The impact of genetic differences, voluntary exercise, and thermal injury on chronic pain and comorbidities in psychologically-stressed mice.

An estimated 80% of Americans suffer from at least one stress-related symptom during a month’s time and the number is increasing year by year. Co-morbidity of pain and psychological disorders is very common, and both can be induced by stressful events. Psychological stress activates the Hypothalamic-Pituitary-Adrenal (HPA) axis and subsequently initiates and/or exacerbates symptoms related to both chronic pain and mood disorders. The impact of stress on allodynia and anhedonic behaviors in highly anxious individuals has not been well studied. The overall goal of this dissertation is to investigate stress-induced negative impacts on anxiety in individuals and search for potential non-pharmacological treatments for comorbid chronic pain and mood disorders in patients with anxiety. By exposing anxiety-prone A/J mice to 10 consecutive days of foot shock stress, we established a feasible small rodent model for studying comorbid pain and depression in an individual with pre-existing anxiety. Foot shock-stressed A/J mice developed persistent bladder hypersensitivity, hind paw mechanical allodynia, and anhedonic behavior. Further, the HPA axis and inflammatory mediators were altered by foot shock stress. Considering other reports have identified that exercise has beneficial effects on both mood disorders and chronic pain, we tested the hypothesis that voluntary wheel running (VWR) can prevent persistent bladder, mechanical hypersensitivity, and anhedonic behavior in foot shock-exposed A/J mice. We discovered that four weeks of VWR decreased mechanical sensitivity, but failed to reach significance in stressed A/J mice. VWR also had no significant impact on either bladder hypersensitivity or anhedonic behavior. However, VWR normalized HPA axis output in stressed A/J mice. Interestingly, A/J mice displayed a unique running pattern after foot shock stress, suggesting that VWR behavior could be used as a potential biobehavioral marker of stress in mice. To explore how genetic differences in baseline anxiety impact the response to stress, we compared hind paw mechanical and bladder sensitivity in anxiety-prone A/J and non-anxious C57Bl/6 mice following foot shock exposure. Both strains developed persistent hind paw allodynia, but bladder hypersensitivity was only present in A/J mice. By recording fecal output as a measure of anxiety during the foot shock exposure, we confirmed that C57Bl/6 mice adapted to the foot shock, whereas A/J mice did not. Finally, we adapted our foot shock model in A/J and C57Bl/6 mice to understand how underlying anxiety and stress exposure impacts the transition from acute to chronic pain following a burn injury. We revealed that psychosocial stress may be one of the key factors for developing persistent pain after burn injury. The whole of my dissertation has provided important and novel information on how stress and underlying anxiety may predispose an individual to develop chronic comorbid pain and mood disorders. Understanding how specific systems, such as the HPA axis and the inflammatory response are affected provides important therapeutic targets for the development of pharmacological and non-pharmacological treatments