT-3 levels. The increase in NT-3 was more pronounced at the protein levels compared to mRNA expression. In addition, the protein levels were significant only in the gastrocnemius and not in the soleus muscle, suggesting that exercise can preferentially target NT-3 synthesis in specific muscles. In summary, this body of work indicates a novel finding of chronic muscle pain and adds new information to our understanding of deep tissue nociception as well as its spinal distribution. This study is the first to demonstrate the beneficial effect of aerobic exercise training on chronic muscle pain in the acid-pain model. These results strengthen the role of NT-3 as an anti-nociceptive neurotrophin in treating muscle pain and provide further support for exercise training as a therapeutic intervention for the growing field of pain medicine.