Neonatal maternal separation in mice as a pre-clinical model for male chronic pelvic pain and voluntary exercise interventions

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is frequently co-diagnosed with other functional pain disorders, most significantly interstitial cystitis/painful bladder syndrome (IC/PBS), as well as mood disorders, particularly depression and/or anxiety. Patients suffering from functional pain disorders frequently report a history of early life stress, which has been associated with maladjusted stress response in adulthood. Basal function of the hypothalamic-pituitary-adrenal (HPA) axis, a major neuroendocrine stress response system, is programed during this critical period of development. Regular voluntary exercise has been shown to have a beneficial impact on depression and anxiety, as well as decreased perceptions of pain associated with HPA axis dysfunction in clinical and pre-clinical studies; however, to our knowledge, exercise has not been investigated as a potential intervention for comorbid urogenital pain disorders. This project reports neonatal maternal separation (NMS) induced mechanical perigenital allodynia, increased susceptibility to experimental colitis, altered micturition patterns, increased mast cell degranulation, and decreased HPA axis output. NMS did not, however, result in anxiety-like nor depression-like behaviors. Acute adult stress did significantly impact some of these measures, but did not enhance the effect of NMS. Lastly, we did see improvement of perigenital sensitivity following early and late exercise interventions, but did see more robust improvements in behavioral measurements after early exercise than late exercise. Late exercise, however, made a greater impact on central gene expression changes in limbic structures involved in HPA axis activity. Here, I have provided novel insight into the mechanisms potentially underlying significantly debilitating chronic pelvic pain disorders following early life stress, as well as evidence on the efficacy of therapeutic exercise, an easily translatable intervention, as a potential treatment strategy for these comorbid disorders. This work presents the first evidence of the impact of exercise on the effects of NMS on male mice, providing preclinical evidence for a treatment option for patients