The Influence of Early Life Experience on Visceral Pain

Abstract

Pain is the most reported and troublesome symptom of nearly all functional disorders affecting the genitourinary and gastrointestinal organs. Patients with irritable bowel syndrome (IBS), interstitial cystitis/painful bladder syndrome (IC/PBS), vulvodynia, and/or chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS; collectively termed chronic pelvic pain syndromes) report pain severe enough to impact quality of life and often suffer from symptoms of or are diagnosed with more than one of these syndromes. This increased comorbidity between chronic pelvic pain syndromes, and with pain disorders of disparate body regions, as well as with mood disorders, can be influenced by disruptions in the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the response to stress and influences the perception of pain. Experiencing trauma, neglect, or abuse in early life can permanently affect the functioning of the HPA axis. As such, a significant proportion of patients suffering from comorbid chronic pelvic pain syndromes report a history of early life stress or trauma. Here we will report on how these early life experiences influence chronic pelvic pain in patients. We will also discuss various rodent models that have been developed to study this phenomenon to understand the mechanisms underlying HPA axis dysfunction, as well as potential underlying mechanisms connecting these syndromes to one another.

Keywords: CRF; chronic pelvic pain; early life stress; hypothalamic-pituitary-adrenal (HPA) axis; neonatal maternal separation (NMS); visceral hypersensitivity.

Figure 1

Schematic representation of early life stress-induced changes in limbic regulation of and downstream targets of the hypothalamic-pituitary-adrenal (HPA) axis. Following exposure to an acute stressor, the hypothalamus will release corticotropin-releasing factor (CRF), which signals the anterior pituitary to release adrenocorticotropic hormone (ACTH). The systemic circulation of ACTH initiates the adrenal cortex to release glucocorticoids (GCs, cortisol in humans, corticosterone in rodents). Both GC and CRF will bind to receptors expressed by higher structures within the HPA axis and by limbic structures, including the amygdala and hippocampus, to reduce HPA axis activity and restore homeostasis upon cessation of the stressor. Early life stress disrupts this system by increasing the release of CRF from the hypothalamus and amygdala, as well as decreasing glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF) in the hippocampus, which has a combined effect of increasing positive feedback onto the HPA axis and driving activation. Downstream actions of CRF include increasing mast cell activation and inducing local inflammatory effects, binding onto enteric neurons that can increase colonic motility, and increasing epithelial permeability by disrupting tight junctions. Together these mechanisms drive increased visceral pain in organs affected in irritable bowel syndrome (IBS), interstitial cystitis/painful bladder syndrome (IC/PBS), chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), and/or vulvodynia.