Cholera Toxin Induces Sustained Hyperexcitability in Submucosal Secretomotor Neurons in Guinea Pig Jejunum

Gwynne, Rachel M; Ellis, Melina; Sjövall, Henrik; Bornstein, Joel C.

doi:10.1053/j.gastro.2008.09.071

Cited by 35 publications

(62 citation statements)

References 40 publications

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“…Cholera toxin-induced secretion is blocked by 5-HT 3 receptor antagonists in vivo (Buchheit, 1989; Kordasti et al, 2006) and a 5-HT 3 antagonist granisetron (1 μM) prevents CT-induced hyperexcitability of submucosal secretomotor neurons in guinea-pig jejunum in vitro (Gwynne et al, 2009). In contrast, granisetron significantly increased the contractile activity induced by CT early in the exposure period (Figure 1D).…”

Section: Resultsmentioning

confidence: 99%

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Luminal Cholera Toxin Alters Motility in Isolated Guinea-Pig Jejunum via a Pathway Independent of 5-HT3 Receptors

Fung¹,

Ellis²,

Bornstein³

2010

Front. Neurosci.

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Cholera toxin (CT) is well established to produce diarrhea by producing hyperactivity of the enteric neural circuits that regulate water and electrolyte secretion. Its effects on intestinal motor patterns are less well understood. We examined the effects of luminal CT on motor activity of guinea-pig jejunum in vitro. Segments of jejunum were cannulated at either end and mounted horizontally. Their contractile activity was video-imaged and the recordings were used to construct spatiotemporal maps of contractile activity with CT (1.25 or 12.5 μg/ml) in the lumen. Both concentrations of CT induced propulsive motor activity in jejunal segments. The effect of 1.25 μg/ml CT was markedly enhanced by co-incubation with granisetron (5-HT3 antagonist, 1 μM), which prevents the hypersecretion induced by CT. The increased propulsive activity was not accompanied by increased segmentation and occurred very early after exposure to CT in the presence of granisetron. Luminal CT also reduced the pressure threshold for saline distension evoked propulsive reflexes, an effect resistant to granisetron. In contrast, CT prevented the induction of segmenting contractions by luminal decanoic acid, so its effects on propulsive and segmenting contractile activity are distinctly different. Thus, in addition to producing hypersecretion, CT excites propulsive motor activity with an entirely different time course and pharmacology, but inhibits nutrient-induced segmentation. This suggests that CT excites more than one enteric neural circuit and that propulsive and segmenting motor patterns are differentially regulated.

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Section: Resultsmentioning

confidence: 99%

“…The increased firing is partly due to a long-term increase in excitability of secretomotor neurons following luminal incubation with CT, an effect prevented by co-incubation of CT with tetrodotoxin (Gwynne et al, 2009). Thus, CT produces neural activity during the incubation period, perhaps even before the enhanced secretion.…”

Section: Introductionmentioning

confidence: 99%

Luminal Cholera Toxin Alters Motility in Isolated Guinea-Pig Jejunum via a Pathway Independent of 5-HT3 Receptors

Fung¹,

Ellis²,

Bornstein³

2010

Front. Neurosci.

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“…Where an effect was seen with the first antagonist, one to two responses were recorded after this washout period to check for reversibility before the second antagonist was added. After each experiment, the morphology of impaled neurons and, where possible, immunoreactivity for NOS was examined using standard processing methods (18,32).…”

Section: Methodsmentioning

confidence: 99%

Electrical stimulation of the mucosa evokes slow EPSPs mediated by NK1 tachykinin receptors and by P2Y₁ purinoceptors in different myenteric neurons

