Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clues to the pathogenesis of functional pain syndromes may be derived from the study of stimuli that precipitate or aggravate symptoms. In this study, cholecystokinin octapeptide (CCK-8, 0.06 microgram/kg) and placebo were given by intravenous infusion (5 min) in random order to control subjects and four groups of patients with unexplained abdominal pain. Induction of pain and nausea were assessed by linear analogue scales while sympathoadrenomedullary responses were assessed by serial changes in plasma concentrations of noradrenaline, adrenaline and dopamine. Scores for pain and nausea were low after infusion of placebo. After infusion of CCK-8, pain scores were significantly higher in patients with spontaneous pain than in control subjects, but significant increases in nausea were restricted to patients with irritable bowel syndrome and a subgroup of patients with pain after cholecystectomy. Although some groups showed increases in plasma concentrations of catecholamines after the infusion of CCK-8, the size of these increases was neither consistent among patients within each group nor predictive of scores of pain and nausea in individual subjects. Pain during the infusion of CCK-8 was a feature common to patients with diverse functional pain syndromes, and did not appear to be attributable to activation of the sympathetic nervous system.
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PMID:Responses to cholecystokinin octapeptide in patients with functional abdominal pain syndromes. 161 Oct 17

The aim of this study was to examine the effects of tricyclic antidepressants on responses of mechanosensitive afferent fibers innervating the rat colon. A total of 53 fibers in the decentralized S1 dorsal root were studied. The effects of the non-specific monoamine reuptake inhibitor imipramine (IMI), the noradrenaline reuptake inhibitor desipramine (DES), and the serotonin reuptake inhibitor clomipramine (CLO) were tested on responses of 22 mechanosensitive afferent fibers to noxious colorectal distension (CRD; 80 mmHg). Cumulative doses of 16 mg/kg of IMI, DES and of CLO reduced responses to noxious CRD to a mean 20%, 22% and 46% of control, respectively. The mean inhibitory doses of the three antidepressants did not differ significantly. Inhibitory effects were independent of potential effects on neurotransmitter reuptake: the effects of IMI and DES were not blocked by the adrenoreceptor antagonist phentolamine, and the effects of IMI and CLO were not affected by the serotonin receptor antagonist metergoline. Attenuation of afferent nerve activity was not mimicked by the anticholinergic glycopyrrolate; the cholinesterase inhibitor neostigmine did not attenuate the effect of IMI on responses to noxious CRD. Interestingly, the opioid receptor antagonist naloxone partially reversed the effects of IMI, and the NMDA receptor channel blocker MK-801 enhanced the inhibitory effects of DES and CLO. These results document that responses of mechanosensitive pelvic nerve afferent fibers to noxious CRD are significantly attenuated by tricyclic antidepressants, a peripheral action that may contribute to the beneficial effects of tricyclic antidepressants in treatment of irritable bowel syndrome.
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PMID:Effects of tricyclic antidepressants on mechanosensitive pelvic nerve afferent fibers innervating the rat colon. 969 63

Antidepressants rapidly relieve pain in irritable bowel syndrome (IBS) and are effective at low doses. Noradrenaline reuptake inhibitors appear to be more effective than selective serotonergic reuptake inhibitors, suggesting that pathways other than those modulated by serotonin may be involved in visceral sensation. Visceral sensitivity is reduced by both centrally and peripherally acting opioids, suggesting the possible existence of an endogenous opioid deficiency in patients with IBS. The alpha(2) adrenoceptor antagonist clonidine, as well as somatostatin, oxytocin, and possibly amitriptyline have also been shown to act as visceral analgesics. As knowledge increases, there are undoubtedly many other possible targets, and new drugs currently undergoing development may provide future benefit in patients with IBS.
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PMID:Pharmacotherapy: non-serotonergic mechanisms. 1207 75

Interactions between the enteric nervous system of the gut and the brain occur bidirectionally over sympathetic and parasympathetic pathways. Coordinated actions of the central, autonomic and enteric nervous systems modulate intestinal motor, sensory and secretory activities by neuromodulators, including 5-HT, noradrenaline and dopamine. 5-HT is an important signaling molecule in the brain-gut axis and the 5-HT released from enterochromaffin cells modulates peristaltic, secretory, vasodilatory, vagal and nociceptive reflexes. Irritable bowel syndrome is associated with altered motility, secretion and sensation; enteric 5-HT signaling may be defective in this disorder. In this editorial, recent data are reviewed and the potential for the development of pharmacologic intervention is assessed.
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PMID:5-HT and the brain-gut axis: opportunities for pharmacologic intervention. 1750 88

