Enhanced excitability of guinea pig ileum myenteric AH neurons during and following recovery from chemical colitis
Introduction
Inflammation of the colon changes motor function of more proximal regions of the gastrointestinal tract in both man [18], [19], [26] and in experimental models [1], [3], [9]. There is some evidence that inflammatory cytokines may be increased in the upper bowel during colitis [2]. Inflammatory cytokines, including IL-1β and IL-6 [10], [24], [28], [31] can directly excite enteric neurons. Additionally, neural reflexes from the distal colon might lead to enhanced excitability of enteric neurons in the proximal gut. Spinal afferents that innervate the inflamed guinea pig intestine are hyperexcitable [20] and may enhance spinal or supraspinal reflexes that could alter motor function in distant non-inflamed regions [12]. Post-ganglionic sympathetic neurons within the prevertebral ganglia that receive synaptic input from viscerofugal neurons in the colon are hyperexcitable during colitis [13] and may also contribute to altered motor function during colitis.
The aim of this study was to test the hypothesis that colonic inflammation alters the excitability of myenteric neurons in the non-inflamed ileum and further that altered excitability contributes to altered motor function of the small bowel. A single enema of trinitrobenzene sulfonic acid (TNBS) was used to induce a limited course of colitis that resolved. Enhanced excitability was observed in AH neurons of the ileum myenteric plexus yet interestingly did not coincide with changes in motor function.
Section snippets
Inflammatory models
All methods were reviewed and approved by the Mayo Clinic Animal Use and Care Committee. Colitis was induced by a single enema of 0.3 ml trinitrobenzene sulfonic acid (TNBS; 27 mg ml−1) in 30% ethanol 7 cm proximal to the anus. After the enema, animals were returned to a controlled environment for a period of 12 h, 24 h, 48 h, 6 d or 56 d before euthanasia by CO2 inhalation. Control animals remained naive to treatment until euthanasia. Inflammatory damage was assessed as previously described [13].
Tissue preparation and electrophysiology
Results
Intracellular recordings were obtained from 57 neurons in 26 preparations. Neurons were classified as AH or S based on the presence or absence of an AHP, two components on the repolarizing phase of the action potential, or fast synaptic input as described previously [4], [30]. In all, 35 AH neurons (61%) and 22 S neurons (39%) were randomly impaled from the myenteric plexus of the guinea pig ileum.
Discussion
The results of this study demonstrate that colitis is associated with an increased excitability of intrinsic primary afferent neurons, identified electrophysiologically as AH neurons [6], of the ileum myenteric plexus. This hyperexcitability does not develop immediately as AH neurons from animals 12 h after TNBS administration demonstrate normal excitability. Rather, enhanced excitability arises at the 24 h time point and persists up to eight weeks, the last time point investigated, when colitis
Conclusions
The results of this study support the concept that colitis causes hyperexcitability of AH neurons in the ileum myenteric plexus. The onset of hyperexcitability occurred 24 h following administration of TNBS, and persisted to eight weeks. There were no changes in synaptic transmission of either AH neurons or S neurons observed in the current study. While AH neurons play a central role in coordinating motor function of the ileum [5], [6], [27], [29], changes in excitability of these neurons did
Acknowledgments
I gratefully acknowledge the secretarial support of Ms. Janice Applequist. This work was supported by NIH grant DK76665.
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