Elsevier

Neuroscience Letters

Volume 545, 17 June 2013, Pages 91-95
Neuroscience Letters

Enhanced excitability of guinea pig ileum myenteric AH neurons during and following recovery from chemical colitis

https://doi.org/10.1016/j.neulet.2013.04.021Get rights and content

Highlights

  • Intrinsic primary afferent neurons of the ileum are hyperexcitable during colitis.

  • Excitability of ileum myenteric AH neurons persists after colitis has resolved.

  • There are no changes in fast synaptic transmission in the ileum during colitis.

  • An early transient reduction in small bowel transit is restored during colitis.

  • Neither reduced transit nor restoration coincide with changes in AH excitability.

Abstract

Inflammation of the colon changes motor function of more proximal regions of the gastrointestinal tract. Colitis alters the neurophysiology of enteric neurons within the region of inflammation, which may contribute to altered colonic motor and secretory function. This study seeks to test the hypothesis that colitis alters the neurophysiology of myenteric neurons in the non-inflamed ileum, and that altered neurophysiology coincides with altered small bowel motor function. Trinitrobenzene sulfonic acid (TNBS)-induced colitis was associated with hyperexcitability of AH neurons in the ileum myenteric plexus, demonstrated by depolarized neurons and increased numbers of action potentials, but without changes in the action potential duration or afterhyperpolarization typical of plasticity in these cells. There were no changes in synaptic transmission of either AH neurons or S neurons observed in the current study. The onset of AH neuron hyperexcitability occurred 24 h following administration of TNBS, and persisted to eight weeks, a time point following the resolution of colitis. Small bowel transit was reduced as early as 12 h after TNBS and resolved by 48 h after TNBS. While AH neurons play a central role in coordinating motor function of the ileum, changes in excitability of these neurons did not coincide with changes in small bowel transit.

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.

References (31)

  • P.A. Hughes et al.

    Post-inflammatory colonic afferent sensitisation: different subtypes, different pathways and different time courses

    Gut

    (2009)
  • A. Kelles et al.

    IL-1beta and IL-6 excite neurones and suppress cholinergic neurotransmission in the myenteric plexus of the guinea pig

    Neurogastroenterol. Motil.

    (2000)
  • E.M. Krauter et al.

    Changes in colonic motility and the electrophysiological properties of myenteric neurons persist following recovery from trinitrobenzene sulfonic acid colitis in the guinea pig

    Neurogastroenterol. Motil.

    (2007)
  • T.L. Krukoff

    Neuropeptide regulation of autonomic outflow at the sympathetic preganglionic neuron. Anatomical and neurochemical specificity

    Ann. N.Y. Acad. Sci.

    (1990)
  • D.R. Linden

    Enhanced excitability of guinea pig inferior mesenteric ganglion neurons during and following recovery from chemical colitis

    Am. J. Physiol Gastrointest. Liver Physiol.

    (2012)
  • Cited by (10)

    • CD8 T cell–Derived Perforin and TNF-α Are Crucial Mediators of Neuronal Destruction in Experimental Autoimmune Enteric Ganglionitis

      2021, American Journal of Pathology
      Citation Excerpt :

      Despite the fact that OVA-loaden hippocampal neurons were not directly in contact with effector T cells, they increased their Ca2+ levels.33 This hypothesis is supported by the observation of a long-lived hyperexcitability of small intestinal intrinsic primary afferent neurons after trinitrobenzenesulfonic acid–induced colitis that persisted for weeks after resolution of colitis.2,34 In contrast to EAEG, in which neither enteric neuronal Fas deficiency nor FasL antagonization was neuroprotective, Fas/FasL plays a role in other pathologies affecting neurons.

    • Gastrointestinal mechanosensory function in health and disease

      2018, Mechanobiology in Health and Disease
    • Communication Between Enteric Neurons, Glia, and Nociceptors Underlies the Effects of Tachykinins on Neuroinflammation

      2018, Cellular and Molecular Gastroenterology and Hepatology
      Citation Excerpt :

      Together, these results indicate that glial responses to nociceptive neuronal NK2R activation are mediated through mechanisms that involve neuron-to-glia and glia-to-glia communication. Tachykinins are an attractive class of candidate mediators of acute inflammatory responses in the ENS because they are released from hyperactive IPANs55 and their expression is altered during intestinal inflammation in animal models and humans.12,14,21,61,67 In support, our results show an up-regulation of TAC1 mRNA during acute colitis and a trending decrease in both NKA and SP immunoreactivity.

    • Electrocautery-induced localized colonic injury elicits increased levels of pro-inflammatory cytokines in small bowel and decreases jejunal alanine absorption

      2015, Cytokine
      Citation Excerpt :

      Human and experimental colitis has been reported to be associated with increased production of pro-inflammatory and anti-inflammatory cytokines in the inflamed colon as well as in non-inflamed segments of the upper small bowel [10–12]. In addition, localized colitis results in significant structural and functional abnormalities of enteric neurons and their reflexes in non-inflamed areas of the proximal gut [13–16]. These are thought to contribute to the altered small bowel motility, secretory dysfunction and possibly to nutrient mal-absorption [6,17,18].

    View all citing articles on Scopus
    View full text