The pathogenesis of the irritable bowel syndrome (IBS) is still unsolved. Lately most attention has been focused on visceral hypersensitivity related to dysfunction of the autonomic nervous system (ANS). The aim of this study was to evaluate changes in the ANS activity and gastric motility in constipation-predominant IBS patients using the heart rate variability (HRV) and gastric myoelectric activity (EGG) recording. 23 patients (45+/-13 yrs) matching Manning criteria and 30 healthy volunteers (47+/-5 yrs) participated in the study. EGG and HRV in fasted and fed subjects with fasted serum catecholamine levels were measured in both groups. Fasting IBS pts showed gastric dysrrhythmia (29+/-14% vs. 11+/-7%), DP was 128.860 +/- 112.000 vs. 46.000+/- 23.200microV2, DF 2.37+/-0.8 vs. 2.9+/-0.2cpm. Feeding (300 kcal) improved dysrrhythmia to 20+/-13% vs. 8+/-5%, DP decreased to 74.500+/-57.720 vs. 165.600+/-89.000microV(2) and DF increased to 2.53+/-0.7 vs. 3.2+/-0.3cpm. In fasted and fed IBS pts SWC (channels 3-4) was about 60+/-11 vs. 84+/-8% and 68+/-14 vs. 92+/-8% respectively. In IBS pts resting HRV parameters were lower (LF - 650.3 vs. 811.6 ms2; HF - 508.8 vs. 854.6 ms2); with higher LF/HF ratio in IBS patients (1.52 vs. 1.2). The serum fasting level of adrenaline and noradrenaline in IBS pts were higher 1.28+/-0.06 vs. 0.65+/-0.05 nmol/L, and 3.54+/-1.2 vs. 2.89+/- 08 nmol/L, p<0.05 respectively. Increased sympathetic drive in IBS pts reflected by high catecholamine levels and LH/HF ratio is responsible for gastric dysrrhythmias and low DF and coupling. Meal has negligible effect on EGG parameters improvement. The ANS dysfunction observed in IBS patients is most probably responsible for disturbances in gastric myoelectric activity presented as gastric dysrrhythmias resulting in gastric emptying delay and dyspeptic symptoms.
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PMID:Dysfunction of the autonomic nervous system activity is responsible for gastric myoelectric disturbances in the irritable bowel syndrome patients. 1790 89

Enhanced stress responsiveness has been implicated as a potential mechanism contributing to the pathophysiology of irritable bowel syndrome (IBS), and should be reflected in altered function of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Both of these systems can modulate mucosal immune function. The aims of this study were: (i) to characterize the basal circadian rhythm of adrenocorticotropin hormone (ACTH) and cortisol in IBS vs healthy controls; (ii) to compare stimulated ACTH, cortisol and noradrenaline responses to a pelvic visceral stressor (sigmoidoscopy) in IBS and controls; and (iii) to correlate neuroendocrine responses with colonic mucosal cytokine expression and symptoms in IBS. Two separate studies were conducted in women. In Study 1, basal cortisol levels were analysed in 41 IBS and 25 controls using 24-h collections of plasma ACTH and cortisol (q10 min sampling). In Study 2, 10 IBS patients with diarrhoea (IBS-D) and 10 controls underwent sigmoidoscopy with measurements of stimulated neuroendocrine responses and cytokine mRNA expression in colonic tissue. Basal ACTH levels were significantly blunted (P < 0.05), while basal and stimulated plasma cortisol levels were higher in patients. Basal cortisol levels prior to an experimental visceral stressor positively correlated with anxiety symptoms (P < 0.004), but not IBS symptoms. Irritable bowel syndrome patients with diarrhoea had significantly decreased mRNA expression of mucosal cytokines [interleukin (IL)-2, IL-6] in the sigmoid colon vs controls (P < 0.05). Although dysregulations in stress-responsive systems such as the HPA axis and mucosal immune function are demonstrated in IBS, they do not appear to have a primary role in modulating IBS severity and abdominal pain.
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PMID:Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome. 1868 12

