1. Introduction
Irritable bowel syndrome (IBS) is a functional digestive disorder characterized by abdominal pain, bloating and altered bowel habits without any organic cause (Drossman 1999b; Mulak and Bonaz 2004). Patients with IBS exhibit enhanced perception of visceral sensation to colonic distension which is associated with hypervigilance at the origin of visceral hypersensitivity (VHS) (Ritchie 1973; Bradette, et al. 1994; Elsenbruch, et al. 2010). VHS is a clinical marker of IBS considered to play a major role in its pathophysiology. The exact cause of VHS is unknown but a number of mechanisms are evoked as represented by neuroplastic changes in primary afferent terminals (peripheral sensitization) due to peripheral inflammation or infection of the gut (i.e. post-infectious IBS) but also in the spinal cord (central sensitization) and in the brain (supraspinal pain modulation) or in descending pathways that modulate spinal nociceptive transmission (Bonaz 2003; Mulak and Bonaz 2004). In addition, stress is able to increase visceral sensitivity either at the central and/or peripheral level (Mulak and Bonaz 2004; Larauche, et al. 2011).
There is a bidirectional communication between the central nervous system (CNS) and the gastrointestinal (GI) tract, i.e. the brain-gut axis, such as signals from the brain can modify the motor, sensory, secretory, and immune functions of the GI tract and, conversely, visceral messages from the GI tract can influence brain functions in a top-down and bottom-up relation. Numerous data argue for a dysfunction of this brain-gut axis in the pathophysiology of IBS (Mulak and Bonaz 2004; Bonaz and Sabate 2009; Tillisch, et al. 2011).
Stress, through the corticotrophin-releasing factor (CRF) system (CRF, urocortins and their receptors CRF1,2), is a key factor involved in the pathophysiology of IBS. Indeed, stress is able to modify visceral sensitivity as well as GI motility, permeability, intestinal microbiota, and immunity of the GI tract, all mechanisms that are involved in the pathophysiology of IBS. In addition, stress is able to modulate the hypothalamic pituitary adrenal (HPA) axis and the autonomic nervous system (ANS) which is the link between the gut and the CNS and an imbalance of the ANS is observed in IBS patients (Pellissier, et al. 2010a; Mazurak, et al. 2012). The main brain areas involved in stress are the prefrontal cortex, the limbic system (e.g. the hippocampus and the amygdala) and the hypothalamus. Relations between the prefrontal cortex and the limbic system are important in the management of stress response.
The amygdala is a key structure involved in the stress effect on the GI tract. Indeed, the amygdala is involved in brain-gut and gut-brain interactions.
At the present time, the only medical treatment of IBS is directed at GI motor/sensory or CNS processing. Unfortunately, this treatment is poorly effective and often associated with high placebo effects, thus revealing the importance of the overlap between pain and placebo neurobiological pathways. The therapeutic approach is essentially focused on the symptoms as represented by anti-spasmodics for pain, laxatives or bulking agents, 5-HT4 agonists and guanylate cyclase-C agonist for intestinal transit regulation and anti-depressives/anxiolytics drugs. Placebo has a ≈ 40% efficacy in IBS patients (Patel, et al. 2005) and pronounced placebo analgesia is coupled with prominent changes of brain activity in visceral pain matrix, as represented by the amygdala (Lu, et al. 2010). Non-pharmacological therapies are of special interest. Cognitive behavioral therapy is associated with reduced limbic activity (e.g. reduced neural activity in the amygdala), GI symptoms, and anxiety (Lackner, et al. 2006). Hypnosis has shown efficacy in IBS (Whorwell, et al. 1984) and is known to modify the activity of the amygdala (Drossman 1999b). All methods focused on stress reduction such as mindfulness-based stress reduction should reduce pain perception (Drossman 1999a). Repetitive transcranial magnetic stimulation of the PFC that decreases the activity of the amygdala (Baeken, et al. 2010) would also be of interest in IBS patients. In this context, vagal nerve stimulation, used for the treatment of refractory epilepsy and depression, should be of interest in the treatment of IBS by modulating the amygdala. Indeed, an inhibitory action of vagal nerve stimulation on amygdala-mPFC neurotransmission, probably due to the deactivation of the amygdala, has been described under VNS (Kraus, et al. 2007). Consequently, new methods aimed at modifying the activity of the amygdala represent a therapeutic challenge in the management of IBS patients.
2. Irritable bowel syndrome
2.1. Definition-background
The irritable bowel syndrome (IBS) is the most common disorder encountered by gastroenterologists. IBS is defined as “a functional bowel disorder in which abdominal pain is associated with defecation or a change in bowel habit with features of disordered defecation and distension”(Drossman 1999b). Classically the syndrome is considered as functional since biological as well as morphological (e.g. colonoscopy) investigations are not able to evidence any detectable organic lesions or anatomical abnormalities (colonic polyps or diverticulosis…) relative to symptomatology of the affected patients. The syndrome has been defined according to Rome III criteria (Longstreth, et al. 2006). There is a female predominance in a ratio of 2:1 (Drossman, et al. 1993). IBS affects up to 10–15% of the population with an estimated 1.7 billion dollars in annual direct cost (Talley, et al. 1991). Generally patients suffer from the absence of a real diagnostic and from the consideration that they have a psychosomatic disease. Pain is perceived by patients as the most distressing symptom and constitutes their major reason for consulting a physician (Sandler, et al. 1984). Extra-intestinal manifestations are also frequently described by the patients (e.g. headache, low back pain, chronic fatigue, interstitial cystitis…) (Whitehead, et al. 2002).
2.2. Pathophysiology
The pathophysiology of IBS is multifactorial. Altered bowel motility, sensory disorders, psychosocial factors are evoked (Drossman, et al. 1999c; Gaynes and Drossman 1999; Bonaz and Sabate 2009). Local features have also been considered as important. The role of food is often evoked by patients and a number of them are intolerant to lactose, fructose, gluten, polyols (Dapoigny, et al. 2004; Morcos, et al. 2009) with an enhancement of their symptoms following an eviction of such foods from diet. There is also good evidence for a role of the GI microbiota in its pathogenesis (Parkes, et al. 2008). Neuroimmune interactions are also involved, based on the development of IBS after infectious gastroenteritis (i.e. post-infectious IBS) (Gwee 2001) or in patients with IBD in clinical remission (i.e. post-inflammatory IBS) (Long and Drossman 2010). A low grade inflammation has been observed in IBS patients with a predominance of mastocytes in close contact with neural fibers explaining why IBS is assimilated to an IBD by some authors (Ford and Talley 2011).
Sensory disorders, and especially VHS, have also been evoked in the pathophysiology of IBS. VHS, represented by the increased sensation of pain when the pelvic colon is distended with an inflated rectal balloon, is a clinical marker of IBS which is observed in most of IBS patients. The exact location of the abnormal processing of visceral pain is unknown, and can have a peripheral origin, i.e. in the digestive tract by altered peripheral functioning of visceral afferents (i.e. bottom-up model), a spinal origin, e.g. spinal hyperalgesia by a defect of the gate control, or a defect of descending inhibitory controls or an altered central processing of afferent information from the gut, i.e. top-down model or a combination of all these hypotheses. IBS patients have an alteration in the spinal modulation of nociceptive process by the inhibitory descending pain modulation systems (Wilder-Smith, et al. 2004) in which the amygdala could be involved.
Psychosocial factors are often found in IBS patients. Among 20 to 50% of IBS patients have psychiatric disorders, such as major depression, anxiety, and somatoform disorders (Garakani, et al. 2003). Low dose of tricyclic antidepressants have shown efficacy in ameliorating the symptoms in patients (Rahimi, et al. 2009). IBS is also frequently associated with fibromyalgia in 30% to 70% of the cases. This syndrome is characterized by somatic hyperalgesia, the physiopathology of which is close to IBS (Mathieu 2009). IBS and fibromyalgia are classified by some authors as central sensitization syndromes (Woolf 2011). A majority of IBS patients associate stressful life events with initiation or exacerbation of their symptoms (Whitehead, et al. 1992) and stress is able to act at all levels of the physiopathology of IBS (see below). Globally, a concept has emerged that IBS is the result of a dysfunction of the brain-gut interplay, as conceptualized in the brain-gut axis. The ANS is, with the HPA axis, the link between the CNS and the gut and an autonomic dysfunction is observed in IBS patients which could be of top-down or bottom-up origin, as observed for VHS.
3. The brain-gut axis
3.1. Definition
The brain talks to the gut and conversely through a bidirectional communication under normal conditions and especially during perturbations of homeostasis. The CNS and the gut communicate through the ANS and the circumventricular organs and the gut contains a “little brain” as represented by the enteric nervous system which is a target of the ANS.
3.2. The enteric nervous system
The enteric nervous system can control functions of the intestine even when it is completely separated from the CNS (Bayliss and Starling 1899). The enteric nervous system contains three categories of neurons, identified as sensory, associative, and motor neurons (both excitatory and inhibitory) which are the final common pathways for the control of signals to the musculature, submucosa, mucosa, and vasculature, both blood and lymphatic. The enteric nervous system contains as many neurons as in the spinal cord (400–600 million) and confers an autonomy to the digestive tract such as the enteric nervous system can function independently of the CNS for the programming of motility and secretion (Furness 2012). Some neuropeptides and receptors are present in both the enteric nervous system and the CNS. The function of the GI tract is modulated by both the enteric nervous system and the ANS.
3.3. The autonomic nervous system (The afferent system)
The ANS is composed of the sympathetic (i.e. the splanchnic nerves) and parasympathetic nervous system (i.e. the vagus nerves and the sacral parasympathetic nucleus represented by the pelvic nerves) which are mixed systems.
The vagus nerve contains essentially 80-90% of afferent fibers vehiculating informations from the abdominal organs to the brain (Altschuler, et al. 1989) with the exception of the pelvic viscera for which informations are vehiculated to S2-S4 levels of the spinal cord by the pelvic nerves with central projections similar to other spinal visceral afferents. The vagus nerve carries mainly mechanoreceptor and chemosensory informations from the gut. If classically vagal afferents do not encode painful stimuli, they are able to modulate nociceptive processing in the spinal cord and the brain (Randich and Gebhart 1992).
The sympathetic nerves contain 50% afferent fibers. Visceral afferents that enter via spinal nerves (i.e; splanchnic and pelvic nerves), at thoracic 5 - lumbar 2 segments of the spinal cord, carry information concerning temperature as well as nociceptive visceral inputs related to mechanical, chemical, or thermal stimulation through C and Aδ fibers, which will reach conscious perception.
The afferent informations of the ANS reach the CNS at the spinal cord level, for the splanchnic nerves, the nucleus tractus solitarius (NTS) level in the dorsal medulla for the vagus nerve, and the sacral parasympathetic (S2-S4) level for the pelvic nerves. At the level of the spinal cord, sympathetic afferents are integrated at the level of laminae I, II outer, V, VII (indirectly) and X. Then the information is sent to the upper level through the spino-thalamic and spino-reticular tracts, the dorsal column with projection to the thalamus (ventral posterolateral nucleus, intralaminar nucleus) and the cerebral cortex (insular, anterior-cingulate, dorsolateral PFC…). Neurons from laminae I, IV, and V responding to visceral stimuli also receive nociceptive cutaneous inputs (Foreman 1999).
At the level of the NTS, vagal afferents are integrated in subnuclei according to visceral somatotopy (e.g. medial, commissural, gelatinosus) (Altschuler, et al. 1993) and then projections to the PB nucleus, in the pons, according to a viscerotopic organization, which in turn projects to numerous structures in the brainstem, hypothalamus, basal forebrain, thalamus, and cerebral cortex (Fulwiler and Saper 1984). In the cerebral cortex, the insular cortex acts as a visceral (e.g. GI) cortex through a NTS-PB-thalamo-cortical pathway according to a viscerotopic map. The insular cortex is connected with the limbic system (bed nucleus of the stria terminalis and CeA) and with the lateral frontal cortical system (Saper 1982). The NTS also sends projections to the ventrolateral medulla, the hypothalamus, and the amygdala/bed nucleus of the stria terminalis contributing to visceral perception. The NTS receives convergent afferents from both the spinal cord (i.e. laminae I, V, VII, and X) and the vagus nerve; some of these afferents probably being at the origin of autonomic reflex responses. This convergence is also observed at the level of the PB and ventrolateral medulla (Saper 2002) thus arguing for a relationship of pain with visceral sensations.
