Abstract
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.
Highlights
Chronic pain is defined as pain lasting longer than 3 months after the resolution or in the absence of an injury
There is significant overlap of neural circuity that process sensations of pain or stress, such as the amygdala, the insula, or areas of the cingulate, along with common neurotransmitters and their receptors, such as glucocorticoid receptor (GR) or corticotropin-releasing hormone (CRH), that are expressed within the GI tract on resident immune cells or intrinsic nerves and within dorsal root ganglia, the spinal cord, and throughout the brain
The major neuroendocrine stress hormone, corticosterone in rodents (CORT), which is secreted in response to activation of the HPA axis by stressors, acts at GR and mineralocorticoid receptor (MR) receptors throughout the body, but can promote enhanced sensitivity of neurons to both noxious and innocuous stimuli, which in turn promotes the development of chronic pain
Summary
Chronic pain is defined as pain lasting longer than 3 months after the resolution or in the absence of an injury. We will briefly review visceral pain pathways and their modulation by (i) stress in adulthood and (ii). We will provide an evidenced-based argument for the use of specific experimental models to advance the understanding of stress-induced chronic pain. We will explain the unique aspects of these models that allows for a carefully crafted investigation of the female vulnerability to stress-induced chronic visceral pain. The science of the epigenetics of human pain management is in its early stages with relatively few studies that have examined epigenetically mediated mechanisms involved in nociception in human subjects, a key aspect of the review will be to highlight the latest insights into epigenetic processes, including DNA methylation, histone modifications and microRNAs, and describe their involvement in the pathophysiology of chronic visceral pain
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