Repository logo
 

KV7 but not dual small and intermediate KCa channel openers inhibit the activation of colonic afferents by noxious stimuli.

Accepted version
Peer-reviewed

Change log

Authors

Bhebhe, Charity N 
Higham, James P 
Gupta, Rohit A 
Raine, Tim 

Abstract

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 coexpressed in the soma of colonic afferent neurons with receptors for the algogenic mediators 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, pretreatment 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 KV7 channel opener retigabine blunted the colonic afferent response to all applied stimuli. Our data therefore highlight the potential utility of KV7, but not SK/IK, channel openers as analgesic agents for the treatment of abdominal pain.NEW & NOTEWORTHY Despite marked coexpression of small (Kcnn1, Kcnn2) and intermediate (Kcnn4) conductance calcium-activated potassium channel transcripts with P2X3 (P2rx3) or bradykinin B2 (Bdkrb2) receptors in colonic sensory neurons, pharmacological activation of these channels had no effect on the colonic afferent response to ATP, bradykinin or luminal distension of the colon. This is in contrast to the robust inhibitory effect of the KV7 channel opener, retigabine.

Description

Keywords

IKCa channels, KV7 channels, SKCa channels, colonic nociception, visceral pain, Humans, Bradykinin, Carbamates, Abdominal Pain, Adenosine Triphosphate, Small-Conductance Calcium-Activated Potassium Channels, Phenylenediamines

Journal Title

Am J Physiol Gastrointest Liver Physiol

Conference Name

Journal ISSN

0193-1857
1522-1547

Volume Title

Publisher

American Physiological Society
Sponsorship
Crohn's & Colitis UK (Unknown)