At the forebrain level, the spinal visceral sensory system constitutes a postero-lateral continuation of the cranial nerve to the visceral sensory thalamus and cortex (Saper 2000). There is also a spino-PB pathway since about 80% of lamina I spinothalamic axons send collaterals to the PB (Hylden, et al. 1989) and a spino–parabrachio–amygdaloid pain pathway which implicates the transmission of nociceptive information to the amygdala. Spinal nociceptive neurons in laminae I, IV, V, VII, and X directly innervate the hypothalamus and medial prefrontal cortex (Cliffer, et al. 1991; Burstein 1996). The messages coming from the gut are integrated in the central autonomic network (see below), which, in turn, adapts the response of the digestive tract through the efferent ANS through reflex loops which are essentially unconscious or become conscious in pathological conditions such as VHS observed in IBS. There is also descending pathways that control somatic as well as visceral pain by modulating visceral informations at the spinal cord level. These pathways are both inhibitory, thus producing analgesia as represented by projections from the periaqueductal gray to the rostroventral medulla, and LC descending fibers to the spinal cord as well as facilitatory producing hyperalgesia (rostroventral medulla and OFF and ON cells) (Tsuruoka, et al. 2010).
3.4. The circumventricular organs
The circumventricular organs are highly vascularized structures with fenestrated capillaries located around the 3rd and 4th ventricles. They are characterized by the lack of a blood–brain barrier and represent points of communication between the blood, the brain, and the cerebrospinal fluid (Benarroch 2011). They are represented by the subfornical organ, median eminence, pineal gland, area postrema, organum vasculosum of the lamina terminalis. The circumventricular organs are sensitive to the vascular content (e.g. circulating interleukins, electrolytes). They activate dendritic cells releasing prostaglandins acting on PGE2 receptor of neurons located closely to these circumventricular organs. These neurons send projections to the hypothalamus, activating the HPA axis, and to the central autonomic network represented by the DMNV and the sympathetic pre-ganglionar neurons of the intermediolateralis column. The circumventricular organs are consequently involved in the central integration of a peripheral message to maintain homeosthasis. For example, they are involved in sodium and water balance, cardiovascular regulation, metabolic and energetic balance, immune function, regulation of body temperature, vomiting, reproduction. During an immune challenge represented by systemic inflammation, cytokines released in the circulation talk to the brain through two routes i.e. neural (vagal afferents) and humoral (circumventricular organs) to activate the HPA axis.
3.5. The central autonomic nervous system
The central autonomic nervous system integrates and modulates afferent informations from the gut and sends reversible inputs to the gut. In the CNS, visceral informations are integrated in the central autonomic nervous system via brain regions involved in the autonomic, endocrine, motor, and behavioral responses (Saper 2002). The brain network can be roughly divided into executive structures, mainly hypothalamic, coordinating structures, mainly included in the limbic system, and high level control structures, mainly the frontal cortex.
The hypothalamus e.g. paraventricular nucleus (PVN), lateral hypothalamus, arcuate nucleus and adjacent retrochiasmatic area innervate the parasympathetic and sympathetic preganglionic neurons. The principal neuromediators are oxytocin and vasopressin (Hallbeck, et al. 2001). Through the release of CRF, the neuromediator of stress, the PVN is involved in the HPA axis response to stress. The limbic system is represented by the amygdala and its nuclei, the bed nucleus of the stria terminalis, considered as the extended amygdala, the septum and the hippocampus. The limbic system modulates the endocrine system and the ANS, two major components of the brain-gut axis. Classically, the amygdala is involved in the integration of emotions and the emotional conditioning which is represented by the association of a conditioned stimulus (i.e. a sound) with an unconditioned stimulus (the reinforcement) (Henke, et al. 1991; Benarroch 2006; LeDoux 2007). The amygdala receives afferents from the NTS, PB nucleus, frontal cortex, and LC and sends projection to the ANS, the frontal cortex and the hippocampus. The amygdala inhibits the DMNV, stimulates the sympathetic nervous system and the stress response through the HPA axis. The amygdala is a CRF-containing nucleus.
The prefrontal, insular, and anterior cingulate cortices are involved in the integration of visceral informations, attention, emotions and in the regulation of humor. The anterior cingulate cortex is divided in a cognitive dorsal part and an affective ventral part i.e. the perigenual part which has been frequently activated in brain imaging by numerous emotional stimuli. Most of these structures (ANS, HPA axis, limbic system, endogenous pathways that modulate pain and discomfort…) are part of the emotional motor system that mediates the effect of emotional states on the GI function, modulates gut functions and communicates emotional changes via the ANS to the gut. The threshold for visceral perception is dependent on the individual’s emotional and cognitive state (Mayer 2000; Mayer 2011).
Visceral as well as stressful informations activate the LC, a nucleus belonging to central noradrenergic system localized in the pons. The LC is the largest group of noradrenergic neurones. It is involved in emotional arousal, autonomic, and behavioural responses to stress and attention-related processes through its dense projections to most areas of the cerebral cortex and alertness-modulating nuclei (e.g. majority of the cerebral cortex, cholinergic neurones of the basal forebrain, cortically-projecting neurones of the thalamus, serotoninergic neurones of the dorsal raphe and cholinergic neurones of the pedunculopontine and laterodorsal tegmental nucleus). The LC also exerts an indirect action on autonomic activity via projections to the PVN and to the cerebral cortex and amygdala, structures which are known to influence the activity of premotor sympathetic neurones in the PVN. LC activation leads to anxiety through an activation of the amygdala (Tasan, et al. 2010).
4. Stress and the gut
4.1. Background
Stress is defined as the response of the organism to a solicitation of the challenging environment. The body engages a “fight or flight” response when exposed to an acute challenge with a sympathetic activation leading to an increase of heart rate and respiration, increased arousal, alertness, and inhibition of acutely non adaptive vegetative functions (feeding, digestion, growth and reproduction). The time course of the reaction corresponds to the general syndrome of adaptation defined by Hans Selye in 1950 (Selye 1950). The reaction of stress is physiological but may become pathological following an unbalance between the capacities of adaptation and the requirement of the environment, thus leading to functional, metabolic, and even lesional disorders.
4.2. The CRFergic system
CRF is a 41-amino acid peptide derived from a 191-amino acid preprohormone. CRF is secreted by the paraventricular nucleus (PVN) of the hypothalamus in response to stress (Vale et al. in 1981) as well as its related peptides the urocortines (Ucn) i.e. Ucn 1, Ucn 2 (also known as stresscopin-related peptide), and Ucn 3 (also known as stresscopin). CRF and the Ucns exert their biological actions on target cells through activation of two 7–transmembrane-domain G protein–coupled receptors, known as CRF receptor type 1 (CRF1) and CRF receptor type 2 (CRF2) which are encoded by 2 distinct genes [for review (Gravanis and Margioris 2005)]. CRF and Ucn 1 have equal affinity for the CRF1 receptor, although Ucn 1 is 40 times more potent than CRF in binding CRF2. In contrast, Ucns 2 and 3 bind selectively to CRF2. The population of CRF synthetizing neurons is predominantly expressed in the parvocellular part of the PVN of the hypothalamus and projects via the external zone of the median eminence to the anterior pituitary. In addition to its role as a hypothalamic hypophysiotropic hormone, CRF acts as a neurotransmitter in several brain areas. CRF has predominantly excitatory actions on neurons in the hippocampus, cortex, LC, and hypothalamic nuclei (Siggins, et al. 1985). CRF1 mediates anxiety-like behaviors whereas CRF2 mediates anxiolytic effects in the defensive withdrawal test (Heinrichs, et al. 1997). Competitive CRF receptor antagonists have been developed to determine the functions of CRF receptors under basal and stress conditions (Bonaz and Tache 1994b). The CRF system plays a critical role in coordinating the autonomic, endocrine, and behavioural responses to stress (Dunn and Berridge 1990).
The effect of stress on the GI tract is now well characterized. Stress induces modifications of motility, secretion, visceral sensitivity, local inflammatory responses (Delvaux 1999; Mawdsley and Rampton 2006; Tache and Bonaz 2007) through a central and/or peripheral action through CRF1,2 related receptors. Alterations of this complex system in humans are linked to a variety of anxiety-related psychiatric disorders and stress-sensitive pain syndromes, including IBS. Dysfunction in the HPA axis regulation attributable to overactivation of CRF/CRF1 signaling in response to chronic stress has been implicated in the pathophysiology of IBS symptoms (Chang, et al. 2009).
4.3. Stress effect on GI functions
4.3.1. Motility and secretion
Stress is known to decrease gastric emptying, lengthen small bowel motility and increase colonic motility (Tache and Bonaz 2007). The effects of stress on gut function are mediated by the ANS represented by the sympathetic, vagal and pelvic parasympathetic innervation of the enteric nervous system (Grundy 2006). At the central level, stress inhibits the parasympathetic nervous system and activates the sympathetic nervous system through the effect of PVN projections on the DMNV and intermediolateral column cells of the spinal cord.
CRF signaling is a key component in the alterations of gut motor function in response to stress in both the brain and the gut. The CRF/CRF1 signalling pathway is involved in stress-induced anxiety/depression (Holsboer and Ising 2008) and alterations of colonic motor and visceral pain while both central and peripheral CRF2 receptor activation may exert a counteracting influence (Tache, et al. 2005; Million, et al. 2006). At the level of the GI tract, stress delays gastric emptying through CRF2 while increasing colonic motility and secretion through CRF1 (Tache and Bonaz 2007). In the small bowel, CRF-like peptides stimulate the contractile activity of the duodenum through CRF1 receptor while inhibiting phasic contractions of the ileum through CRF2 receptor (Porcher, et al. 2005).
Stress also induces an activation of the sacral parasympathetic nucleus through the projections of the Barrington nucleus through CRF activation thus stimulating recto-colonic motility (Tache and Bonaz 2007). Numerous data have established the involvement of peripheral CRF signalling in the modulation of secretory function under stress conditions via activation of both CRF1 and CRF2 receptors, activation of cholinergic enteric neurons, mast cells and possibly serotonergic pathways (Larauche, et al. 2009).
4.3.2. Intestinal permeability
An increase of intestinal permeability is observed in the colon of IBS patients, associated with visceral or somatic hypersensitivity (Zhou and Verne 2011). Stress is able to disrupt the intestinal epithelial barrier thus increasing the penetration of luminal antigens into the lamina propria, leading to nociceptors sensitization and favoring the development of visceral hypersensitivity (Ait-Belgnaoui, et al. 2005). This increase of intestinal permeability is due to an activation of peripheral CRF signaling involving both CRF2 and CRF1 (Buckinx, et al. 2011) as well as mast cell activation (Santos, et al. 2001).
4.4. Stress effect on intestinal inflammation
Stress is able to increase intestinal inflammation by increasing intestinal permeability (see above) thus activating mast cells and visceral afferents in a local loop. Stress favours intestinal inflammation by stimulating the sympathetic nervous system and inhibiting the vagus nerve thus decreasing the cholinergic anti-inflammatory pathway. Stress, through its immune-suppressive function also favours inflammation (Ghia, et al. 2006; Mawdsley, et al. 2006; Bonaz 2010).
4.5. Stress effect on the microbiota
Bacteria in the gut (400–1,000 different bacterial species) have an important role in the immune response, including inflammation (Lee and Mazmanian 2010). Stress is able to modify the intestinal microbiota (Bailey, et al. 2010). Alteration of the microbiota favors translocation of bacteria from the intestinal lumen to the interior of the body where they can stimulate the immune system (Clarke, et al. 2010). This can in turn have significant impact on the host and affect behavior, visceral sensitivity and inflammatory susceptibility (Collins and Bercik 2009).
