Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome

Center for Neurobiology of Stress, David Geffen School of Medicine, University of California, Los Angeles, CA 90073, USA.
Neurogastroenterology and Motility (Impact Factor: 3.59). 09/2008; 21(2):149-59. DOI: 10.1111/j.1365-2982.2008.01171.x
Source: PubMed


Enhanced stress responsiveness has been implicated as a potential mechanism contributing to the pathophysiology of irritable bowel syndrome (IBS), and should be reflected in altered function of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Both of these systems can modulate mucosal immune function. The aims of this study were: (i) to characterize the basal circadian rhythm of adrenocorticotropin hormone (ACTH) and cortisol in IBS vs healthy controls; (ii) to compare stimulated ACTH, cortisol and noradrenaline responses to a pelvic visceral stressor (sigmoidoscopy) in IBS and controls; and (iii) to correlate neuroendocrine responses with colonic mucosal cytokine expression and symptoms in IBS. Two separate studies were conducted in women. In Study 1, basal cortisol levels were analysed in 41 IBS and 25 controls using 24-h collections of plasma ACTH and cortisol (q10 min sampling). In Study 2, 10 IBS patients with diarrhoea (IBS-D) and 10 controls underwent sigmoidoscopy with measurements of stimulated neuroendocrine responses and cytokine mRNA expression in colonic tissue. Basal ACTH levels were significantly blunted (P < 0.05), while basal and stimulated plasma cortisol levels were higher in patients. Basal cortisol levels prior to an experimental visceral stressor positively correlated with anxiety symptoms (P < 0.004), but not IBS symptoms. Irritable bowel syndrome patients with diarrhoea had significantly decreased mRNA expression of mucosal cytokines [interleukin (IL)-2, IL-6] in the sigmoid colon vs controls (P < 0.05). Although dysregulations in stress-responsive systems such as the HPA axis and mucosal immune function are demonstrated in IBS, they do not appear to have a primary role in modulating IBS severity and abdominal pain.