Gwynne

Bornstein²

2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Gwynne RM, Bornstein JC. Electrical stimulation of the mucosa evokes slow EPSPs mediated by NK1 tachykinin receptors and by P2Y1 purinoceptors in different myenteric neurons. Am J Physiol Gastrointest Liver Physiol 297: G179 -G186, 2009. First published April 30, 2009 doi:10.1152/ajpgi.90700.2008.-Slow excitatory postsynaptic potentials (EPSPs) in enteric neurons arise from diverse sources, but which neurotransmitters mediate specific types of slow EPSPs is unclear. We investigated transmitters and receptors mediating slow EPSPs in myenteric neurons evoked by electrical stimulation of the mucosa in guinea pig small intestine. Segments of ileum or jejunum were dissected to allow access to the myenteric plexus adjacent to intact mucosa, in vitro. AH and S neurons were impaled with conventional intracellular electrodes. Trains of stimuli delivered to the mucosa evoked slow EPSPs in AH neurons that were blocked or depressed by the neurokinin-1 (NK1) tachykinin antagonist SR140333 (100 nM) in 10 of 11 neurons; the NK3 tachykinin receptor antagonist SR142801 (100 nM) had no effect on slow EPSPs in seven of nine AH neurons. Single pulses to the mucosa evoked fast EPSPs and slow depolarizations in S neurons. The depolarizations were divided into intermediate (durations 300 -900 ms) or slow (durations 1.3-9 s) EPSPs. The slow EPSPs were blocked by pyridoxal phosphate-6-axophenyl-2-4-disulfonic acid (30 M, N ϭ 3) or the specific P2Y1 antagonist MRS 2179 (10 M, N ϭ 6) and were predominantly in anally projecting S neurons that were immunoreactive for nitric oxide synthase (NOS). In contrast, intermediate EPSPs were predominantly evoked in NOS-negative neurons; these were abolished by MRS 2179 (N ϭ 8). Thus activation of pathways running from the mucosa excites three different types of slow EPSP in myenteric neurons, which are mediated by either a tachykinin (NK1, AH neurons) or a purine nucleotide (P2Y1, S neurons). AH neurons; S neurons; ATP; neurokinin-1 THE NEURAL PATHWAYS CONTROLLING intestinal motility are contained within the myenteric plexus of the enteric nervous system (ENS). These pathways are activated by various stimuli such as the presence of nutrients in the lumen (16,19) and distension of the gut wall to adapt motility according to conditions within the lumen (for review see Ref. 5). Studies of the guinea pig ileum have identified at least 15 classes of myenteric neurons that can be distinguished by their morphologies, neurochemical codes, and functions. These include one or more populations of intrinsic sensory (or primary afferent) neurons, orally directed (ascending) and anally directed (descending) interneurons, and excitatory and inhibitory motor neurons supplying the circular and longitudinal muscle layers (9). However, the diversity of the ENS is such that the functions of some classes cannot always be clearly defined. For example, there are recent reports that some interneurons in the myenteric plexus of the guinea pig distal colon respond directly to stretch (39, 40). Furthermore, under some conditi...

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“…Activation of 5-HT 2A receptors elicits colonic secretion. Likewise, 5-HT 3 stimulation evokes chloride secretion, whereas 5-HT 3 antagonists blunt 5-HT-mediated colonic secretion in response to cholera toxin, GI pathogens, and corticotropin releasing factor [13,14]. 5-HT 4 activation elicits chloride and bicarbonate secretion from intestinal and colonic epithelia.…”

Section: Intestinal Secretionmentioning

confidence: 99%

Serotonin and the GI tract

Hasler

2009

Curr Gastroenterol Rep

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Serotonin (5-hydroxytryptamine, 5-HT) participates in several functions of the gastrointestinal tract. Receptors in seven families (5-HT(1)-5-HT(7)) were identified, many of which are present on enterocytes, intrinsic and extrinsic neurons, interstitial cells, and gut myocytes. Most 5-HT is released from enterochromaffin cells in response to physiologic and pathologic stimuli. Roles of 5-HT in health include control of normal gut motor activity, secretion, and sensation, and regulation of food intake and cell growth. Abnormalities of serotonergic function contribute to symptom genesis in functional bowel disorders, inflammatory and infectious diseases of the gut, emetic responses to varied stimuli, obesity, and dysregulation of cell growth. Therapies acting as agonists or antagonists of 5-HT receptors or that modulate 5-HT reuptake play prominent roles in managing these conditions, although use of many agents is hampered by cardiopulmonary complications. Novel agents are in testing, which may exhibit efficacy without significant toxicity.

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Cholera Toxin Induces Sustained Hyperexcitability in Submucosal Secretomotor Neurons in Guinea Pig Jejunum

Cited by 35 publications

References 40 publications

Luminal Cholera Toxin Alters Motility in Isolated Guinea-Pig Jejunum via a Pathway Independent of 5-HT3 Receptors

Luminal Cholera Toxin Alters Motility in Isolated Guinea-Pig Jejunum via a Pathway Independent of 5-HT3 Receptors

Electrical stimulation of the mucosa evokes slow EPSPs mediated by NK1 tachykinin receptors and by P2Y₁ purinoceptors in different myenteric neurons

Serotonin and the GI tract

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