4.6. Stress effect on visceral sensitivity
Stress is known to increase visceral sensitivity [(Larauche, et al. 2012) for review]. Either acting at the central and/or peripheral (e.g. digestive) level, stress is able to increase visceral perception and emotional response to visceral events by a disturbance of the brain-gut axis at its different levels, central, gut and the ANS. Genetic model of depression or anxiety, such as the high-anxiety Wistar-Kyoto (WKY) rats or Flinders Sensitive Line rats have shown increased sensitivity to colorectal distension (Overstreet and Djuric 2001). In the same way genetic models deleting CRF1 exhibit a decrease in colonic sensitivity to colonic distension (Trimble, et al. 2007) while models overexpressing CRF1 exhibit enhanced response to colonic distension (Million, et al. 2007). These data argue for the filiation stress-anxiety-inflammation and visceral hypersensitivity.
Again, the CRF signalling, at both the central and peripheral level, is a key element involved in stress-induced visceral hypersensitivity. Recent data argue for an equally important contribution of the peripheral CRF/CRF1 signalling pathway locally expressed in the gut to the GI stress response (Larauche, et al. 2009). At the peripheral level, mast cells degranulation observed in the colon following stress and peripheral administration of CRF (Wallon, et al. 2008) induces visceral hypersensitivity via the release of mediators (histamine, tryptase, prostaglandin E2, nerve growth factor) that can stimulate or sensitize sensory afferents (van den Wijngaard, et al. 2009; 2010). Intravenous administration of CRF increases GI motility and visceral pain sensitivity in IBS patients compared with healthy controls, whereas administration of a non-selective CRF receptor antagonist improved these responses (Million, et al. 2005; Tache, et al. 2005; Tsukamoto, et al. 2006).
4.7. Gut pathologies are engineered by stress
The GI tract is a sensitive target to stress. Numerous data argue for a role of stress in the pathophysiology of IBS. Patients with IBS report more stressful life events than medical comparison groups or healthy subjects (Drossman, et al. 1996; 2000; Drossman 2011). Stress is strongly associated with symptom onset and symptom severity in IBS patients. Illness experience, health care-seeking behavior, and treatment outcome are adversely affected by stressful life events, chronic social stress, anxiety disorders, maladaptive coping style. A history of emotional, sexual, or physical abuse is often found in IBS patients [(Chitkara, et al. 2008) for review]. For example, there is a significantly higher prevalence (i.e. 44%) of sexual or physical abuse in patients with functional GI disorders than in controls with organic GI disorders (Drossman, et al. 1990). Psychiatric comorbidity, especially major depression, anxiety, and somatoform disorders, occur in 20 to 50% of IBS patients (Garakani, et al. 2003) and more likely precede the onset of the GI symptoms, thus suggesting a role for psychiatric disorders in functional GI disorder development (Sykes, et al. 2003).
Functional brain imaging studies have shown that there is a major influence of cognitive-affective processes on GI sensations and its CNS correlates in health and functional digestive disorders as IBS (Mayer, et al. 2006; Van Oudenhove, et al. 2007). Cognitive-affective processes including arousal, attention and negative emotions strongly influence visceral pain perception through modulation of its neural correlates (Mayer 2011). Feeling emotions requires the participation of brain regions, such as the somatosensory cortices and the upper brainstem nuclei that are involved in the mapping and/or regulation of internal organism states (Damasio, et al. 2000). This has led to the biopsychosocial concept of IBS (Drossman 1996b). These data are in agreement with the role of hypervigilance in the visceral hypersensitivity observed in IBS patients (Naliboff, et al. 2008). Spence et al. (Spence and Moss-Morris 2007) have characterized predictors of post-infectious IBS such as perceived stress, anxiety, somatisation and negative illness beliefs at the time of infection in favor of a cognitive-behavioural model of IBS. The importance of psychosocial factors and somatisation compared to gastric sensorimotor function is most pronounced in hypersensitive patients with functional dyspepsia, another functional GI disorder (Van Oudenhove, et al. 2008).
5. Gut and emotional memories
Early life trauma (neglect, abuse, loss of caregiver or life threatening situation) increases susceptibility to develop later affective disorders such as depression, anxiety, and is a key factor in the development of IBS (Bradford, et al. 2012). Traumatic events, such as war, environmental disasters, physical abuse or a bad accident in adulthood can induce post-traumatic stress disorder (PTSD) with increased prevalence of GI symptoms, such as IBS (Cohen, et al. 2006).
The role of stress sensitization is also reproduced in preclinical studies. Adults rats previously subjected to neonatal maternal separation (MS) exhibit visceral hypersensitivity to colorectal distension in basal conditions (Ren, et al. 2007). This visceral hypersensitivity is exacerbated in acute stress (e.g. water avoidance stress: WAS; Avoidance to water for 1 h by standing on a small platform; Bonaz & Taché 1994b) conditions (Coutinho, et al. 2002). Chronic exposure to repeated WAS is used to study visceral hypersensitivity and is very close to clinical conditions. However, habituation of the CRFergic system is observed in chronic conditions (Bonaz and Rivest 1998) and may induce analgesia. It seems that these conflicting data are influenced by the basal state conditions of the animals before applying the repeated stressor (surgery and single housing) (Larauche, et al. 2010).
6. The amygdala in IBS pathophysiology
The amygadala is a key element in the pathogeny of IBS.
6.1. Anatomical and functional basis
6.1.1. Amygdala structures
The amygdala is divided into a primitive group of nuclei associated with the olfactory system (central, medial and cortical nuclei, and nucleus of the lateral olfactory tract), and a phylogenetically new group of nuclei (lateral and basal) (Knapska, et al. 2007). The lateral (LA), basolateral (BLA), and central nuclei (CeA) are important for sensory processing (Neugebauer 2006; LeDoux 2007). The amygdala is part of the central autonomic nervous system that is involved in the brain-gut axis. The amygdala is a key element in emotional/affective behavior (LeDoux 2007), including the emotional responses to pain such as anxiety and fear of pain (Gauriau and Bernard 2002; Neugebauer, et al. 2004; Neugebauer 2006) as well as in the reciprocal relationship between pain and affective state (Meagher, et al. 2001; Rhudy and Meagher 2003). Affective content is attached to sensory information through associative processing in the LA–BLA circuitry and is then transmitted to the CeA which is the output nucleus for major amygdala functions (Maren 2005; Phelps and LeDoux 2005). The CeA serves to attach emotional significance to afferent nociceptive transmission and coordinates appropriate autonomic, affective and motor behavioral responses through its outputs to the hypothalamus, cortex and brainstem (Neugebauer, et al. 2004).
6.1.2. Amygdala inputs
The CeA receives numerous sensory informations from descending cortical, thalamic (perigeniculate, paraventricular) and brainstem inputs (Whalen and Kapp 1991), as well as from the olfactory system, medial PFC, insula, brainstem viscerosensory and nociceptive centers (NTS, PB), and from all parts of the amygdala. The amygdala increases the excitability of CNS sites regulating behavioral, neuroendocrine, and autonomic responses to stress (LeDoux, et al. 1988) and thus is able to modify GI functions. The amygdala is involved in the affective processing of sensory information and in the generation of anxiety and fear (Davis 1997), elements which are involved in the pathogeny of IBS.
6.1.3. CRF as a key mediator in amygdala
The amygdala, and particularly the CeA, is a major site of extrahypothalamic CRF, in cell bodies and terminals as well as CRF1 and, to a lesser extent, CRF2 receptors. The amygdala is a key element of the extrahypothalamic circuits through which CRF contributes to anxiety-like behavior and affective disorders (Aguilera, et al. 1987; Sajdyk, et al. 1999; Reul and Holsboer 2002; Fu and Neugebauer 2008). Excepting the hypothalamus, the amygdala is the major site of urocortin III (the endogenous ligands for CRF2 receptors) expression (Li, et al. 2002). In particular, activation of CRF neurons in the CeA that project to the LC increase its firing thus resulting in a noradrenaline release in the structures it is projecting to (Bouret, et al. 2003). LC activation leads to anxiety through the activation of the amygdala and, conversely, anxiety producing stimuli (stressful and fear-inducing stimuli) that increase the activity of the amygdala lead to LC activation (Samuels and Szabadi 2008).
6.1.4. Amygdala output to gut
The CEA is involved in the modulation of the ANS because of its brainstem projections to the DMNV, NTS, PB and the periaqueductal gray (Rizvi, et al. 1991), known to modulate the spinal cord processing of noxious information through descending inhibitory controls (Le Bars, et al. 1992). The CEA innervates hypothalamic nuclei, modulating the HPA axis (Rodrigues, et al. 2009). The CeA also projects to the medial peri-LC dendritic region, resulting in increased norepinephrine release and other monoamine systems in the brainstem and forebrain (Gray 1993; Fudge and Emiliano 2003; Pare 2003) which are involved in arousal and hypervigilance.
6.1.5. Modulators of amygdala
The LC has an inhibitory effect on the BLA and the activation of this pathway leads to a disinhibition of the CeA, since the BLA has a predominantly inhibitory influence over the CeA (Rosenkranz, et al. 2006). The LC is involved in the stress response through CRF1 receptors as well as CRF afferent fibers from the Barrington nucleus which is ventro-laterally located to the LC. The Barrington nucleus projects to the sacral parasympathetic nucleus to increase the motility of the distal recto-colon (Valentino, et al. 1993). Colorectal distension increases the firing of the LC through CRF1 through a LC-Barrington nucleus pathway (Rouzade-Dominguez, et al. 2001). In addition, the LC is involved in the brain noradrenergic modulation of the GI tract motility (Bonaz, et al. 1992a; 1992b; 1995). Consequently, the Barrington-LC-amygdalo complex is ideally positioned to bidirectionally coordinate brain-gut interactions.
6.2. Amygdala and the pathophysiology of IBS
6.2.1. Amygdala and visceral hyperalgesia
The use of C-Fos expression as a marker of neuronal activation has shown that somato-visceral (Bonaz and Fournet 2000; Sinniger, et al. 2004; 2005), and visceral (Wang, et al. 2009) pain as well as stress- or abdominal surgery-induced GI disturbances (Bonaz and Tache 1994a; 1994b; 1997; Bonaz and Rivest 1998) and colitis (Porcher, et al. 2004) induced the activation of the amygdala. In addition, the amygdala is one of the central areas from where digestive sensations are elicited in epileptic patients (Mulak, et al. 2008) during intracerebral electrical stimulations. In a model of visceral pain induction such as inflating a balloon into the rectum, an activation of the amygdala is observed in healthy volunteers (Baciu, et al. 1999) while aberrant functional responses (e.g. deactivation of the amygdala) to noxious rectal stimulation was observed in areas of the brain involved in emotional sensory processing, particularly the amygdala, insula, and prefrontal cortex in IBS patients (Bonaz, et al. 2002; Elsenbruch, et al. 2010; Tillisch, et al. 2011) thus arguing for an abnormal brain processing of visceral pain following rectal distension.
