Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin

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.

Keywords: animal model; brain; colon; early life; gastrointestinal tract; irritable bowel syndrome; pain; stress.

Figure 1

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.

Figure 2

Rodent models of stress-induced visceral hypersensitivity in adult animals. Here we highlight four experimental approaches for increasing visceral sensitivity in adult rodents. In each stress model, we present the duration of the stressor required to produce visceral hypersensitivity and have indicated which sex has been investigated. Please note that the duration and timing of the stressors reflect the range of procedures used within the literature, rather than a specific experimental protocol.

Figure 3

Rodent models of early life stress (ELS)-induced visceral hypersensitivity. Here we highlight three experimental approaches for increasing visceral sensitivity in adult rodents in response to early life stress. In each model, we have summarized the typical post-natal period of the stress exposure, the duration of the stressor, and the effect on colonic sensitivity in adulthood, along with the sex of the rat reliably showing colonic hypersensitivity. Please note that the duration and timing of the ELS reflects the range of procedures used within the literature, rather than a specific experimental protocol.

Figure 4

Epigenetic regulation of chronic stress-induced visceral pain. Epigenetics describes the processes by which the environment influences gene expression to cause persistent changes in behaviors. Stressors (early life stress, adult stressors, or both) induce changes in the methylation status of DNA promoter regions to enhance or repress transcription rates. Stressors also change the state of histone acetylation around the gene promoter regions to facilitate or hinder the binding of the transcription complex, which also affects gene transcription. These stress-induced changes in DNA methylation and histone acetylation cause changes in gene expression that persist well beyond the duration of the stressor. Additionally, due to hormonal differences across the lifespan, sex differences in response to stressors can also modify the epigenetically induced changes in gene expression. The net effect is the development of chronic visceral pain following stressors that persist through the individual's lifetime due to epigenetically induced changes in gene expression leading to enhanced neuronal sensitivity.