title: The relationship between inflammation-induced neuronal excitability and disrupted motor activity in the guinea pig distal colon.
abstract: BACKGROUND
  Colitis is associated with increased excitability of afterhyperpolarization neurons (AH neurons) and facilitated synaptic transmission in the myenteric plexus. These changes are accompanied by disrupted propulsive motility, particularly in ulcerated regions. This study examined the relationship between myenteric AH neuronal hyperexcitability and disrupted propulsive motility.
  
  
  METHODS
  The voltage-activated Na(+) channel opener veratridine, the intermediate conductance Ca(2+) -activated K(+) channel inhibitor TRAM-34 and the 5-HT(4) receptor agonist tegaserod were used to evaluate the effects of neuronal hyperexcitability and synaptic facilitation on propulsive motility in normal guinea pig distal colon. Because trinitrobenzene sulfonic acid (TNBS)-colitis-induced hyperexcitability of myenteric afferent neurons involves increases in hyperpolarization-activated, cyclic nucleotide-gated (HCN) channel activity, the HCN channel inhibitors Cs(+) and ZD7288 were used to suppress AH neuronal activity in TNBS-colitis.
  
  
  RESULTS
  In non-inflamed preparations, veratridine halted propulsive motility (P<0.001). The rate of propulsive motor activity was significantly reduced following addition of TRAM-34 and tegaserod (P<0.001). In TNBS-inflamed preparations, in which motility was temporarily halted or obstructed at sites of ulceration, both Cs(+) and ZD7288 normalized motility through the inflamed regions. Immunohistochemistry studies demonstrated that the proportion of AH neurons in the myenteric plexus was unchanged in ulcerated regions, but there was a 10% reduction in total number of neurons per ganglion.
  
  
  CONCLUSIONS
  These findings support the concept that inflammation-induced neuroplasticity in myenteric neurons, involving changes in ion channel activity that lead to enhanced AH neuronal excitability, can contribute to impaired propulsive colonic motility.
authors.affiliation: Department of Anatomy & Neurobiology, University of Vermont, Burlington, VT 05405, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Hoffman
authors.forename: N D
authors.initials: ND
authors.lastname: McKnight
authors.forename: K A
authors.initials: KA
authors.lastname: Sharkey
authors.forename: G M
authors.initials: GM
authors.lastname: Mawe
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology*; D003106:Colon / Q000187:drug effects / Q000503:physiopathology*; D017615:Enteric Nervous System / Q000187:drug effects / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009197:Myenteric Plexus / Q000187:drug effects / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid / Q000009:adverse effects; D014701:Veratridine / Q000494:pharmacology
chemical_list: D007211:Indoles; D011720:Pyrazoles; D011743:Pyrimidines; C411671:TRAM 34; C082246:ICI D2788; C105050:tegaserod; D014701:Veratridine; D014302:Trinitrobenzenesulfonic Acid