Activation of corticosteroid receptor (both glucocorticoid and mineralocorticoid receptors) in the CeA is involved in the induction of anxiety and visceral hypersensitivity (Myers and Greenwood-Van Meerveld 2007b). High levels of glucocorticoids result in CRF mRNA level increases in the amygdala (Makino, et al. 1994). The group of Greenwood-Van Meerveld ) have shown that implants of corticosterone micropellets in the CeA increase anxiety-like behavior as well as visceral hypersensitivity to colonic distension and increased responsiveness of viscera-sensitive lumbosacral spinal neurons that mediate visceromotor reflexes to colo-rectal distension (Greenwood-Van Meerveld, et al. 2001; Myers, et al. 2005; Greenwood-van Meerveld, et al. 2006; Myers and Greenwood-Van Meerveld 2007a). Indeed, exposure of the amygdala to corticosterone-releasing micropellets caused an increase in action potential frequency in the dorsal horn neurons in the L6-S1 spinal segments suggesting that a descending neuronal pathway, originating in the amygdala, could be triggered by continuous activation by corticosterone. The neurons responding with excitation to colorectal distension were short-lasting and long-lasting excitatory neurons based on the duration of the reponse (Venkova et al. 2009). Mineralocorticoid receptors but not glucocorticoid receptors in the amygdala trigger descending pathways facilitating viscero-nociceptive processing in the spinal cord (Venkova, et al. 2009). In addition, a WAS known to activate the amygdala (Bonaz and Tache 1994b), performed during 7 consecutive days induced VHS that was abolished by glucocorticoid receptor and mineralocorticoid receptor antagonists in the amygdala. These results argue for a role of amygdaloid glucocorticoid receptor and mineralocorticoid receptor in IBS.
The CRF signaling is also involved in pain processing. WKY is a rat strain for studying anxiety and IBS. WKY express a greater amount of CRF and CRF1 mRNA in the CeA and the PVN (Bravo, et al. 2011). In this model, it has been shown that colonic hypersensitivity to luminal distension is reversed by peripheral administration of a CRF1 antagonist (O'Malley, et al. 2011). Infusion of CRF1 antagonist into the CeA attenuates the hypersensitivity to colonic distension in the WKY rats, thus confirming the role of CRF1 receptor in the amygdala in VHS mechanism (Johnson, et al. 2012). The basal expression of CRF in the LC is increased in WKY rats and a selective CRF1 receptor antagonist abolished the activation of LC neurons by colorectal distension and intracisternal CRF in rats (Kosoyan, et al. 2005). These data strengthen the role of the CeA and LC in VHS through CRF1 which is in agreement with the interactions between both nuclei involved in emotional-arousal circuit. Indeed, CRF neurons in the CeA project directly to the LC and increase the firing rate of LC neurons thus increasing noradrenaline release in the vast terminal fields of this ascending noradrenergic system. In humans, oral administration of a selective CRF1 antagonist (GW876008) is followed by a significant BOLD signal reductions within the amygdala during pain expectation in IBS patients (Hubbard, et al. 2011). CRF1 receptors in the amygdala contribute to pain-related sensitization, whereas the normally inhibitory function of CRF2 receptors is suppressed in the arthritis pain model. Thus, due to the opposing effect of CRF1 and CRF2 receptors, CRF can induce a dual effect in the amygdala. The differential effects of CRF1 and CRF2 receptor antagonists on pain-related processing in the amygdala have reciprocal opposing influences on anxiety-like behaviors. CRF1 and CRF2 receptors in the amygdala mediate opposing effects on nociceptive processing (Ji and Neugebauer 2007). Numerous data argue for a role of CRF1 and CRF2 to mediate pro- and anti-nociceptive effects of CRF respectively. It has been shown that low concentrations of CRF facilitate nociceptive processing in the CeA neurons through CRF1 while higher concentrations of CRF have inhibitory effects through CRF2 receptors. This is in agreement with the concept that CRF2 receptors serve to dampen or reverse CRF1-initiated responses (Tache and Bonaz 2007). These results clarify the controversial role of CRF in pain modulation and show that the CRFergic system in the amygdala may be a key link between pain and affective states and disorders.
6.3. Amygdala and stress conditioning
6.3.1. The synchronic stress engineering
Systemic cortisol is a classical marker of the HPA axis activation. The amygdala and hippocampus have numerous receptors for cortisol and are consequently highly susceptible to the products of the HPA axis. Glucocorticoid occupation of hippocampal receptors has a suppressive effect on the HPA axis (van Haarst, et al. 1997) whereas glucocorticoid occupation of amygdala receptors have a facilitating effect on the HPA axis, often increasing CRF expression within the amygdala (Makino, et al. 1994). CRF receptors are greatly expressed in the amygdala and hippocampus early in development (Baram and Hatalski 1998), thus explaining why young animals are especially vulnerable to threat. In agreement, early-life stress induces a decrease of hippocampal volume and functional alterations when measured in adulthood (Nemeroff, et al. 2006). Structural changes have also been observed in IBS patients using brain imaging (Blankstein, et al. 2010; Seminowicz, et al. 2010). Also, circulating glucocorticoids can have contrasting effects in the amygdala and hippocampus, and these two structures can play contrasting roles in the activity of the HPA axis. In the context of an overactivity of the HPA axis due to an enhanced stress responsiveness, greater basal levels of systemic cortisol have been reported in IBS patients (Chang, et al. 2009). Circulating cortisol regulates the HPA axis and is also able to act within the amygdala by binding to selective glucocorticoid and mineralocorticoid receptors, highly expressed in the amygdala (Sapolsky, et al. 1983) to facilitate behavioral and psychological stress responses including GI motility.
6.3.2. Amygdala and stress memorisation
Functional imaging studies indicate that the mPFC is engaged in fear extinction process in relation with the amygdala (Phelps, et al. 2004). The amygdala is an important region involved in the acquisition of fear conditioning, a learning that corresponds to the association between a conditioned stimulus andan unconditioned stimulus. The infralimbic region of the mPFC participates in the mechanism of fear extinction (Rosenkranz, et al. 2003; Quirk and Vidal-Gonzalez 2006b) and also in the recall of fear extinction with an active inhibition of the previous fear condition responses. This is mediated by a down regulation of amygdala outputs with mPFC neurons exciting (glutamate) inhibitory neurons (GABA) within the BLA or in the intercalated region inhibiting in turn amygdala outputs from the CeA (Vidal-Gonzalez, et al. 2006). The activity of intentional regulation of treat related-cues by the PFC is decreased in anxious patients and the conditioned fear extinction is also less active, in PTSD-anxious patients and this is associated with symptoms provocations (Bradette, et al. 1994). The amygdala is also activated by uncertainty and the capacity of the PFC to regulate attention, (re) interpretation of the situation will modulate the level of the response of amygdala to uncertainty. In IBS, uncertainty plays an important role in the perception of pain. Therefore it seems important to study the fronto-amygdalar relations in IBS patients. The inhibitory control of the mPFC on CeA would maintain an homeostatic state with an equilibrated sympatho-vagal balance and low glucocorticoids circulating levels. In the case of a deficit in PFC activity with a lack of inhibitory regulatory communications with the amygdala, a chronic imbalance of the ANS with an increase sympathetic activity should appear as we have observed in IBS patients exhibiting a low heart rate variability and a high score of anxiety (Pellissier, et al. 2010a). Moreover, there is a strong relation between the activity of the ANS and the immune system as recently shown by the cholinergic anti-inflammatory pathway (Huston and Tracey 2011). Hence, when the parasympathetic system is hypoactive as a consequence of anxiety for instance, it could facilitate inflammation which could be deleterious for health and well-being (Bonaz 2003). The hypoactivity of the PFC and the enhancement of amygdala (re)-activity are strongly influenced by stress as demonstrated by a number of studies. It has recently been shown an increase in the dendritic arborization, and synaptic connectivity in the LA/B neurons under chronic stress conditions (Vyas, et al. 2002; Vyas, et al. 2006). LA/B neurons from stressed animals display increased firing rates and greater responsiveness (Kavushansky and Richter-Levin 2006) since the mediators of stress i.e. norepinephrine, and glucocorticoids decrease GABA inhibition (Rodriguez Manzanares, et al. 2005), thereby allowing for increased excitability in LA/B. In the meantime, an atrophy and spine loss of neurons in the mPFC following stress and glucocorticoid exposition is observed (Czeh, et al. 2008) allowing an over-activation of amygdala under chronic stress exposition.
6.3.3. Amygdala and early stress
Environmental events during early postnatal life can influence the formation of neural circuits that provide limbic and cortical control over autonomic emotional motor output since a differential timing of hypothalamic and limbic forebrain synaptic inputs to autonomic neurons has been observed during the first 1–2 weeks postnatal (Rinaman, et al. 2011). This provides a potential structural correlate for early experience-dependent effects on later responsiveness to emotionally evocative stimuli and an enhanced risk for the development of psychopathologies such as mood and aggressive disorders. MS is classically used as a model of brain-gut axis dysfunction (O'Mahony, et al. 2011) and early life trauma are often observed in IBS patients (Bradford, et al. 2012). The amygdala is functionally active early in life and demonstrates continued refinement, through increased cortical connections, throughout childhood and adolescence. The amygdala is particularly vulnerable to stressors early in life. Reduced hippocampal volumes (Woon, et al. 2010) and increased amygdala volumes (Tottenham, et al. 2010) have been associated with early life stress.
6.3.4. The maternal separation model (MS)
Numerous studies have shown that the HPA axis of MS rodents shows hyperactivity in the PVN and amygdala (Plotsky and Meaney 1993; Coutinho, et al. 2002; Plotsky, et al. 2005; Schwetz, et al. 2005). Offspring of mothers that exhibit more licking and grooming of pups show reduced plasma ACTH and corticosterone responses to acute stress and decreased levels of hypothalamic CRF mRNA in correlation with the frequency of maternal licking and grooming during the first 10 days of life (Plotsky, et al. 2005). Thus, it is likely that a major part of the alterations associated with early life stress are related to CRF hyperproduction that account for amygdala hyperactivity. Maternal care during the first week of life is associated with increased GABAergic inhibition of amygdala activity (Diorio and Meaney 2007). These data reflect the importance of early environmental factors in regulating the development of the hypothalamic CRF system in relation with amygdala activity and the vulnerability to stress. Moreover, there is a sex-specific difference in the effects of early life stress on HPA axis activity consistent with the higher prevalence of major depression with hypercortisolism in women than in men. Moreover, women who experienced early life stress are more likely to develop depression as well as IBS (Bradford, et al. 2012). Sex-hormones influence amygdala development in human populations (Rose, et al. 2004). An alteration in the central CRF system has been evidenced in two different rat models of comorbid depression and functional GI disorders (e.g. IBS) represented by neonatal MS and the WKY rat, a genetically stress-sensitive rat strain, that display increased visceral hypersensitivity and alterations in the HPA axis. These rat strains express a greater amount of CRF and CRF1 mRNA in the amygdala (CeA) as well as in the PVN (Bravo, et al. 2011). They also present a positive correlation between increased central CRF and CRF1 receptor expression, with elevated anxiety-like behavior and colonic hypersensitivity (Gunter, et al. 2000; Shepard and Myers 2008). An increase of CRF1 mRNA was observed in the PVN and amygdala while CRF2 mRNA, classically counteracting CRF1 in the CNS, was lower in the amygdala of MS rats. Such modifications, by affecting the HPA axis regulation, may contribute to behavioral changes associated with stress-related disorders, and alter the affective component of visceral pain modulation, which is enhanced in IBS patients (Bravo, et al. 2011).
6.4. The alteration of amygdala control in IBS
The amygdala has interconnections with the anterior cingulate cortex, the PFC, the hippocampus, the hypothalamus (e.g. PVN), the bed nucleus of the stria terminalis, the lateral septum, the thalamus, the periacqueductal gray, the PB, the LC, the raphe nuclei, and the dorsal vagal complex (area postrema, nucleus tractus solitarius and DMNV) (Knapska, et al. 2007). All these regions have been shown to be activated in experimental models of stress, inflammation, and pain as represented by c-fos expression and/or CRF receptor mRNA induction (Bonaz and Tache 1994a; Bonaz and Rivest 1998; Bonaz, et al. 2000; Porcher, et al. 2004; Sinniger, et al. 2004; 2005) or electrical stimulations (Mulak, et al. 2008). In addition, brain imaging techniques (fMRI, PET), have contributed to the better understanding of IBS. An activation of most of the brain structures referenced above, and particularly the amygdala, has been observed in healthy volunteers following rectal pain while an abnormal brain processing of pain was observed in IBS and IBD patients (Baciu, et al. 1999; Bonaz, et al. 2002; Agostini, et al. 2011). In addition, brain structural changes of the HPA axis and limbic structures have been recently reported in IBS patients (Blankstein, et al. 2010; Seminowicz, et al. 2010). Because psycho- or pharmacotherapy tends to result in normalization of activity of key structures such as the PFC including anterior cingulate cortex, hippocampus, or amygdala, either through a top-down or bottom-up effect (Quide, et al. 2012), the determination of psycho-physiological vulnerability in IBS patients should be a flag to consider the psychological needs in the follow-up of such patients in the prevention of relapses of such diseases (Pellissier, et al. 2010b).
