Stress-related alterations of visceral sensation: animal models for irritable bowel syndrome study (original) (raw)
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Frontiers in Psychiatry, 2015
Visceral pain is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. It is a hallmark of functional gastrointestinal disorders such as irritable-bowel syndrome (IBS). Currently, the treatment strategies targeting visceral pain are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here, we discuss the complex etiology of visceral pain reviewing our current understanding in the context of the role of stress, gender, gut microbiota alterations, and immune functioning. Furthermore, we review the role of glutamate, GABA, and epigenetic mechanisms as possible therapeutic strategies for the treatment of visceral pain for which there is an unmet medical need. Moreover, we discuss the most widely described rodent models used to model visceral pain in the preclinical setting. The theory behind, and application of, animal models is key for both the understanding of underlying mechanisms and design of future therapeutic interventions. Taken together, it is apparent that stress-induced visceral pain and its psychiatric comorbidities, as typified by IBS, has a multifaceted etiology. Moreover, treatment strategies still lag far behind when compared to other pain modalities.The development of novel, effective, and specific therapeutics for the treatment of visceral pain has never been more pertinent.
BIOLOGICAL INTERACTION OF STRESS AND IRRITABLE BOWEL SYNDROME
A variety of stressors play a role in the development of irritable bowel syndrome. Irritable bowel syndrome is a biopsychosocial disorder that results from dysregulation of central or enteric nervous system function. The physiological effects of psychological and physical stressors on gut function and brain-gut interactions are mediated by outputs of the emotional motor system in terms of autonomic, neuroendocrine, attentional, and pain modulatory responses. Certain investigational studies reported to date indicate that the activation of CRF1 pathways may result in a combination of effects that are key features of symptoms in some irritable bowel syndrome patients. These include stimulation of colonic motility, defecation or watery diarrhea, gut hypersensitivity that increases the perception of stimuli within the bowel, focused attention (hypervigilance) toward the gut sensations, and mast cell activation. Blocking the CRF1 receptors may alleviate all these effects. Stress thus can be included in an integrative model explaining the pathophysiology of functional bowel disorder. Advances in the understanding of the relationship between stress and visceral perception may constitute a basis for a therapeutic approach of functional bowel disorders targeted on the central nervous system.
Stress and visceral pain: From animal models to clinical therapies
Experimental Neurology, 2012
Epidemiological studies have implicated stress (psychosocial and physical) as a trigger of first onset or exacerbation of irritable bowel syndrome (IBS) symptoms of which visceral pain is an integrant landmark. A number of experimental acute or chronic exteroceptive or interoceptive stressors induce visceral hyperalgesia in rodents although recent evidence also points to stressrelated visceral analgesia as established in the somatic pain field. Underlying mechanisms of stress-related visceral hypersensitivity may involve a combination of sensitization of primary afferents, central sensitization in response to input from the viscera and dysregulation of descending pathways that modulate spinal nociceptive transmission or analgesic response. Biochemical coding of stress involves the recruitment of corticotropin releasing factor (CRF) signaling pathways. Experimental studies established that activation of brain and peripheral CRF receptor subtype 1 plays a primary role in the development of stress-related delayed visceral hyperalgesia while subtype 2 activation induces analgesic response. In line with stress pathways playing a role in IBS, non-pharmacologic and pharmacologic treatment modalities aimed at reducing stress perception using a broad range of evidence-based mind-body interventions and centrally-targeted medications to reduce anxiety impact on brain patterns activated by visceral stimuli and dampen visceral pain.
Complex Neurobehavioral Testing of a Rat Model of the Irritable Bowel Syndrome
Neurophysiology, 2018
In albino Wistar rats, the irritable bowel syndrome (IBS) was induced by chronic restraint stress (restriction of the animals in plastic containers, 6 h per day during 7 days). In the Y-like maze, IBS rats demonstrated smaller numbers of spontaneous alternations (indices of immediate spatial memory; P < 0.05) than control animals. In the elevated plus maze, IBS rats showed a significantly reduced time spent in the open arms (P < 0.03) compared to the controls, suggesting anxiety-like effects. Moreover, episodes of stretching in this maze were more numerous in the IBS group (P < 0.05), also suggesting anxiogenic effects. Some depression-like behavior of IBS rats was observed in the forced swimming test, as was demonstrated by a significantly shorter mobility time, as compared to the control group (P < 0.05). In the radial 8-arm maze, however, chronic stress-induced IBS did not significantly affect the number of reference memory errors and time necessary for completing the task. Still, some working memory deficit was observed in the IBS group in this test, as the number of the respective errors was significantly greater (P < 0.05) in such rats vs. controls within some time intervals. In the open field test, suppression of locomotor activity (reduced number of square crossings), significantly increased number of rearings (suggesting higher anxiety), and altered fecal elimination in the IBS group were obvious (P < 0.05). Also, an increased time of grooming was observed in IBS rats in the above test (characterizing a higher anxiety level in the stress-exposed IBS group). When zoosocial behavior was tested in a threechambered apparatus (10-min-long period of testing), rats of the IBS group spent significantly more time in the empty compartment (without a stranger rat) and less time in the compartment with a conspecific of the same age and weight (P < 0.01), which indicates decreased social motivation in the IBS group. Our results suggest that the aforementioned chronic stress-induced IBS model results in increased anxiety, depression, and suppressed social behavior. The IBS affects immediate and working memory (with nearly no effect, however, on reference memory).
