K V 7 but not dual small and intermediate K Ca channel openers inhibit the activation of colonic afferents by noxious stimuli.

In numerous subtypes of central and peripheral neurons, small and intermediate conductance Ca2+ -activated K+ (SK and IK, respectively) channels are important regulators of neuronal excitability. Transcripts encoding SK channel subunits, as well as the closely related IK subunit, are co-expressed in the soma of colonic afferent neurons with receptors for the algogenic mediators adenosine triphosphate (ATP) and bradykinin, P2X3 and B2 , highlighting the potential utility of these channels as drug targets for the treatment of abdominal pain in gastrointestinal diseases such as irritable bowel syndrome. Despite this, pre-treatment with the dual SK/IK channel opener SKA-31 had no effect on the colonic afferent response to ATP, bradykinin or noxious ramp distention of the colon. Inhibition of SK or IK channels with apamin or TRAM-34, respectively, yielded no change in spontaneous baseline afferent activity, indicating these channels are not tonically active. In contrast to its lack of effect in electrophysiological experiments, comparable concentrations of SKA-31 abolished ongoing peristaltic activity in the colon ex vivo . Treatment with the KV 7 channel opener retigabine blunted the colonic afferent response to all applied stimuli. Our data therefore highlight the potential utility of KV 7, but not SK/IK, channel openers as analgesic agents for the treatment of abdominal pain.