7. Therapeutic implications-treatment targeting amygdala activity reduction in IBS
The effect of stress on amygdala functioning has therapeutic implications both with non-pharmacological and pharmacological treatment to reduce stress perception. Psychological mind-body interventions including psychotherapy, cognitive behavioral therapy, hypnotherapy, relaxation exercises or mindfulness mediation have been shown to improve symptoms of IBS patients (Kearney and Brown-Chang 2008; Ford 2009; Whorwell 2009). Repetitive transcranial magnetic stimulation of the PFC, based on the central role of the mPFC in cognitive theory of mind, can cause changes in acute pain perception and has been used in a model of central sensitization syndrome such as fibromyalgia (Mhalla, et al. 2011; Short, et al. 2011) but no data have been currently published in IBS patients. Modulation of the ANS by restoring the sympatho-vagal balance (DeBenedittis, et al. 1994; Nishith, et al. 2003; Gemignani, et al. 2006) as well as modifying coping strategies vigilance state and globally the restoration of a functional brain-gut axis, are at the origin of the efficacy of these treatments. Brain imaging techniques have shown modulation of brain activation, as for example in the amygdala, by such treatments (Goldin and Gross 2010; Lawrence, et al. 2011). Conventional treatment as represented by anti-depressives, anxiolytics, drug targeting the central sensitization syndrome [α2δ ligand (pregabalin, gabapentin); tachykinin receptor antagonists] either directly and/or indirectly are supposed to target the hyperfunctioning of the amygdala (Ghaith, et al. 2010; Gale and Houghton 2011; Trinkley and Nahata 2011; Larauche, et al. 2012). In the context of the microbiota-brain-gut axis, probiotics, prebiotics, antibiotics such as rifaximin, an antibacterial agent that is virtually unabsorbed after oral administration and is devoid of systemic side effects, are of interest (Bercik, et al. 2011; Fukudo, et al. 2011; Fukudo and Kanazawa 2011). If targeting CRF signaling with CRF1 receptor antagonists, based on pre-clinical and/or clinical data (brain imaging) has been used successfully in humans to treat depression and anxiety (Kunzel, et al. 2003) their efficacy is still matter of debate in the treatment of IBS patients (Sweetser, et al. 2009).
8. Conclusion
A growing body of evidence argues for an important role of stress, through the HPA axis, limbic system activity (e.g. the amygdala), and the ANS, i.e. the sympathetic and the parasympathetic (e.g. the vagus nerve) nervous system, in the initiation and perpetuation of IBS. Stress, pain, and immune activation are common risk factors involved in the pathogenesis of IBS which are able to act through this neuro-endocrine-immune axis. The amygdala, through its connections with the PFC, LC, hippocampus, HPA axis, and ANS is a key structure involved in the pathogeny of IBS. Animal models of activation of the CRFergic system in the amygdala, as represented by maternal separation stress or WKY rats, developed VHS as observed in most of IBS patients. Thereofore, a therapeutic targeting of the amygdala either through pharmacological or non-pharmacological approach should be of interest for the treatment of IBS.
References
- 1.
Agostini A N Filippini D Cevolani R Agati C Leoni R Tambasco C Calabrese F Rizzello P Gionchetti M Ercolani andM Leonardi M Campieri 2011 Brain functional changes in patients with ulcerative colitis: a functional magnetic resonance imaging study on emotional processing. 17 8 1769 1777 - 2.
Aguilera G M. A Millan andR. L Hauger K. J Catt 1987 Corticotropin-releasing factor receptors: distribution and regulation in brain, pituitary, and peripheral tissues. 512 48 66 - 3.
Ait-belgnaoui A S Bradesi J Fioramonti andV Theodorou L Bueno 2005 Acute stress-induced hypersensitivity to colonic distension depends upon increase in paracellular permeability: role of myosin light chain kinase 141 EOF - 4.
Altschuler S. M X. M Bao D Bieger andD. A Hopkins R. R Miselis 1989 Viscerotopic representation of the upper alimentary tract in the rat: sensory ganglia and nuclei of the solitary and spinal trigeminal tracts. 283 2 248 268 - 5.
Altschuler S. M J Escardo andR. B Lynn R. R Miselis 1993 The central organization of the vagus nerve innervating the colon of the rat. 104 2 502 509 - 6.
Fournet and C.M. Segebarth (Baciu M. V B. L Bonaz E Papillon R. A Bost J. -F Le Bas J 1999 Central processing of rectal pain: A functional MR imaging study. Am J Neuroradiol.20 10 1920 1924 - 7.
Baeken C R De Raedt P Van Schuerbeek M. A Vanderhasselt J De Mey andA Bossuyt R Luypaert 2010 Right prefrontal HF-rTMS attenuates right amygdala processing of negatively valenced emotional stimuli in healthy females Behav Brain Res214 2 450 455 - 8.
Bailey M. T S. E Dowd N. M Parry J. D Galley andD. B Schauer M Lyte 2010 Stressor exposure disrupts commensal microbial populations in the intestines and leads to increased colonization by Citrobacter rodentium. Infection and immunity78 4 1509 1519 - 9.
andBaram T. Z C. G Hatalski 1998 Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain 21 11 471 476 - 10.
andBayliss W. M E. H Starling 1899 The movements and innervation of the small intestine The Journal of physiology24 2 99 143 - 11.
Benarroch E. E 2006 Pain-autonomic interactions Neurological Science 27: S130 S133. - 12.
Benarroch E. E 2011 Circumventricular organs: receptive and homeostatic functions and clinical implications. 77 12 1198 1204 - 13.
Bercik P A. J Park D. A Sinclair A Khoshdel J Lu X Huang Y Deng P. A Blennerhasset M Fahnestock D Moine B Berger J. D Huizinga W Kunze P. G Mclean G. E Bergonzelli andS. M Collins E. F Verdu 2011 The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication Neurogastroenterology Motility23 1132 e1544. - 14.
andBienkowski M. S L Rinaman 2012 Common and distinct neural inputs to the medial central nucleus of the amygdala and anterior ventrolateral bed nucleus of stria terminalis in rats." Brain structure & function. - 15.
Blankstein U J Chen andN. E Diamant K. D Davis 2010 Altered brain structure in irritable bowel syndrome: potential contributions of pre-existing and disease-driven factors 138 5 1783 1789 - 16.
Bonaz B L Martin E Beurriand andJ Hostein C Feuerstein 1992a Involvement of hypothalamic noradrenergic systems in the modulation of intestinal motility in rats. Brain Res 583(1-2):332 EOF 5 EOF - 17.
Bonaz B L Martin E Beurriand M Manier andJ Hostein C Feuerstein 1992b Locus ceruleus modulates migrating myoelectric complex in rats. Am J Physiol 262(6 Pt 1): G1121 1126 - 18.
andBonaz B Y Tache 1994a Induction of Fos immunoreactivity in the rat brain after cold-restraint induced gastric lesions and fecal excretion. Brain Res652 1 56 64 - 19.
stress-induced c-fos expression in the rat brain and stimulation of fecal output: role of corticotropin-releasing factor." Brain Res andBonaz B Y Tache 1994b Water-avoidance 641 1 21 28 - 20.
Bonaz B L Martin E Beurriand andJ Hostein C Feuerstein 1995 Brain noradrenergic systems modulate the ceco-colonic myoelectric activity in rats. 7 2 101 110 - 21.
andBonaz B Y Tache 1997 Corticotropin-releasing factor and systemic capsaicin-sensitive afferents are involved in abdominal surgery-induced Fos expression in the paraventricular nucleus of the hypothalamus. Brain Res 748(1-2):12 EOF 20 EOF - 22.
andBonaz B S Rivest 1998 Effect of a chronic stress on CRF neuronal activity and expression of its type 1 receptor in the rat brain. Am J Physiol 275(5 Pt 2): R1438 1449 - 23.
andBonaz B J Fournet 2000 Acid-sensitive esophagus: a model of abnormal visceroception]." Gastroenterologie clinique et biologique24 10 903 905 - 24.
Bonaz B P. J Riviere V Sinniger X Pascaud J. L Junien andJ Fournet C Feuerstein 2000 Fedotozine, a kappa-opioid agonist, prevents spinal and supra-spinal Fos expression induced by a noxious visceral stimulus in the rat. 12 2 135 147 - 25.
Fournet and C. Segebarth (Bonaz B M Baciu E Papillon R Bost N Gueddah J. F Le Bas J 2002 Central processing of rectal pain in patients with irritable bowel syndrome: an fMRI study Am J Gastroenterol97 3 654 661 - 26.
Bonaz B 2003 Visceral sensitivity perturbation integration in the brain-gut axis in functional digestive disorders. Suppl4 27 42 - 27.
andBonaz B J. M Sabate 2009 Brain-gut axis dysfunction]." Suppl 1: S48 58 - 28.
Bonaz B 2010 Brain-gut interactions]." La Revue de medecine interne / fondee... par la Societe nationale francaise de medecine interne31 8 581 585 - 29.
Bouret S A Duvel andS Onat S. J Sara 2003 Phasic activation of locus ceruleus neurons by the central nucleus of the amygdala. 23 8 3491 3497 - 30.
Bradette M M Delvaux G Staumont J Fioramonti andL Bueno J Frexinos 1994 Evaluation of colonic sensory thresholds in IBS patients using a barostat. Definition of optimal conditions and comparison with healthy subjects. Dig Dis Sci39 3 449 457 - 31.
Bradford K W Shih E. J Videlock A. P Presson B. D Naliboff andE. A Mayer L Chang 2012 Association between early adverse life events and irritable bowel syndrome the official clinical practice journal of the American Gastroenterological Association10 4 385 390 e383. - 32.
Bravo J. A andT. G Dinan J. F Cryan 2011 Alterations in the central CRF system of two different rat models of comorbid depression and functional gastrointestinal disorders Int J Neuropsychopharmacol14 5 666 683 - 33.
Buckinx R D Adriaensen andL. V Nassauw J. P Timmermans 2011 Corticotrophin-releasing factor, related peptides, and receptors in the normal and inflamed gastrointestinal tract Frontiers in neuroscience 5: 54. - 34.
Burstein R 1996 Somatosensory and visceral input to the hypothalamus and limbic system. 107 257 267 - 35.
Chang L S Sundaresh J Elliott P. A Anton P Baldi A Licudine M Mayer T Vuong M Hirano B. D Naliboff andV. Z Ameen E. A Mayer 2009 Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society21 2 149 159 - 36.
Chitkara D. K M. A. L Van Tilburg andN Blois-martin W. E Whitehead 2008 Early life risk factors that contribute to irritable bowel syndrome in adults: a systematic review 103 765 774 - 37.
Clarke T. B K. M Davis E. S Lysenko A. Y Zhou andY Yu J. N Weiser 2010 Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity 16 2 228 231 - 38.
Jr. (Cliffer K. D andR Burstein G. J Giesler 1991 Distributions of spinothalamic, spinohypothalamic, and spinotelencephalic fibers revealed by anterograde transport of PHA-L in rats. 11 3 852 868 - 39.
Cohen H A Jotkowitz D Buskila S Pelles-avraham Z Kaplan andL Neumann A. D Sperber 2006 Post-traumatic stress disorder and other co-morbidities in a sample population of patients with irritable bowel syndrome 17 8 567 571 - 40.
