Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society
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Neurogastroenterol. Motil. · Mar 2010
Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain.
BACKGROUND Linaclotide is a novel, orally administered investigational drug currently in clinical development for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation. Visceral hyperalgesia is a major pathophysiological mechanism in IBS-C. Therefore, we investigated the anti-nociceptive properties of linaclotide in rodent models of inflammatory and non-inflammatory visceral pain and determined whether these pharmacological effects are linked to the activation of guanylate cyclase C (GC-C). ⋯ However, in post-inflammatory conditions linaclotide significantly reduced hypersensitivity only in wt mice, but not in GC-C null mice. CONCLUSIONS & INFERENCES These findings indicate that linaclotide has potent anti-nociceptive effects in several mechanistically different rodent models of visceral hypersensitivity and that these pharmacological properties of linaclotide are exerted through the activation of the GC-C receptor. Therefore, linaclotide may be capable of decreasing abdominal pain in patients suffering from IBS-C.
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Neurogastroenterol. Motil. · Jan 2010
Electrical colonic stimulation reduces mean transit time in a porcine model.
Electrical stimulation is a new way to treat digestive disorders such as constipation. Colonic propulsive activity can be triggered by battery operated devices. This study aimed to demonstrate the effect of direct electrical colonic stimulation on mean transit time in a chronic porcine model. ⋯ Colonic transit time measured in a chronic porcine model is reduced by direct sequential electrical stimulation. Minimal tissue lesion is elicited by stimulation or implanted material. Electrical colonic stimulation could be a promising approach to treat specific disorders of the large bowel.
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The approach of this review is to give a pragmatic approach to using laxatives, based on a combination of what is known about mechanism of action and the available literature on evidence.
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Neurogastroenterol. Motil. · Nov 2009
5-HT 3 receptors mediate the time-dependent vagal afferent modulation of nociception during chronic food allergen-sensitized visceral hyperalgesia in rats.
Converging lines of evidence demonstrate a vagally mediated antinociceptive pathway in animals undergoing acute visceral insults, the contribution of this system to visceral pain following chronic noxious stimuli is unknown. 5-HT(3) receptor (5-HT(3)Rs) on spinal afferents are crucially involved in nociceptive processing, the role of 5-HT(3)Rs on vagal afferents is unclear. The aim of the present study was to determine the contribution of vagal afferents to visceral nociception in rats undergoing chronic luminal allergen stimulation and whether it involves vagal 5-HT(3)Rs. Sensitized rats received chicken egg albumin (EA, 1 mg mL(-1)) in drinking water for 2 weeks (day 1-14). ⋯ Intraluminal infusion of a 5-HT(3)R antagonist (granisetron), whether alone or infused after local mucosa anaesthetic with 1% lidocaine, mimicked the effects of vagotomy. The mRNA levels for 5-HT(3B) or 5-HT(3A) subunit in the NG showed an opposite time-course to that of visceral pain, which increased from day 2, then decreased gradually to levels lower than those of controls. Our results demonstrate a time-dependent vagal afferent modulation of chronic allergen-sensitized visceral hyperalgesia, which may involve a 5-HT(3)R pathway.
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Neurogastroenterol. Motil. · Nov 2009
Personality differences affect brainstem autonomic responses to visceral pain.
Brainstem autonomic nuclei integrate interoceptive inputs including pain, with descending modulation, to produce homeostatic and defence outputs. Cardiac Vagal Control is especially implicated in psychophysiological processes for both health and disease and is indexed non-invasively by heart rate variability. The study aim was to determine the nature of psychophysiological response profiles for visceral pain. ⋯ Two distinct psychophysiological response profiles to visceral pain exist that are influenced by personality. These may reflect different psychobiological bases for active and passive defence repertoires. Prevalence and clinical relevance of these endophenotypes as vulnerability factors for pain and emotion disorders warrant further exploration.