Chronic stress precipitates or exacerbates the symptoms of functional bowel disorders, including motility dysfunction. The cellular mechanisms of these effects are not understood. We tested the hypothesis that heterotypic chronic stress (HeCS) elevates the release of norepinephrine from the adrenal medulla, which enhances transcription of the gene-regulating expression of Ca(v)1.2 (L-type) channels in colonic circular smooth muscle cells, resulting in enhanced colonic motor function. The experiments were performed in rats using a 9-day heterotypic chronic stress (HeCS) protocol. We found that HeCS, but not acute stress, time dependently enhances the contractile response to ACh in colonic circular smooth muscle strips and in single dissociated smooth muscle cells, the plasma levels of norepinephrine and the mRNA and protein expressions of the alpha(1C) subunit of Ca(v)1.2 channels. These effects result in faster colonic transit and increase in defecation rate. The effects of HeCS are blocked by adrenalectomy but not by depletion of norepinephrine in sympathetic neurons. The inhibition of receptors for glucocortocoids, corticotropin-releasing hormone or nicotine also does not block the effects of heterotypic chronic stress. Norepinephrine acts on alpha- and beta(3)-adrenergic receptors to induce the transcription of alpha(1C) subunit. We conclude that HeCS alters colonic motor function by elevating the plasma levels of norepinephrine. Colonic motor dysfunction is associated with enhanced gene transcription of Ca(v)1.2 channels in circular smooth muscle cells. These findings suggest the potential cellular mechanisms by which heterotypic chronic stress may exacerbate motility dysfunction in patients with irritable bowel syndrome.
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PMID:Norepinephrine mediates the transcriptional effects of heterotypic chronic stress on colonic motor function. 1935 22

Evidence suggests that patients with irritable bowel syndrome (IBS) are hyper-responsive to environmental, physical and visceral stimuli. IBS patients also frequently report poor sleep quality. This study compared serum cortisol and plasma catecholamine levels during sleep between women with IBS (n = 30) and healthy controls (n = 31), and among subgroups within the IBS sample based on predominant stool patterns, IBS-diarrhoea (n = 14), IBS-constipation (n = 7) and IBS-alternators (n = 9). Cortisol was measured from serial blood samples drawn every 20 min, and catecholamines every hour, in a sleep laboratory from 8 pm until awakening. Because of the varied sleep schedules of the individual participants, each subject's hormone series time base was referenced with respect to their onset of Stage 2 sleep. Overall, there were no significant differences in cortisol or catecholamine patterns between women with IBS and controls, nor were there any group by time interactions. However, women with constipation-predominant IBS demonstrated significantly increased noradrenaline, adrenaline and cortisol levels throughout the sleep interval, and women with diarrhoea-predominant IBS were significantly lower on noradrenaline and cortisol. These results suggest that differences in neuroendocrine levels during sleep among IBS predominant bowel pattern subgroups may be greater than differences between IBS women and controls. Neuroendocrine profiles during sleep may contribute to our understanding of symptom expression in IBS.
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PMID:Catecholamine and cortisol levels during sleep in women with irritable bowel syndrome. 1957 81

The balance between descending controls, both excitatory and inhibitory, can be altered in various pain states. There is good evidence for a prominent alpha(2)-adrenoceptor-mediated inhibitory system and 5-HT(3) (and likely also 5-HT(2)) serotonin receptor-mediated excitatory controls originating from brainstem and midbrain areas. The ability of cortical controls to influence spinal function allows for top-down processing through these monoamines. The links between pain and the comorbidities of sleep problems, anxiety, and depression may be due to the dual roles of noradrenaline and of 5-HT in these functions and also in pain. These controls appear, in the cases of peripheral neuropathy, spinal injury, and cancer-induced bone pain to be driven by altered peripheral and spinal neuronal processes; in opioid-induced hyperalgesia, however, the same changes occur without any pathophysiological peripheral process. Thus, in generalized pain states in which fatigue, mood changes, and diffuse pain occur, such as fibromyalgia and irritable bowel syndrome, one could suggest an abnormal engagement of descending facilitations with or without reduced inhibitions but with central origins. This would be an endogenous central malfunction of top-down processing, with the altered monoamine systems underlying the observed symptoms. A number of analgesic drugs can either interact with or have their actions modulated by these descending systems, reinforcing their importance in the establishment of pain but also in its control.
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PMID:Preclinical and early clinical investigations related to monoaminergic pain modulation. 1978 74

The following brief overview reflects our own opinion of where the most likely advances to treating pain (unrelated to IBS and migraine) may come from with respect to ligands directly interacting with specific 5-HT receptors. It is fully appreciated, and possibly more likely, that 5-HT plays a modulatory role in the mediation of analgesic effects of certain compounds, for example tricyclic antidepressants and the newer, safer class of serotonin/noradrenaline re-uptake inhibitors, for example duloxetine and milnacipran. However, we find that recent pre-clinical findings highlight the potential of peripherally acting 5-HT(1) and 5-HT(2A) receptor agonists and centrally penetrating 5-HT(7) receptor agonists to reduce chronic pain. We encourage experimentation using human tissues and healthy volunteers to improve the confidence in rationale of targeting such receptors for treatment of pain in humans. However for this to happen the available pharmacological toolbox will also need to be further improved and any safety concerns understood to provide the necessary impetus to go to the clinic.
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PMID:It might be a big family but the pain remains-last chance saloon for selective 5-HT receptor ligands? 2137 31


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