Collins S. M 2001 Stress and the gastrointestinal tract. IV. Modulation of intestinal inflammation by stress: basic mechanisms and clinical relevance The G315 G318. - 41.
andCollins S. M P Bercik 2009 The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease 136 6 2003 2014 - 42.
Coutinho S. V P. M Plotsky M Sablad J. C Miller H Zhou A. I Bayati andJ. A Mcroberts E. A Mayer 2002 Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat Gastrointestinal and liver physiology 282(2): G307 316 - 43.
Czeh B C Perez-cruz andE Fuchs G Flugge 2008 Chronic stress-induced cellular changes in the medial prefrontal cortex and their potential clinical implications: does hemisphere location matter? Behav Brain Res190 1 1 13 - 44.
Damasio A. R T. J Grabowski A Bechara H Damasio L. L Ponto andJ Parvizi R. D Hichwa 2000 Subcortical and cortical brain activity during the feeling of self-generated emotions. Nat Neurosci3 10 1049 1056 - 45.
S. Bruley des Varannes, L. Bueno, B. Coffin, P. Ducrotte, B. Flourie, M. Lemann, A. Lepicard and O. Reigneau (Dapoigny M J Bellanger B Bonaz 2004 Irritable bowel syndrome in France: a common, debilitating and costly disorder. Eur J Gastroenterol Hepatol16 10 995 1001 - 46.
Davis M 1997 Neurobiology of fear responses: the role of the amygdala. 9 3 382 402 - 47.
Debenedittis G M Cigada A Bianchi andM. G Signorini S Cerutti 1994 Autonomic changes during hypnosis: a heart rate variability power spectrum analysis as a marker of sympatho-vagal balance. 42 2 140 152 - 48.
Delvaux M. M 1999 Stress and visceral perception. Suppl A:32A EOF 36A EOF - 49.
andDiorio J M. J Meaney 2007 Maternal programming of defensive responses through sustained effects on gene expression Journal of psychiatry & neuroscience : JPN32 4 275 284 - 50.
Drossman D. A J Leserman G Nachman Z. M Li H Gluck andT. C Toomey C. M Mitchell 1990 Sexual and physical abuse in women with functional or organic gastrointestinal disorders. 113 11 828 833 - 51.
Drossman D. A Z Li E Andruzzi R. D Temple N. J Talley W. G Thompson W. E Whitehead J Janssens P Funch-jensen andE Corazziari et al 1993 U.S. householder survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact. Dig Dis Sci38 9 1569 1580 - 52.
Drossman D. A Z Li J Leserman andT. C Toomey Y. J Hu 1996a Health status by gastrointestinal diagnosis and abuse history. 110 4 999 1007 - 53.
Drossman D. A 1996b Gastrointestinal illness and the biopsychosocial model. 22 4 252 254 - 54.
Drossman D. A 1999a Do psychosocial factors define symptom severity and patient status in irritable bowel syndrome? A):41S EOF 50S EOF - 55.
Drossman D. A 1999b The Rome criteria process: diagnosis and legitimization of irritable bowel syndrome. Am J Gastroenterol94 10 2803 2807 - 56.
Drossman D. A F. H Creed K. W Olden J Svedlund andB. B Toner W. E Whitehead 1999c Psychosocial aspects of the functional gastrointestinal disorders Gut 45 Suppl 2: II25 30 - 57.
Drossman D. A W. E Whitehead B. B Toner N Diamant Y. J Hu andS. I Bangdiwala H Jia 2000 What determines severity among patients with painful functional bowel disorders? Am J Gastroenterol95 4 974 980 - 58.
Drossman D. A 2011 Abuse, trauma, and GI illness: is there a link ?" The American Journal of Gastroenterology106 14 25 - 59.
andDunn A. J C. W Berridge 1990 Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain research. reviews15 2 71 100 - 60.
Elsenbruch S C Rosenberger P Enck M Forsting andM Schedlowski E. R Gizewski 2010 Affective disturbances modulate the neural processing of visceral pain stimuli in irritable bowel syndrome: an fMRI study Gut 59(489e495): 10.1136/gut.2008.175000. - 61.
Ford A. C 2009 Management of irritable bowel syndrome. 55 3 273 287 - 62.
andFord A. C N. J Talley 2011 Mucosal inflammation as a potential etiological factor in irritable bowel syndrome: a systematic review 46 4 421 431 - 63.
Foreman R. D 1999 Mechanisms of cardiac pain. Annu Rev Physiol61 143 167 - 64.
andFu Y V Neugebauer 2008 Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior The the official journal of the Society for Neuroscience28 15 3861 3876 - 65.
andFudge J. L A. B Emiliano 2003 The extended amygdala and the dopamine system: another piece of the dopamine puzzle. 15 3 306 316 - 66.
Fukudo S M Hongo andH Kaneko R Ueno 2011 Efficacy and safety of oral lubiprostone in constipated patients with or without irritable bowel syndrome: a randomized, placebo-controlled and dose-finding study. 23 6 544 e205. - 67.
andFukudo S M Kanazawa 2011 Gene, environment, and brain-gut interactions in irritable bowel syndrome." J Gastroenterol Hepatol 26 Suppl3 110 115 - 68.
andFulwiler C. E C. B Saper 1984 Subnuclear organization of the efferent connections of the parabrachial nucleus in the rat. Brain Res319 3 229 259 - 69.
Furness J. B 2012 The enteric nervous system and neurogastroenterology. Gastroenterology & hepatology. - 70.
andGale J. D L. A Houghton 2011 Alpha 2 Delta (alpha(2)delta) Ligands, Gabapentin and Pregabalin: What is the Evidence for Potential Use of These Ligands in Irritable Bowe l Syndrome." Frontiers in pharmacology 2: 28. - 71.
Garakani A T Win S Virk S Gupta andD Kaplan P. S Masand 2003 Comorbidity of irritable bowel syndrome in psychiatric patients: a review. 10 1 61 67 - 72.
andGauriau C J. F Bernard 2002 Pain pathways and parabrachial circuits in the rat 87 2 251 258 - 73.
andGaynes B. N D. A Drossman 1999 The role of psychosocial factors in irritable bowel syndrome Bailliere’s best practice & research. Clinical gastroenterology13 3 437 452 - 74.
Gemignani A L Sebastiani A Simoni andE. L Santarcangelo B Ghelarducci 2006 Hypnotic trait and specific phobia: EEG and autonomic output during phobic stimulation Brain Res Bull69 2 197 203 - 75.
Ghaith O M El-Halabi andJ. G Hashash A. I Sharara 2010 Investigational agents for the irritable bowel syndrome 19 10 1161 1178 - 76.
Ghia J E. , P Blennerhassett H Kumar-ondiveeran andE. F Verdu S. M Collins 2006 The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model 131 1122 1130 - 77.
andGoldin P. R J. J Gross 2010 Effects of mindfulness-based stress reduction (MBSR) on emotion regulation in social anxiety disorder 10 1 83 91 - 78.
andGravanis A A. N Margioris 2005 The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications. 12 13 1503 1512 - 79.
Gray T. S 1993 Amygdaloid CRF pathways. Role in autonomic, neuroendocrine, and behavioral responses to stress. 697 53 60 - 80.
Greenwood-Van Meerveld B., M. Gibson, W. Gunter, J. Shepard, R. Foreman and D. Myers (2001 Stereotaxic delivery of corticosterone to the amygdala modulates colonic sensitivity in rats. Brain Res 893(1-2):135 EOF 42 EOF - 81.
Greenwood-van Meerveld B., A.C. Johnson, J. Schulkin and D.A. Myers (2006 Long-term expression of corticotropin-releasing factor (CRF) in the paraventricular nucleus of the hypothalamus in response to an acute colonic inflammation 1071 91 96 - 82.
Grundy D 2006 Signalling the state of the digestive tract 125 76 80 - 83.
Meerveld (Gunter W. D J. D Shepard R. D Foreman andD. A Myers B Greenwood-van 2000 Evidence for visceral hypersensitivity in high-anxiety rats. Physiol Behav69 3 379 382 - 84.
Gwee K. A 2001 Postinfectious Irritable Bowel Syndrome 4 4 287 291 - 85.
Hallbeck M andD Larhammar A Blomqvist 2001 Neuropeptide expression in rat paraventricular hypothalamic neurons that project to the spinal cord. 433 2 222 238 - 86.
Heinrichs S. C J Lapsansky T. W Lovenberg andE. B De Souza D. T Chalmers 1997 Corticotropin-releasing factor CRF1, but not CRF2, receptors mediate anxiogenic-like behavior. 71 1 15 21 - 87.
Henke P. G andA Ray R. M Sullivan 1991 The amygdala. Emotions and gut functions. 36 11 1633 1643 - 88.
andHolsboer F M Ising 2008 Central CRH system in depression and anxiety--evidence from clinical studies with CRH1 receptor antagonists. Eur J Pharmacol 583(2-3):350 EOF 7 EOF - 89.
Hubbard C. S J. S Labus J Bueller J Stains B Suyenobu G. E Dukes D. L Kelleher K Tillisch andB. D Naliboff E. A Mayer 2011 Corticotropin-releasing factor receptor 1 antagonist alters regional activation and effective connectivity in an emotional-arousal circuit during expectation of abdominal pain The the official journal of the Society for Neuroscience31 35 12491 12500 - 90.
andHuston J. M K. J Tracey 2011 The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy." 269 1 45 53 - 91.
Hylden J. L andF Anton R. L Nahin 1989 Spinal lamina I projection neurons in the rat: collateral innervation of parabrachial area and thalamus. 28 1 27 37 - 92.
andJi G V Neugebauer 2007 Differential effects of CRF1 and CRF2 receptor antagonists on pain-related sensitization of neurons in the central nucleus of the amygdala. 97 6 3893 3904 - 93.
Johnson A. C L Tran andJ Schulkin B. G Meerveld 2012 Importance of stress receptor-mediated mechanisms in the amygdala on visceral pain perception in an intrinsically anxious rat. - 94.
andKavushansky A G Richter-levin 2006 Effects of stress and corticosterone on activity and plasticity in the amygdala. 84 7 1580 1587 - 95.
andKearney D. J J Brown-chang 2008 Complementary and alternative medicine for IBS in adults: mind-body interventions Nature clinical practice. Gastroenterology & hepatology5 11 624 636 - 96.
Knapska E K Radwanska andT Werka L Kaczmarek 2007 Functional internal complexity of amygdala: focus on gene activity mapping after behavioral training and drugs of abuse. 87 4 1113 1173 - 97.
Kosoyan H. P andD. E Grigoriadis Y Tache 2005 The CRF(1) receptor antagonist, NBI-35965, abolished the activation of locus coeruleus neurons induced by colorectal distension and intracisternal CRF in rats." Brain Res1056 1 85 96 - 98.
Kraus T K Hosl O Kiess A Schanze andJ Kornhuber C Forster 2007 BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation J Neural Transm114 11 1485 1493 - 99.
Kunzel H. E A. W Zobel T Nickel N Ackl M Uhr A Sonntag andM Ising F Holsboer 2003 Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects. 37 6 525 533 - 100.
Mahl and A.H. Lockwood (Lackner J. M M Lou Coad H. R Mertz D. S Wack L. A Katz S. S Krasner R Firth T. C 2006 Cognitive therapy for irritable bowel syndrome is associated with reduced limbic activity, GI symptoms, and anxiety Behav Res Ther44 5 621 638 - 101.
Larauche M andC Kiank Y Tache 2009 Corticotropin releasing factor signaling in colon and ileum: regulation by stress and pathophysiological implications. Suppl7 33 46 - 102.
Larauche M G Gourcerol M Million andD. W Adelson Y Tache 2010 Repeated psychological stress-induced alterations of visceral sensitivity and colonic motor functions in mice: influence of surgery and postoperative single housing on visceromotor responses 13 4 343 354 - 103.
Larauche M andA Mulak Y Tache 2011 Stress-related alterations of visceral sensation: animal models for irritable bowel syndrome study Journal of neurogastroenterology and motility17 3 213 234 - 104.