Gastroenterology, 2004
Background & Aims: Stress is an important causative factor in irritable bowel syndrome (IBS). It remains unknown whether stress-related changes in gut function are mediated by altered autonomic efferent gut-specific innervation. We studied the effect of acute physical and psychological stress on autonomic innervation and visceral sensitivity in healthy volunteers and patients with IBS. Methods: Twenty-four patients (20 women) with constipation-predominant IBS and 12 healthy volunteers (8 women) underwent either physical (cold water hand immersion) or psychological (dichotomous listening) stress on separate occasions. Assessments included stress perception (visual analogue scale), gut-specific autonomic innervation (rectal mucosal blood flow [RMBF] by laser Doppler flowmetry), and viscerosomatic sensitivity (anal and rectal electrosensitivity). Results: Patients with IBS had a heightened baseline perception of stress (P < .01). RMBF decreased during physical stress (29.6% ؎ 2.8% and 28.7% ؎ 3.9%) and psychological stress (24.4% ؎ 2.1% and 23.5% ؎ 4.3%) in patients with IBS and controls, respectively (mean ؎ SEM). During physical stress, rectal perception (23.2% ؎ 6% vs .6% ؎ 3% [IBS vs control group, P < .05]) and rectal pain thresholds (27.0% ؎ 4% vs 1.3% ؎ 5%, P < .001) decreased in patients with IBS only. Psychological stress reduced thresholds for rectal perception (19.4% ؎ 6% vs 8% ؎ 6%, P < .01) and rectal pain (28.4% ؎ 4% vs 3.4% ؎ 3.8%, P < .001) in patients with IBS only. Acute stress elevated anal perception thresholds in patients with IBS but not controls (physical stress: 14.7% ؎ 14% vs ؊9.3% ؎ 11%, P < .05; psychological stress: 24.7% ؎ 9% vs 11% ؎ 11%, P < .05). Conclusions: Acute stress alters gut-specific efferent autonomic innervation in both controls and patients with IBS, although normalization is delayed in IBS. By contrast, only patients with IBS show heightened visceral sensation, suggesting involvement of a different regulatory mechanism, either central or peripheral.
Romanian Biotechnological Letters
Irritable bowel syndrome (IBS) is a digestive tract functional disorder, without anatomical or structural problems, manifesting through stool abnormalities, diarrhea or constipation or both forms alternating between them over time, accompanied by abdominal pain, bloating or flatulence. These symptoms contribute not only to poor digestive absorption, disturbed intestinal motility, but can alter gut microbiota, induce intestinal inflammation through immunity mediators, and negatively impact the psychology of the person. The literature concerning animal models of IBS encompasses numerous studies based on unpredictabile chronic mild stressors applied on rodents, rats. Generally, the stress paradigms consist in exposing the animals to a series of randomly alternating micro-stressors. A key aspect when applying the low intensity stress factors is to maximize their degree of unpredictability by a randomized order, as well as the period of exposure which may last from 2 to 16 weeks. Considering the time and resource-demanding procedures for establishing such IBS stress models, we were interested in developing a reliable and effective model that would result also in the emotional depressive changes accompanying the gastrointestinal disturbances. Thus, our approach was to combine water avoidance stress, an equally reliable acute and chronic stressor, as a constantly repeated factor, with randomized unpredictable mild stressors. Thus, this is a new approach and a new combination that we presumed to be efficient even if applied for a shorter period of one week. Our results are suggesting that the current protocol of 1-week-long multiple heterotypic combination with homotypic chronic stress can be effective to replicate the behavioral manifestations similar to IBS symptoms and the accompanying depression-like features. We would presume this would be more efficient if applied for longer time, although in the present case it did work, even if applied for a shorter period of one week.
Stress and the Microbiota-Gut-Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome
CNS Neuroscience & Therapeutics, 2015
Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects a significant proportion of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience comorbid behavioral disorders, such as anxiety or depression; thus, IBS is described as a disorder of the gut-brain axis. Stress is implicated in the development and exacerbation of visceral pain disorders. Chronic stress can modify central pain circuitry, as well as change motility and permeability throughout the gastrointestinal (GI) tract. More recently, the role of the gut microbiota in the bidirectional communication along the gutbrain axis, and subsequent changes in behavior, has emerged. Thus, stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviors. This review will highlight the evidence by which stress and the gut microbiota interact in the regulation of visceral nociception. We will focus on the influence of stress on the microbiota and the mechanisms by which microbiota can affect the stress response and behavioral outcomes with an emphasis on visceral pain.
Stress and gastrointestinal motility in animals: a review of the literature
Neurogastroenterology & Motility, 2008
In the last decade an increasing number of studies have been published dealing with the effects of experimental stress on gastrointestinal functions in animals and humans. Initial interest in gastrointestinal stress responses in the late 1940s and early 1950s' was followed b y continued interest only in experimental ulcer research.' The recent 'revival' of interest in stress is due to some methodological progress: first, our understanding of gastrointestinal functions, specifically gastrointestinal motility has grown after new measurement techniques became widely available to enable gastrointestinal stress effects t o be determined directly-instead of its indirect outcome such as stool frequency or gastrointestinal symptoms. Second, interest has grown in functional abdominal disorders such as the irritable bowel syndrome or nonulcer dyspepsia, which are often believed to be, at least in part, stress related." Finally, stress has become a major paradigm b y which to investigate brain-gut interactions, specifically with respect to the yet unanswered question of the extent of autonomy or CNS control to regulate gastrointestinal function^.^ Our review is split into two parts. The first part focused on clinical aspects in h u m a n studies.' This part will deal with animal studies and discusses their relevance with respect to basic research questions.