5-HT2B receptors modulate visceral hypersensitivity in a stress-sensitive animal model of brain-gut axis dysfunction

O’Mahony, Siobhain M.; Bulmer, D; Coelho, Anne-Marie; Fitzgerald, Patrick; Bongiovanni, Cheryl M.; Lee, K.; Winchester, W.; Dinan, Timothy G.; Cryan, John F.

doi:10.1111/j.1365-2982.2009.01432.x

Cited by 76 publications

(59 citation statements)

References 49 publications

(78 reference statements)

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“…In conclusion, our study shows for the first time that peripheral 5-HT 2B R activation can both prevent and cure CCI-induced neuropathic pain, whereas previous studies have reported opposite findings in other pain models, such as migraine [29,50,51] and visceral pain [45,47]. In these cases, the etiology of pain is quite different from that of neuropathic pain.…”

contrasting

confidence: 47%

Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain

Urtikova

Berson

Steenwinckel

et al. 2012

Pain

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-nociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain.. PAIN, Elsevier, 2012, 153 (6), pp.1320-31. <10.1016/j.pain.2012.03.024>. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 receptor. CCI resulted in a biphasic upregulation of 5-HT 2B receptor expression in lumbar dorsal root ganglia, consisting of a transient early increase (23-fold), two days after surgery, before the development of neuropathic pain, followed by a steady, five times increase, levels remaining constant thereafter until the pain disappeared. 5-HT 2B receptors were immmunolocalized mostly on primary sensory neurons and infiltrating macrophages. Intrathecal injection of RS127445, a selective 5-HT 2B receptor antagonist, enhanced mechanical and cold allodynia. A single application of BW732C86, a 5-HT 2B agonist, to the sciatic nerve immediately after ligature completely prevented mechanical allodynia and significantly decreased cold allodynia. This effect was dose-dependent and reversed by a 5-HT 2B antagonist. We also observed a marked decrease in macrophage infiltration of the sciatic nerve, neuropathic pain markers and cytokine induction. Our data reveal the relationships between serotonin, the immune system and neuropathic pain, and demonstrate a critical role of 5-HT 2Breceptors in blood-derived macrophages.

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contrasting

confidence: 47%

Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain

Urtikova

Berson

Steenwinckel

et al. 2012

Pain

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“…34,35 5-HT 2B R antagonists suppress VMR responses in Wistar Kyoto rats 35 and in a model of trinitrobenzene sulfonic acid (TNBS)–induced colonic hypersensitivity. 36 Also, tegaserod is an antagonist at the 5-HT 2B R, in addition to its more potent action as a 5-HT 4 R agonist.…”

Section: Discussionmentioning

confidence: 99%

Activation of Colonic Mucosal 5-HT4 Receptors Accelerates Propulsive Motility and Inhibits Visceral Hypersensitivity

et al. 2012

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BACKGROUND & AIMS 5-hydroxytryptamine receptor (5-HT4R) agonists promote gastrointestinal motility and attenuate visceral pain, but concerns about adverse reactions have restricted their availability. We tested the hypotheses that 5-HT4 receptors are expressed in the colonic epithelium and that 5-HT4R agonists can act intraluminally to increase motility and reduce visceral hypersensitivity. METHODS Mucosal expression of the 5-HT4R was evaluated by reverse-transcriptase polymerase chain reaction and immunohistochemical analysis of tissues from 5-HT4R(BAC)-enhanced green fluorescent protein mice. Amperometry, histology, and short-circuit current measurements were used to study 5-HT, mucus, and Cl− secretion, respectively. Propulsive motility was measured in guinea pig distal colon, and visceromotor responses were recorded in a rat model of colonic hypersensitivity. 5-HT4R compounds included cisapride, tegaserod, naronapride, SB204070, and GR113808. RESULTS Mucosal 5-HT4 receptors were present in the small and large intestines. In the distal colon, 5-HT4 receptors were expressed by most epithelial cells, including enterochromaffin and goblet cells. Stimulation of 5-HT4Rs evoked mucosal 5-HT release, goblet cell degranulation, and Cl− secretion. Luminal administration of 5-HT4R agonists accelerated propulsive motility; a 5-HT4R antagonist blocked this effect. Bath application of 5-HT4R agonists did not affect motility. Oral or intracolonic administration of 5-HT4R agonists attenuated visceral hypersensitivity. Intracolonic administration was more potent than oral administration, and was inhibited by a 5-HT4R antagonist. CONCLUSIONS Mucosal 5-HT4 receptor activation can mediate the prokinetic and antinociceptive actions of 5-HT4R agonists. Colon-targeted, intraluminal delivery of 5-HT4R agonists might be used to promote motility and alleviate visceral pain, while restricting systemic bioavailability and resulting adverse side effects.

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“…Moreover, the interface between psychiatry and IBS is well established, with anxiety and depressive disorders the most frequently occurring comorbid conditions [3]. It is therefore not surprising that rodent models of anxiety and depression, such as the Wistar Kyoto (WKY) rat [4], display GI features akin to those associated with IBS, for example increased abdominal visceral pain [5-7], reduced colonic accommodation [8] and altered colonic fluid and electrolyte transport [9,10], all key pathophysiological features which support the use of the WKY rat as a valid pre-clinical paradigm for examining stress-related GI disorders, and in particular IBS [11]. …”

Section: Introductionmentioning

confidence: 99%

Disodium Cromoglycate Reverses Colonic Visceral Hypersensitivity and Influences Colonic Ion Transport in a Stress-Sensitive Rat Strain

et al. 2013

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The interface between psychiatry and stress-related gastrointestinal disorders (GI), such as irritable bowel syndrome (IBS), is well established, with anxiety and depression the most frequently occurring comorbid conditions. Moreover, stress-sensitive Wistar Kyoto (WKY) rats, which display anxiety- and depressive-like behaviors, exhibit GI disturbances akin to those observed in stress-related GI disorders. Additionally, there is mounting preclinical and clinical evidence implicating mast cells as significant contributors to the development of abdominal visceral pain in IBS. In this study we examined the effects of the rat connective tissue mast cell (CTMC) stabiliser, disodium cromoglycate (DSCG) on visceral hypersensitivity and colonic ion transport, and examined both colonic and peritoneal mast cells from stress-sensitive WKY rats. DSCG significantly decreased abdominal pain behaviors induced by colorectal distension in WKY animals independent of a reduction in colonic rat mast cell mediator release. We further demonstrated that mast cell-stimulated colonic ion transport was sensitive to inhibition by the mast cell stabiliser DSCG, an effect only observed in stress-sensitive rats. Moreover, CTMC-like mast cells were significantly increased in the colonic submucosa of WKY animals, and we observed a significant increase in the proportion of intermediate, or immature, peritoneal mast cells relative to control animals. Collectively our data further support a role for mast cells in the pathogenesis of stress-related GI disorders.

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5-HT2B receptors modulate visceral hypersensitivity in a stress-sensitive animal model of brain-gut axis dysfunction

Abstract: Taken together, blockade of 5-HT(2B) receptors offers an exciting novel therapeutic target for pain relief in stress-related gastrointestinal disorders such as IBS.

Cited by 76 publications

References 49 publications

Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain

Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain

Activation of Colonic Mucosal 5-HT4 Receptors Accelerates Propulsive Motility and Inhibits Visceral Hypersensitivity

Disodium Cromoglycate Reverses Colonic Visceral Hypersensitivity and Influences Colonic Ion Transport in a Stress-Sensitive Rat Strain

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