Larauche M andA Mulak Y Tache 2012 Stress and visceral pain: from animal models to clinical therapies 233 1 49 67 - 105.
Lawrence J. M F Hoeft andK. E Sheau S. C Mackey 2011 Strategy-dependent dissociation of the neural correlates involved in pain modulation 115 4 844 851 - 106.
Le Bars D., L. Villanueva, D. Bouhassira and J.C. Willer (1992 Diffuse noxious inhibitory controls (DNIC) in animals and in man. Patologicheskaia fiziologiia i eksperimental’naia terapiia(4):55 EOF 65 EOF - 107.
LeDoux J.E., J. Iwata, P. Cicchetti and D.J. Reis (1988 Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. 8 7 2517 2529 - 108.
LeDoux J. (2007 The amygdala." Current Biology 17(20): R868 R874. - 109.
andLee Y. K S. K Mazmanian 2010 Has the microbiota played a critical role in the evolution of the adaptive immune system? 330 6012 1768 1773 - 110.
Li C J Vaughan andP. E Sawchenko W. W Vale 2002 Urocortin III-immunoreactive projections in rat brain: partial overlap with sites of type 2 corticotrophin-releasing factor receptor expression. 22 3 991 1001 - 111.
andLong M. D D. A Drossman 2010 Inflammatory bowel disease, irritable bowel syndrome, or what?: A challenge to the functional-organic dichotomy." Am J Gastroenterol105 8 1796 1798 - 112.
Longstreth G. F W. G Thompson W. D Chey L. A Houghton andF Mearin R. C Spiller 2006 Functional bowel disorders 130 5 1480 1491 - 113.
Lu H. C J. C Hsieh C. L Lu D. M Niddam Y. T Wu T. C Yeh C. M Cheng andF. Y Chang S. D Lee 2010 Neuronal correlates in the modulation of placebo analgesia in experimentally-induced esophageal pain: a 3T-fMRI study 148 1 75 83 - 114.
Makino S andP. W Gold J Schulkin 1994 Corticosterone effects on corticotropin-releasing hormone mRNA in the central nucleus of the amygdala and the parvocellular region of the paraventricular nucleus of the hypothalamus. Brain Res 640(1-2):105 EOF 12 EOF - 115.
Maren S 2005 Synaptic mechanisms of associative memory in the amygdala. 47 6 783 786 - 116.
Mathieu N 2009 Somatic comorbidities in irritable bowel syndrome: fibromyalgia, chronic fatigue syndrome, and interstitial cystitis]." Suppl 1: S17 25 - 117.
Mawdsley J. E M. G Macey R. M Feakins andL Langmead D. S Rampton 2006 The effect of acute psychologic stress on systemic and rectal mucosal measures of inflammation in ulcerative colitis 131 410 419 - 118.
andMawdsley J. E D. S Rampton 2006 The role of psychological stress in inflammatory bowel disease 327 EOF 336 EOF - 119.
Mayer E. A 2000 The neurobiology of stress and gastrointestinal disease Gut47 861 869 - 120.
Mayer E. A andB. D Naliboff A. D. B Craig 2006 Neuroimaging of the brain-gut axis: from basic understanding to treatment of functional GI disorders 131 1925 1942 - 121.
Mayer E. A 2011 Gut feelings: the emerging biology of gut-brain communication. Nature Neuroscience12 453 466 - 122.
Mazurak N N Seredyuk H Sauer andM Teufel P Enck 2012 Heart rate variability in the irritable bowel syndrome: a review of the literature. 24 3 206 216 - 123.
Meagher M. W andR. C Arnau J. L Rhudy 2001 Pain and emotion: effects of affective picture modulation. Psychosom Med63 1 79 90 - 124.
Attal and D. Bouhassira (Mhalla A S Baudic D Ciampi De Andrade M Gautron S Perrot M. J Teixeira N 2011 Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia 152 7 1478 1485 - 125.
Million M C Maillot D. A Adelson T Nozu A Gauthier J Rivier G. P Chrousos A Bayati andH Mattsson Y Tache 2005 Peripheral injection of sauvagine prevents repeated colorectal distension-induced visceral pain in female rats. 26 7 1188 1195 - 126.
Million M L Wang Y Wang D. W Adelson P. Q Yuan C Maillot S. V Coutinho J. A Mcroberts A Bayati H Mattsson V Wu J. Y Wei J Rivier W Vale andE. A Mayer Y Tache 2006 CRF2 receptor activation prevents colorectal distension induced visceral pain and spinal ERK1/2 phosphorylation in rats. 55 2 172 181 - 127.
Million M L Wang M. P Stenzel-poore S. C Coste P. Q Yuan C Lamy J Rivier andT Buffington Y Tache 2007 Enhanced pelvic responses to stressors in female CRF-overexpressing mice Regulatory, integrative and comparative physiology 292(4): R1429 1438 - 128.
Morcos A andT Dinan E. M Quigley 2009 Irritable bowel syndrome: role of food in pathogenesis and management 10 4 237 246 - 129.
andMulak A B Bonaz 2004 Irritable bowel syndrome: a model of the brain-gut interactions. RA55 62 - 130.
Mulak A P Kahane D Hoffmann andL Minotti B Bonaz 2008 Brain mapping of digestive sensations elicited by cortical electrical stimulations Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society20 6 588 596 - 131.
and B. Greenwood Van-Meerveld (Myers D. A M Gibson J Schulkin 2005 Corticosterone implants to the amygdala and type 1 CRH receptor regulation: effects on behavior and colonic sensitivity. Behav Brain Res161 1 39 44 - 132.
andMyers B B Greenwood-van Meerveld 2007a Corticosteroid receptor-mediated mechanisms in the amygdala regulate anxiety and colonic sensitivity Gastrointestinal and liver physiology 292(6): G1622 1629 - 133.
andMyers B B Greenwood-van Meerveld 2007b Corticosteroid receptor-mediated mechanisms in the amygdala regulate anxiety and colonic sensitivity The G1622 G1629. - 134.
Meerveld ( andMyers B B Greenwood-van 2010 Elevated corticosterone in the amygdala leads to persistant increases in anxiety-like behavior and pain sensitivity - 135.
Naliboff B. D A. M Waters J Labus L Kilpatrick M. G Craske L Chang H Negoro H Ibrahimovic andE. A Mayer E Ornitz 2008 Increased acoustic startle responses in IBS patients during abdominal and nonabdominal threat Psychosomatic Medicine70 920 927 - 136.
Nemeroff C. B J. D Bremner E. B Foa H. S Mayberg andC. S North M. B Stein 2006 Posttraumatic stress disorder: a state-of-the-science review 40 1 1 21 - 137.
Neugebauer V W Li andG. C Bird J. S Han 2004 The amygdala and persistent pain a review journal bringing neurobiology, neurology and psychiatry10 3 221 234 - 138.
Neugebauer V 2006 Chapter 11 Subcortical processing of nociceptive information: basal ganglia and amygdala. J. Vinken and G.W. Bruyn81 141 158 - 139.
Nishith P S. P Duntley P. P Domitrovich M. L Uhles andB. J Cook P. K Stein 2003 Effect of cognitive behavioral therapy on heart rate variability during REM sleep in female rape victims with PTSD. 16 3 247 250 - 140.
O Mahony S. M. , N. P Hyland andT. G Dinan J. F Cryan 2011 Maternal separation as a model of brain-gut axis dysfunction 214 1 71 88 - 141.
O Malley andD. , T. G Dinan J. F Cryan 2011 Neonatal maternal separation in the rat impacts on the stress responsivity of central corticotropin-releasing factor receptors in adulthood 214 1 221 229 - 142.
andOverstreet D. H V Djuric 2001 A genetic rat model of cholinergic hypersensitivity: implications for chemical intolerance, chronic fatigue, and asthma. 933 92 102 - 143.
Pare D 2003 Role of the basolateral amygdala in memory consolidation. 70 5 409 420 - 144.
Parkes G. C J Brostoff andK Whelan J. D Sanderson 2008 Gastrointestinal microbiota in irritable bowel syndrome: their role in its pathogenesis and treatment Am J Gastroenterol103 6 1557 1567 - 145.
Patel S. M W. B Stason A Legedza S. M Ock T. J Kaptchuk L Conboy K Canenguez J. K Park E Kelly E Jacobson andC. E Kerr A. J Lembo 2005 The placebo effect in irritable bowel syndrome trials: a meta-analysis Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society17 3 332 340 - 146.
Pellissier S C Dantzer F Canini andN Mathieu B Bonaz 2010a Psychological adjustment and autonomic disturbances in inflammatory bowel diseases and irritable bowel syndrome 35 5 653 662 - 147.
a definition of a global psycho-physiological criterion of vulnerability to relapse in inflammatory bowel diseases." ThePellissier S C Dantzer F Canini andN Mathieu B Bonaz 2010b Toward 105 1446 1447 - 148.
and J.E. LeDoux (Phelps E. A M. R Delgado K. I Nearing 2004 Extinction learning in humans: role of the amygdala and vmPFC. 43 6 897 905 - 149.
and J.E. LeDoux (Phelps E. A 2005 Contributions of the amygdala to emotion processing: from animal models to human behavior. 48 2 175 187 - 150.
andPlotsky P. M M. J Meaney 1993 Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats." Brain research. Molecular brain research18 3 195 200 - 151.
Plotsky P. M K. V Thrivikraman C. B Nemeroff C Caldji andS Sharma M. J Meaney 2005 Long-term consequences of neonatal rearing on central corticotropin-releasing factor systems in adult male rat offspring. 30 12 2192 2204 - 152.
Porcher C V Sinniger A Juhem andP Mouchet B Bonaz 2004 Neuronal activity and CRF receptor gene transcription in the brains of rats with colitis Gastrointestinal and liver physiology 287(4): G803 814 - 153.
Porcher C A Juhem A Peinnequin andV Sinniger B Bonaz 2005 Expression and effects of metabotropic CRF1 and CRF2 receptors in rat small intestine. American journal of physiology. Gastrointestinal and liver physiology 288(5): G1091 1103 - 154.
Quide Y A. B Witteveen W El-Hage andD. J Veltman M Olff 2012 Differences between effects of psychological versus pharmacological treatments on functional and morphological brain alterations in anxiety disorders and major depressive disorder: a systematic review Neurosci Biobehav Rev36 1 626 644 - 155.
Quirk G. J andR Garcia F Gonzalez-lima 2006a Prefrontal mechanisms in extinction of conditioned fear Biol Psychiatry60 4 337 343 - 156.
andQuirk G. J I Vidal-gonzalez 2006b Keeping the memories flowing. Nat Neurosci9 10 1199 1200 - 157.
Rahimi R S Nikfar andA Rezaie M Abdollahi 2009 Efficacy of tricyclic antidepressants in irritable bowel syndrome: a meta-analysis WJG15 13 1548 1553 - 158.
andRandich A G. F Gebhart 1992 Vagal afferent modulation of nociception. Brain research. reviews17 2 77 99 - 159.
Ren T H. , J Wu D Yew E Ziea L Lao W. -k Leung B Berman andP. -j Hu J. J. Y Sung 2007 Effects of neonatal maternal separation on neurochemical and sensory response to colonic distension in a rat model of irritable bowel syndrome The G849 G856. - 160.
andReul J. M F Holsboer 2002 On the role of corticotropin-releasing hormone receptors in anxiety and depression. 4 1 31 46 - 161.
andRhudy J. L M. W Meagher 2003 Negative affect: effects on an evaluative measure of human pain. 104 3 617 626 - 162.
Rinaman L andL Banihashemi T. J Koehnle 2011 Early life experience shapes the functional organization of stress-responsive visceral circuits Physiology & Behavior104 632 640 - 163.
Ritchie J 1973 Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. 14 2 125 132 - 164.
Rizvi T. A M Ennis andM. M Behbehani M. T Shipley 1991 Connections between the central nucleus of the amygdala and the midbrain periaqueductal gray: topography and reciprocity. 303 1 121 131 - 165.
