Mechanisms of Stress-induced Visceral Pain

Abstract

Evidence suggests that long-term stress facilitates visceral pain through sensitization of pain pathways and promotes chronic visceral pain disorders such as the irritable bowel syndrome (IBS). This review will describe the importance of stress in exacerbating IBS-induced abdominal pain. Additionally, we will briefly review our understanding of the activation of the hypothalamic-pituitary-adrenal axis by both chronic adult stress and following early life stress in the pathogenesis of IBS. The review will focus on the glucocorticoid receptor and corticotropin-releasing hormone-mediated mechanisms in the amygdala involved in stress-induced visceral hypersensitivity. One potential mechanism underlying 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 stress-induced visceral nociception, alterations in DNA methylation and histone acetylation patterns within the brain, have been linked to alterations in nociceptive signaling via increased expression of pro-nociceptive neurotransmitters. This review will discuss the latest studies investigating the long-term effects of stress on visceral sensitivity. Additionally, we will critically review the importance of experimental models of adult stress and early life stress in enhancing our understanding of the basic molecular mechanisms of nociceptive processing.

Keywords: Amygdala; Early life adversity; Irritable bowel syndrome; Models; Visceral pain; animal.

Figure 1

Pathophysiology of irritable bowel syndrome (IBS): activation of the brain-gut axis. Working model of stress-induced brain-gut dysfunction in IBS. Physical or psychological threats (actual or perceived) are stressors that activate both the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) to allow the individual to respond to the threat and to restore homeostasis. Prolong activation of the body’s stress response can lead to immune system dysfunction including activation of mast cells in the periphery and microglia in the spinal cord and the brain, release of proinflam-matory cytokines, and changes in host microbiota. Taken together, chronic stress and immune dysfunction provides an underlying mechanism for alterations in gut phenotypes including neuromuscular dysfunction, abnormal barrier function, and visceral hypersensitivity. Once established, these abnormal gut phenotypes facilitate further activation of the stress systems and immune dysfunction that maintains IBS symptoms.

Figure 2

Amygdala-mediated mechanisms for stress-induced colonic hypersensitivity. The body’s neuroendocrine stress response (hypothalamic-pituitary-adrenal [HPA] axis) is initiated at the hypothalamus and causes the synthesis and release of corticotropin-releasing hormone (CRH) onto the anterior pituitary. Upon binding of CRH to its type 1 receptor, the pituitary gland secretes adrenocorticotropic hormone (ACTH) into the peripheral blood circulation leading to production of cortisol in humans or corticosterone (CORT) in rodents. Following release into the circulation, CORT binds to the glucocorticoid receptor (GR) to initiate negative feedback of the HPA axis at the level of the hypothalamus and the hippocampus. In contrast, CORT binding to GR at the amygdala leads to facilitation of HPA axis, thus promoting persistent stress activation.,– In this review, we discuss our recent data showing that stress activation or implantation of a CORT micropellet at the amygdala produces persistent colonic hypersensitivity to balloon distension along with decreased GR expression and increased CRH expression.– Our findings have also revealed that a decrease in GR expression could be due to increased methylation (Me) of the GR promoter along with decreased acetylation (Ac) of histone 3 (H3) at the GR promoter., The persistent decrease in GR expression decreases the binding of GR to a negative GR response (nGRE) element in the CRH promoter, thus removing GR-induced repression of CRH expression. The loss of the repression of the CRH promoter induced a persistent increase in CRH expression, and inhibiting the increase in CRH expression reversed the stress-induced colonic hypersensitivity.