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Available from: Emeran A Mayer, Mar 11, 2014
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    • "Subsets of these patients report stress-related symptom onset or increased severity, have difficulty coping with stressful situations, and suffer from depression and/or anxiety (Arnold et al., 2006; Larauche et al., 2012; Bullones Rodriguez et al., 2013). The comorbidity between mood disorders and chronic pelvic pain is due, in part, to altered functioning of corticotropin-releasing factor (CRF)-responsive regions of the brain, including the hypothalamic–pituitary– adrenal (HPA) axis, which regulates stress response and influences the perception of pain (Heim et al., 1998; Chang et al., 2009; Mayson and Teichman, 2009). Under stressful conditions, CRF is secreted from the paraventricular nucleus (PVN) of the hypothalamus and induces the systemic release of adrenocorticotropic hormone (ACTH) from the anterior pituitary corticotrophs. "
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    ABSTRACT: Early life stress can permanently alter functioning of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the stress response and influences the perception of pain. Chronic pelvic pain patients commonly report having experienced childhood neglect or abuse, which increases the likelihood of presenting with comorbid chronic pain and/or mood disorders. Animal models of neonatal stress commonly display enhanced anxiety-like behaviors, colorectal hypersensitivity, and disruption of proper neuro-immune interactions in adulthood. Here, we tested the hypothesis that early life stress impacts vaginal sensitivity by exposing mice to neonatal maternal separation (NMS) for 3hr/day during the first two (NMS14) or three (NMS21) postnatal weeks. As adults, female mice underwent vaginal balloon distension (VBD), which was also considered an acute stress. Before or after VBD, mice were assessed for anxiety-like behavior, hindpaw sensitivity, and changes in gene and protein expression related to HPA axis function and regulation. NMS21 mice displayed significantly increased vaginal sensitivity compared to naïve mice, as well as significantly reduced anxiety-like behavior at baseline, which was heightened following VBD. NMS21 mice exhibited significant thermal and mechanical hindpaw hypersensitivity at baseline and following VBD. NMS14 mice displayed no change in anxiety-like behavior and only exhibited significantly increased hindpaw mechanical and thermal sensitivity following VBD. Centrally, a significant decrease in negative regulation of the HPA axis was observed in the hypothalamus and hippocampus of NMS21 mice. Peripherally, NMS and VBD affected the expression of inflammatory mediators in the vagina and bladder. Corticotropin releasing factor (CRF) receptor and transient receptor potential (TRP) channel protein expression was also significantly, and differentially, affected in vagina, bladder, and colon by both NMS and VBD. Together these data indicate that NMS affects both central and peripheral aspects of the HPA axis, which may drive changes in vaginal sensitivity and the development of comorbid chronic pain and mood disorders.
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    • "mechanical allodynia and thermal hyperalgesia (Zhang et al., 2012), and (b) a mouse model of chronic psychosocial stress along with visceral hiperalgesia (Tramullas et al., 2012). This evidence highlights that changes in both the HPA axis activity and the immune function are involved in chronic stress-induced hyperalgesia (Blackburn- Munro and Blackburn-Munro, 2001; Fries et al., 2005; Chang et al., 2009; Sominsky et al., 2013). Yet, it is not completely clear the way the HPA axis, immune and nociceptive functions are connected as to lead to the development of enduring cutaneous pain after repeated exposure to stress. "
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    ABSTRACT: Although it is widely known that immunological, hormonal and nociceptive mechanisms are altered by exposure to repeated stress, the interplaying roles of each function in the development of post-stress hyperalgesia are not completely clear. Thus, we wanted to establish how interleukin 1-beta (IL-1β), corticosterone and microglia interact to contribute in the development of hyperalgesia following repeated forced swim. Rats were subjected to either forced swim, sham swim or non-conditioned. Each group was then treated with minocycline, ketoconazole, or saline. Thermal nociception was measured via the hot plate test, before and after the behavioral conditioning, whereas blood and lumbar spinal cord tissue samples were obtained at the end of the protocol. Serum levels of corticosterone, spinal tissue concentration of IL-1β and spinal OX-42 labeling (microglial marker) were determined. Rats exposed to forced swim stress developed thermal hyperalgesia along with elevated spinal tissue IL-1β, increased OX-42 labeling and relatively diminished serum corticosterone. Pre-treatment with minocycline and ketoconazole prevented the development of thermal hyperalgesia and the increase in IL-1β, without significantly modifying serum corticosterone. These results suggest that the development of forced swim-induced thermal hyperalgesia requires the simultaneous presence of increased spinal IL-1β, microglial activation, and relatively decreased serum corticosterone.
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    • "A relationship between ELA and the development of IBS in adulthood has been described in clinical literature and animal models. Furthermore, both ELA and IBS are characterized by female predominance and dysregulation of the HPA axis (Drossman et al., 1997; Whitehead et al., 2002; Dinan et al., 2006; Tarullo and Gunnar, 2006; Hyman et al., 2008; Chang et al., 2009). Therefore, the mechanisms by which ELA induces visceral hypersensitivity likely involve ovarian hormones and signaling within the HPA axis. "
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    ABSTRACT: A history of early life adversity (ELA) has health-related consequences that persist beyond the initial maltreatment and into adulthood. Childhood adversity is associated with abnormal glucocorticoid signaling within the hypothalamic-pituitary-adrenal (HPA) axis and the development of functional pain disorders such as the irritable bowel syndrome (IBS). IBS and many adult psychopathologies are more frequently diagnosed in women, and ovarian hormones have been shown to modulate pain sensitivity. Therefore, the sexually dimorphic effects of ELA and the role of ovarian hormones in visceral pain perception represent critical research concepts to enhance our understanding of the etiology of IBS. In this review, we discuss current animal models of ELA and the potential mechanisms through which ovarian hormones modulate the HPA axis to alter nociceptive signaling pathways and induce functionally relevant changes in pain behaviors following ELA.
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