Doux and R.M. Sapolsky (Rodrigues S. M J. E Le 2009 The influence of stress hormones on fear circuitry 32 289 313 - 166.
Rodriguez Manzanares P.A., N.A. Isoardi, H.F. Carrer and V.A. Molina (2005 Previous stress facilitates fear memory, attenuates GABAergic inhibition, and increases synaptic plasticity in the rat basolateral amygdala. 25 38 8725 8734 - 167.
Rose A. B D. P Merke L. S Clasen M. A Rosenthal G. L Wallace A. C Vaituzis andJ. D Fields J. N Giedd 2004 Effects of hormones and sex chromosomes on stress-influenced regions of the developing pediatric brain. 1032 231 233 - 168.
Rosenkranz J. A andH Moore A. A Grace 2003 The prefrontal cortex regulates lateral amygdala neuronal plasticity and responses to previously conditioned stimuli. 23 35 11054 11064 - 169.
Rosenkranz J. A andD. M Buffalari A. A Grace 2006 Opposing influence of basolateral amygdala and footshock stimulation on neurons of the central amygdala Biol Psychiatry59 9 801 811 - 170.
Rouzade-dominguez M. L andA. L Curtis R. J Valentino 2001 Role of Barrington’s nucleus in the activation of rat locus coeruleus neurons by colonic distension Brain Res917 2 206 218 - 171.
Sajdyk T. J D. A Schober andD. R Gehlert A Shekhar 1999 Role of corticotropin-releasing factor and urocortin within the basolateral amygdala of rats in anxiety and panic responses Behav Brain Res 100(1-2):207 EOF - 172.
andSamuels E. R E Szabadi 2008 Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation Current neuropharmacology6 3 235 253 - 173.
Sandler R. S D. A Drossman andH. P Nathan D. C Mckee 1984 Symptom complaints and health care seeking behavior in subjects with bowel dysfunction. 87 2 314 318 - 174.
Santos J P. C Yang J. D Soderholm andM Benjamin M. H Perdue 2001 Role of mast cells in chronic stress induced colonic epithelial barrier dysfunction in the rat Gut48 5 630 636 - 175.
Saper C. B 1982 Convergence of autonomic and limbic connections in the insular cortex of the rat. 210 2 163 173 - 176.
Saper C. B 2000 Hypothalamic connections with the cerebral cortex. 126 39 48 - 177.
Saper C. B 2002 The central autonomic nervous system: conscious visceral perception and autonomic pattern generation. 25 433 469 - 178.
Sapolsky R. M andB. S Mcewen T. C Rainbow 1983 Quantitative autoradiography of [3H]corticosterone receptors in rat brain. Brain Res271 2 331 334 - 179.
Schwetz I J. A Mcroberts S. V Coutinho S Bradesi G Gale M Fanselow M Million G Ohning Y Tache andP. M Plotsky E. A Mayer 2005 Corticotropin-releasing factor receptor 1 mediates acute and delayed stress-induced visceral hyperalgesia in maternally separated Long-Evans rats Gastrointestinal and liver physiology 289(4): G704 712 - 180.
Selye H 1950 Stress and the general adaptation syndrome British medical journal1 4667 1383 1392 - 181.
Seminowicz D. A J. S Labus J. A Bueller K Tillisch B. D Naliboff andM. C Bushnell E. A Mayer 2010 Regional gray matter density changes in brains of patients with irritable bowel syndrome 139 1 48 57 e42. - 182.
andShepard J. D D. A Myers 2008 Strain differences in anxiety-like behavior: association with corticotropin-releasing factor Behav Brain Res186 2 239 245 - 183.
Short E. B J. J Borckardt B. S Anderson H Frohman W Beam andS. T Reeves M. S George 2011 Ten sessions of adjunctive left prefrontal rTMS significantly reduces fibromyalgia pain: a randomized, controlled pilot study. 152 11 2477 2484 - 184.
Siggins G. R D Gruol andJ Aldenhoff Q Pittman 1985 Electrophysiological actions of corticotropin-releasing factor in the central nervous system. Pt 2):237 EOF 42 EOF - 185.
Sinniger V C Porcher P Mouchet andA Juhem B Bonaz 2004 c-fos and CRF receptor gene transcription in the brain of acetic acid-induced somato-visceral pain in rats. 110 3 738 750 - 186.
Sinniger V andP Mouchet B Bonaz 2005 Effect of nor-trimebutine on neuronal activation induced by a noxious stimulus or an acute colonic inflammation in the rat. 77 23 2927 2941 - 187.
and J.E. LeDoux (Sotres-bayon F D. E Bush 2004 Emotional perseveration: an update on prefrontal-amygdala interactions in fear extinction Learn Mem11 5 525 535 - 188.
andSpence M. J R Moss-morris 2007 The cognitive behavioural model of irritable bowel syndrome: a prospective investigation of patients with gastroenteritis Gut56 8 1066 1071 - 189.
Dockens and A.R. Zinsmeister (Sweetser S M Camilleri S. J Linker Nord D. D Burton L Castenada R Croop G Tong R 2009 Do corticotropin releasing factor-1 receptors influence colonic transit and bowel function in women with irritable bowel syndrome? American journal of physiology. Gastrointestinal and liver physiology 296(6): G1299 1306 - 190.
Sykes M. A E. B Blanchard J Lackner andL Keefer S Krasner 2003 Psychopathology in irritable bowel syndrome: support for a psychophysiological model. 26 4 361 372 - 191.
Tache Y M Million A. G Nelson andC Lamy L Wang 2005 Role of corticotropin-releasing factor pathways in stress-related alterations of colonic motor function and viscerosensibility in female rodents. Gend Med2 3 146 154 - 192.
andTache Y B Bonaz 2007 Corticotropin-releasing factor receptors and stress-related alterations of gut motor function. 117 1 33 40 - 193.
rd (Talley N. J A. R Zinsmeister andC Van Dyke L. J Melton 1991 Epidemiology of colonic symptoms and the irritable bowel syndrome. 101 4 927 934 - 194.
Tasan R. O N. K Nguyen S Weger S. B Sartori N Singewald R Heilbronn andH Herzog G Sperk 2010 The central and basolateral amygdala are critical sites of neuropeptide Y/Y2 receptor-mediated regulation of anxiety and depression The the official journal of the Society for Neuroscience30 18 6282 6290 - 195.
Tillisch K andE. A Mayer J. S Labus 2011 Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome 140 91 100 - 196.
Tottenham N T. A Hare B. T Quinn T. W Mccarry M Nurse T Gilhooly A Millner A Galvan M. C Davidson I. M Eigsti K. M Thomas P. J Freed E. S Booma M. R Gunnar M Altemus andJ Aronson B. J Casey 2010 Prolonged institutional rearing is associated with atypically large amygdala volume and difficulties in emotion regulation Developmental science13 1 46 61 - 197.
Meerveld (Trimble N A. C Johnson andA Foster B Greenwood-van 2007 Corticotropin-releasing factor receptor 1-deficient mice show decreased anxiety and colonic sensitivity Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society19 9 754 760 - 198.
andTrinkley K. E M. C Nahata 2011 Treatment of irritable bowel syndrome. 36 3 275 282 - 199.
Tsukamoto K Y Nakade C Mantyh K Ludwig andT. N Pappas T Takahashi 2006 Peripherally administered CRF stimulates colonic motility via central CRF receptors and vagal pathways in conscious rats The R1537 R1541. - 200.
Tsuruoka M D Wang andJ Tamaki T Inoue 2010 Descending influence from the nucleus locus coeruleus/subcoeruleus on visceral nociceptive transmission in the rat spinal cord 165 4 1019 1024 - 201.
Vale W J Spiess andC Rivier J Rivier 1981 Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science213 4514 1394 1397 - 202.
Valentino R. J andS. L Foote M. E Page 1993 The locus coeruleus as a site for integrating corticotropin-releasing factor and noradrenergic mediation of stress responses. 697 173 188 - 203.
van den Wijngaard R.M., T.K. Klooker, O. Welting, O.I. Stanisor, M.M. Wouters, D. van der Coelen, D.C. Bulmer, P.J. Peeters, J. Aerssens, R. de Hoogt, K. Lee, W.J. de Jonge and G.E. Boeckxstaens (2009 Essential role for TRPV1 in stress-induced (mast cell-dependent) colonic hypersensitivity in maternally separated rats Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society21 10 1107 e1194. - 204.
van den Wijngaard R.M., T.K. Klooker, W.J. de Jonge and G.E. Boeckxstaens (2010 Peripheral relays in stress-induced activation of visceral afferents in the gut Autonomic neuroscience : basic & clinical 153(1-2):99 EOF 105 EOF - 205.
Van Haarst A. D andM. S Oitzl E. R De Kloet 1997 Facilitation of feedback inhibition through blockade of glucocorticoid receptors in the hippocampus. 22 11 1323 1328 - 206.
Van Oudenhove L andS. J Coen Q Aziz 2007 Functional brain imaging of gastrointestinal sensation in health and disease. 13 25 3438 3445 - 207.
Van Oudenhove L J Vandenberghe B Geeraerts R Vos P Persoons B Fischler andK Demyttenaere J Tack 2008 Determinants of symptoms in functional dyspepsia: gastric sensorimotor function, psychosocial factors or somatisation? Gut57 12 1666 1673 - 208.
Meerveld (Venkova K andR. D Foreman B Greenwood-van 2009 Mineralocorticoid and glucocorticoid receptors in the amygdala regulate distinct responses to colorectal distension 56 2 514 521 - 209.
Vidal-gonzalez I B Vidal-gonzalez andS. L Rauch G. J Quirk 2006 Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear Learn Mem13 6 728 733 - 210.
Rao and S. Chattarji (Vyas A R Mitra B. S Shankaranarayana 2002 Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. The Journal of neuroscience: the official journal of the Society for Neuroscience22 15 6810 6818 - 211.
Vyas A andS Jadhav S Chattarji 2006 Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala 143 2 387 393 - 212.
Wallon C P. C Yang A. V Keita A. C Ericson D. M Mckay P. M Sherman andM. H Perdue J. D Soderholm 2008 Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro 57 1 50 58 - 213.
Wang L V Martinez andM Larauche Y Tache 2009 Proximal colon distension induces Fos expression in oxytocin-, vasopressin-, CRF- and catecholamines-containing neurons in rat brain Brain Res1247 79 91 - 214.
andWhalen P. J B. S Kapp 1991 Contributions of the amygdaloid central nucleus to the modulation of the nictitating membrane reflex in the rabbit. 105 1 141 153 - 215.
Whitehead W. E andM. D Crowell J. C Robinson 1992 Effects of stressful life events on bowel symptoms: subjects with irritable bowel syndrome compared with subjects without bowel dysfunction. Gut33 825 830 - 216.
Whitehead W. E andO Palsson K. R Jones 2002 Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? 122 4 1140 1156 - 217.
Whorwell P. J andA Prior E. B Faragher 1984 Controlled trial of hypnotherapy in the treatment of severe refractory irritable-bowel syndrome. 2 8414 1232 1234 - 218.
Whorwell P. J 2009 Behavioral therapy for IBS Nature clinical practice. Gastroenterology & hepatology6 3 148 149 - 219.
Wilder-smith C. H D Schindler K Lovblad andS. M Redmond A Nirkko 2004 Brain functional magnetic resonance imaging of rectal pain and activation of endogenous inhibitory mechanisms in irritable bowel syndrome patient subgroups and healthy controls Gut53 1595 1601 - 220.
Woolf C. J 2011 Central sensitization: implications for the diagnosis and treatment of pain Suppl): S2 15 - 221.
Woon F. L andS Sood D. W Hedges 2010 Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysis Progress in neuro-psychopharmacology & biological psychiatry34 7 1181 1188 - 222.
andZhou Q G. N Verne 2011 New insights into visceral hypersensitivity- clinical implications in IBS." Nature Reviews Gastroenterology & Hepatology8 349 355