Evidence for alterations in central noradrenergic signalling in irritable bowel syndrome. Neuroimage
Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. NeuroImage
(Impact Factor: 6.36).
08/2012; 63(4):1854-63. DOI: 10.1016/j.neuroimage.2012.08.028
Alterations in noradrenergic (NE) signaling have been implicated in the pathophysiology of irritable bowel syndrome (IBS), and adrenergic receptors are potential treatment targets.
To characterize central NE signaling in IBS, 11 patients and 11 healthy controls (HCs) were studied 3 times during an auditory oddball vigilance task after double-blind ingestion of the α2-adrenoreceptor (α2AR) antagonist yohimbine (YOH), the α2AR agonist clonidine (CLO), or placebo (PLA). Regional cerebral glucose metabolism was measured with [(18)F] fluorodeoxyglucose (FDG) positron emission tomography (PET). Measures of anxiety, early-life trauma, plasma NE and blood pressure were acquired.
Patients had higher plasma NE levels than HCs before and after ingestion of all drugs (all p<0.05). YOH increased plasma NE and more anxiety in patients than in HCs. After YOH, NE levels directly correlated with drug-induced increases in anxiety in IBS patients (r=0.61), but not in HCs. IBS patients showed less YOH-mediated reduction of activity in a central arousal circuit, consistent with fewer functional presynaptic α2AR. In HCs, but not in patients, activation of amygdala and subgenual anterior cingulate cortex (sgACC) was inversely correlated with activation of anterior mid cingulate cortex (aMCC), and state anxiety covaried directly with activity in limbic and right frontotemporal cortices, but indirectly with activity in the left frontotemporal cortex. YOH-mediated reduction of activity in brainstem and amygdala inversely correlated with early life trauma.
IBS patients showed evidence for increased noradrenergic activity consistent with downregulation of presynaptic inhibitory α2ARs. Activity within central arousal circuits was biased toward greater excitability and reduced corticolimbic inhibition in IBS. Early life trauma may be one mediator of these abnormalities.
Available from: Ana Charrua
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ABSTRACT: To evaluate sympathetic system activity in bladder pain syndrome/interstitial cystitis (BPS/IC) patients and to investigate if chronic adrenergic stimulation in intact rats induces BPS/IC-like bladder modifications.
Clinical study-In BPS/IC patients and aged and body mass index matched volunteers TILT test was undertaken and catecholamines were measured in plasma and 24 hr urine samples. Experimental study-Phenylephrine was injected subcutaneously (14 days) to female Wistar rats. Pain behavior, spinal Fos expression, urinary spotting, number of fecal pellets expelled, frequency of reflex bladder contractions, and urothelial height were analyzed. Urothelium permeability was investigated by trypan blue staining. Immunoreactivity against caspase 3 and bax were studied in the urothelium and against alpha-1-adrenoreceptor and TRPV1 in suburothelial nerves. Mast cell number was determined in the sub-urothelium. In rats with lipopolysaccharide-induced cystitis, urinary catecholamines, and Vesicular Monoamine Transporter 2 (VMAT2) expression in bladder nerves were analyzed.
The TILT test showed an increase of sympathetic activity. Noradrenaline levels in blood at resting conditions and in 24-hr urine samples were higher in BPS/IC patients. Phenylephrine administration increased visceral pain, spinal Fos expression, bladder reflex activity, urinary spotting and the number of expelled fecal pellets. The mucosa showed urothelial thinning and increased immunoreactivity for caspase 3 and bax. Trypan blue staining was only observed in phenylephrine treated animals. Suburothelial nerves co-expressed alpha1 and TRPV1. Mastocytosis was present in the suburothelium. Cystitis increased sympathetic nerve density and urinary noradrenaline levels.
Excessive adrenergic stimulation of the bladder may contribute to the pathophysiological mechanisms of BPS/IC. Neurourol. Urodynam. © 2013 Wiley Periodicals, Inc.
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ABSTRACT: This chapter will focus on the growing body of evidence identifying the biological basis of mind-body interactions which may explain the role of psychosocial factors and psychiatric disorders in functional gastrointestinal disorders (FGID). First, a model of FGID as disorders of gut-brain signaling will be outlined, illustrating the principal (patho)physiological mechanisms of brain processing of visceral sensory signals in a homeostatic-afferent network, which is subject to modulation by emotional-arousal and cortical-modulatory regions through the descending modulatory system. Second, recent evidence, mainly from functional brain imaging studies, will be discussed, supporting substantial cognitive and affective modulation of homeostatic-afferent signals in healthy subjects as well as a key pathophysiological role of these mechanisms in FGID, as postulated in the model. I will emphasize similar findings in irritable bowel syndrome and functional dyspepsia research, despite methodological differences between studies. Abnormalities in activity and connectivity of emotional-arousal and cortical-modulatory circuits involved in pain modulation, which may lead to increased activity in homeostatic-afferent pain-processing regions through failing descending modulation, have indeed been shown to underlie the heightened anticipatory anxiety and increased perceptual sensitivity for visceral sensations in both of these disorders. This may help identify multidimensional endophenotypes, taking into account a combination of psychological and neurophysiological mechanisms, which may not be specific to a single FGID, but indeed common to (visceral) pain disorders in general. These may be crucial to make progress in the understanding of the pathophysiology of complex, heterogeneous, symptom-based disorders such as FGID, which may help identify more homogeneous subgroups and ultimately treatments that are better tailored to the individual patient.
Available from: Guillaume Fond
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ABSTRACT: Irritable bowel syndrome (IBS) has been associated with high prevalence of psychological disorders. However, it remains unclear whether IBS and each of its subtypes (predominant diarrhea IBS-D, constipation IBS-C, mixed IBS-M) are associated with higher anxiety and depressive symptoms levels. This study aimed to determine the associations of IBS and each of its subtypes with anxiety and/or depression. We conducted a systematic review and meta-analysis using five electronic databases (PubMed, PsychINFO, BIOSIS, Science Direct, and Cochrane CENTRAL). We selected case-control studies comparing anxiety and depression levels of patients with IBS to healthy controls, using standardized rating scales. Outcomes were measured as random pooled standardized mean differences (SMD). Ten studies were included in our analysis (885 patients and 1,384 healthy controls). Patients with IBS had significant higher anxiety and depression levels than controls (respectively, SMD = 0.76, 95 % CI 0.47; 0.69, p < 0.01, I2 = 81.7 % and SMD = 0.80, 95 % CI 0.42; 1.19, p < 0.01, I2 = 90.7 %). This significant difference was confirmed for patients with IBS-C and -D subtypes for anxiety, and only in IBS-D patients for depression. However, other IBS subtypes had a statistical trend to be associated with both anxiety and depressive symptomatology, which suggests a lack of power due to the small number of studies included. Patients with IBS had significantly higher levels of anxiety and depression than healthy controls. Anxiety and depression symptomatology should be systematically checked and treated in IBS patients, as psychological factors are important moderators of symptom severity, symptom persistence, decisions to seek treatment, and response to treatment.
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