Visceral Pain: Recent Knowledge and Advancement

100.4K
views
62
authors
13
articles
Cover image for research topic "Visceral Pain: Recent Knowledge and Advancement"
Editors
2
Impact
Loading...
Review
26 January 2018
The Influence of Early Life Experience on Visceral Pain
Isabella M. Fuentes
 and 
Julie A. Christianson
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.

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.

8,905 views
53 citations
Review
22 November 2017
Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin
Beverley Greenwood-Van Meerveld
 and 
Anthony C. Johnson
Mediators of chronic stress-induced visceral pain. Prolonged exposure to stressor can cause central dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis by changing the expression of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in limbic brain areas, such as the amygdala. Such changes lead to increased expression of corticotropin-releasing hormone (CRH), which facilitates further activation of the HPA axis and neuronal sensitization of the central pain matrix. Stress also disrupts endocannabinoid signaling that participates in fast-feedback inhibition of the HPA axis to modulate neuronal sensitivity within with the central pain matrix. Preclinical studies in visceral and neuropathic pain models have demonstrated roles for CRH to modulate spinal sensitization as well as GABA-ergic and glutamatergic signaling to modulate spinal sensitization to promote chronic pain. Within the dorsal root ganglia, roles for endocannabinoid signaling modulated by the GR have been demonstrated models of stress-induced pain. Additionally, local release of CRH within the enteric nervous system can modify sensitivity of extrinsic primary afferents to distension. Thus, multiple neurotransmitters, neuromodulators, and/or stress-responsive receptors are activated by chronic stressor leading to the development of chronic visceral pain.

Visceral pain is generally poorly localized and characterized by hypersensitivity to a stimulus such as organ distension. In concert with chronic visceral pain, there is a high comorbidity with stress-related psychiatric disorders including anxiety and depression. The mechanisms linking visceral pain with these overlapping comorbidities remain to be elucidated. Evidence suggests that long term stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic visceral pain disorders such as irritable bowel syndrome (IBS). Early life stress (ELS) is a risk-factor for the development of IBS, however the mechanisms responsible for the persistent effects of ELS on visceral perception in adulthood remain incompletely understood. In rodent models, stress in adult animals induced by restraint and water avoidance has been employed to investigate the mechanisms of stress-induce pain. ELS models such as maternal separation, limited nesting, or odor-shock conditioning, which attempt to model early childhood experiences such as neglect, poverty, or an abusive caregiver, can produce chronic, sexually dimorphic increases in visceral sensitivity in adulthood. Chronic visceral pain is a classic example of gene × environment interaction which results from maladaptive changes in neuronal circuitry leading to neuroplasticity and aberrant neuronal activity-induced signaling. One potential mechanism underlying the persistent effects of stress on visceral sensitivity could be epigenetic modulation of gene expression. While there are relatively few studies examining epigenetically mediated mechanisms involved in visceral nociception, stress-induced visceral pain has been linked to alterations in DNA methylation and histone acetylation patterns within the brain, leading to increased expression of pro-nociceptive neurotransmitters. This review will discuss the potential neuronal pathways and mechanisms responsible for stress-induced exacerbation of chronic visceral pain. Additionally, we will review the importance of specific experimental models of adult stress and ELS in enhancing our understanding of the basic molecular mechanisms of pain processing.

27,835 views
74 citations
Recommended Research Topics