An estimated 20% of the US population suffers from chronic pelvic pain, which encompasses a number of debilitating disorders including interstitial cystitis, irritable bowel syndrome, vulvodynia, chronic prostatitis and endometriosis, and costs more than $30 billion in direct medical and indirect costs annually. Up to 50% of women with chronic pelvic pain experience symptoms from more than one disorder, creating a greater negative impact on quality of life and complicating already less-than-optimal treatment strategies. Early life stress or trauma is a significant risk factor for developing functional pain disorders and is due, in part, to altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates stress response and influences the perception of pain. Proper feedback within the hypothalamus, as well as regulatory input from higher limbic structures, influences the response to stress and subsequent return to homeostasis. Several key molecules are involved in this process, including corticotropin releasing factor (CRF), the principal initiator of the strss response through the CRF1 receptor;the related urocortins (Ucn), which can inhibit stress response through the CRF2 receptor;and glucocorticoids, which mediate downstream stress responses, as well as influence both positive and negative feedback onto the HPA axis. Rodent models of neonatal stress display disruption of proper feedback onto the HPA axis, resulting in visceral hyperalgesia, permanent changes in central and peripheral pain processing, and increased peripheral expression of inflammatory mediators. The goal of the current proposal is to understand how early life stress predisposes an individual to developing pelvic pain syndromes during adulthood. Our central hypothesis is that neonatal maternal separation (NMS) disrupts proper functioning of CRF-responsive brain regions and peripheral targets, resulting in altered bladder function and sensitivity, as well as enhanced susceptibility to stress-induced symptomology and comorbidity. We have designed three specific aims (SAs) to test this hypothesis. SA1 will determine the effect of neonatal and adult stress on limbic regulation of the HPA axis and downstream neurogenic inflammation of the bladder. SA2 will examine how neonatal and adult stress affects central and peripheral CRF/Ucn2-dependent control of micturition. SA3 will evaluate the efficacy of CRF antagonism for attenuating neonatal and adult stress-induced bladder dysfunction, hypersensitivity and neurogenic inflammation, as well as comorbid vaginal hypersensitivity. At the completion of this project, we will have gained new information about how early life stress drives neuronal plasticity, primes the nervous system for future insult, and increases the susceptibility for developing comorbid functional pain disorders. By focusing on stress-induced changes in visceral sensitivity, we will gain insight as to how best treat a specific subpopulation of patients suffering from IC, vulvodynia, and potentially a number of other comorbid stress-induced functional pain disorders.

Public Health Relevance

The symptomatically diagnosed functional pain disorders are notoriously difficult to treat due to their wide array of underlying etiologies. The goal of this proposal is to identify potential treatments for a subset of patients that experienced early life stress and are predisposed to stress-induced symptom onset and exacerbation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-UGPP-G (08))
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Mullins, Christopher V
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University of Kansas
Anatomy/Cell Biology
Schools of Medicine
Kansas City
United States
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Fuentes, I M; Christianson, J A (2016) Ion channels, ion channel receptors, and visceral hypersensitivity in irritable bowel syndrome. Neurogastroenterol Motil 28:1613-1618
Pierce, Angela N; Di Silvestro, Elizabeth R; Eller, Olivia C et al. (2016) Urinary bladder hypersensitivity and dysfunction in female mice following early life and adult stress. Brain Res 1639:58-73
Fuentes, Isabella M; Pierce, Angela N; O'Neil, Pierce T et al. (2015) Assessment of Perigenital Sensitivity and Prostatic Mast Cell Activation in a Mouse Model of Neonatal Maternal Separation. J Vis Exp :e53181