Abstract
Background and Aims: Cholera toxin (CT)-induced hypersecretion requires activation of secretomotor pathways in the enteric nervous system (ENS). AH neurons, which have been identified as a population of intrinsic sensory neurons (ISNs), are a source of excitatory input to the secretomotor pathways. We therefore examined effects of CT in the intestinal lumen on myenteric and submucosal AH neurons.Methods: Isolated segments of guinea pig jejunum were incubated for 90 min with saline plus CT (12.5 μg/ml) or CT + neurotransmitter antagonist, or CT + tetrodotoxin (TTX) in their lumen. After washing CT away, submucosal or myenteric plexus preparations were dissected keeping circumferentially adjacent mucosa intact. Submucosal AH neurons were impaled adjacent to intact mucosa and myenteric AH neurons were impaled adjacent to, more than 5 mm from, and in the absence of intact mucosa. Neuronal excitability was monitored by injecting 500 ms current pulses through the recording electrode.Results: After CT pre-treatment, excitability of myenteric AH neurons adjacent to intact mucosa (n = 29) was greater than that of control neurons (n = 24), but submucosal AH neurons (n = 33, control n = 27) were unaffected. CT also induced excitability increases in myenteric AH neurons impaled distant from the mucosa (n = 6) or in its absence (n = 5). Coincubation with tetrodotoxin or SR142801 (NK3 receptor antagonist), but not SR140333 (NK1 antagonist) or granisetron (5-HT3 receptor antagonist) prevented the increased excitability induced by CT. Increased excitability was associated with a reduction in the characteristic AHP and an increase in the ADP of these neurons, but not a change in the hyperpolarization-activated inward current, Ih.Conclusions: CT increases excitability of myenteric, but not submucosal, AH neurons. This is neurally mediated and depends on NK3, but not 5-HT3 receptors. Therefore, CT may act to amplify the secretomotor response to CT via an increase in the activity of the afferent limb of the enteric reflex circuitry.
Highlights
When the bacterium Vibrio cholera invades the gut, its exotoxin, cholera toxin (CT), causes hypersecretion in the small intestine, which can produce severe diarrhea that quickly leads to dehydration and death if left untreated
The morphologies of 12 myenteric and 46 submucosal AH neurons were examined after electrophysiological experiments and processed to confirm and correlate their morphology with their electrophysiological properties
We tested whether the presence of, or proximity to, the mucosa affects the excitability of AH neurons in control and CT conditions, as we have reported previously for submucosal secretomotor neurons (Gwynne et al, 2009)
Summary
When the bacterium Vibrio cholera invades the gut, its exotoxin, cholera toxin (CT), causes hypersecretion in the small intestine, which can produce severe diarrhea that quickly leads to dehydration and death if left untreated. The ENS is a complex nerve circuitry embedded within the walls of the gastrointestinal tract which regulates vital gut functions, including motility and secretion. It incorporates two distinct ganglionated networks- the myenteric (MP) and submucosal (SMP) plexuses. In one long-standing model of toxin-induced hypersecretion, CT is postulated to activate persistent release of 5-HT from the mucosa, which activates secretomotor reflex pathways in the ENS. Recent work has focused on the effects of CT exposure on the properties of the enteric neurons in the secretomotor and motility reflex pathways (Kordasti et al, 2006; Gwynne et al, 2009; Fung et al, 2010). Cholera toxin (CT)-induced hypersecretion requires activation of secretomotor pathways in the enteric nervous system (ENS). We examined effects of CT in the intestinal lumen on myenteric and submucosal AH neurons
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