Neonatal maternal separation in mice as a pre-clinical model for female chronic pelvic pain

Abstract

Chronic pelvic pain is currently estimated to impact 9.2 million women in the United States. As many as half of these women will have comorbid conditions, such as chronic pain in multiple pelvic organs, mood disorder, and/or somatic functional pain disorders, which are often of unknown etiology and complicate already less-than-optimal treatment strategies. Functional pain patients are more likely than the general population to report histories of early life adverse events, including abuse, neglect, and trauma. Exposure to these early life stressors can have a profound lifelong impact on neurodevelopment, behavior, and the neuroendocrine response to stress by influencing the hypothalamic-pituitary-adrenal (HPA) axis, the tone of which is set during this critical period of development. Using an animal model of early life stress, this project evaluated changes in behavior and urogenital hypersensitivity in adulthood, assessed alterations in the regulation of the HPA axis, and investigated voluntary exercise as a potential therapeutic intervention. This project was the first of its kind to study the impact of early life stress on adult behavior relevant to pain and associated comorbidities in female mice. Specifically, molecular approaches evaluated how early life stress influenced long-term changes in the expression of genes that regulate the HPA axis. The impact of early life stress on the neuroendocrine response to acute stress in adulthood was evaluated by characterizing HPA axis output and the downstream immune response to stress in the pelvic organs. Finally, this project provided novel preclinical model of exercise as an intervention for early life stress-induced urogenital pain and associated comorbid behaviors. Together, this work provides insight into how early life stress alters the function of the nervous system, impacts the neuroimmune profile of the female genitourinary tract, and whether exercise, an easily translatable intervention method, can attenuate the impact of early life adverse events.