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 Ca2+-activated K+ channel inhibitor TRAM-34 and the 5-HT4 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.
Key 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 and Inferences 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.