The selective kappa opioid receptor agonist ICI 204,448 inhibits the response of colonic spinal afferent fibres to distension

V Cibert-Goton2, A Blackshaw1, DC Bulmer2. 1QMUL - Neurogastroenterology Group - Wingate Institute, London, UK, 2QMUL - Neurogastroenterology Group - National Centre for Bowel Research and Surgical Innovation, London, UK

The effects of kappa opioid receptor activation on colonic sensory nerve activity has not been studied in detail and may underlie the recently demonstrated clinical efficacy of this class of drug in patients with irritable bowel syndrome (IBS). The aim of the present study was to examine the effect of the selective kappa opioid receptor agonist ICI 204,448 on the response of colonic splanchnic nerve activity.

Experiments were performed on isolated colorectum obtained from C57/B6 mice euthanased in accordance with schedule 1 of the UK Animals Scientific Procedures Act (1986). Extracellular recordings were made using suction electrodes from lumbar splanchnic nerves of tubular preparations perfused luminally (0.1ml/min) and serosally (7ml/min) with carbogenated Krebs solution supplemented with nifedipine (10µM) and atropine (10µM). Repeat phasic distensions (80mmHg, 10min apart) of the colon were performed and the effect of treatment with ICI 204,448 (0.1-10µM n=3-6) or vehicle (0.01%DMSO n=5) was examined following an initial stabilisation period. Peak increases in afferent discharge to distension were determined, and changes in afferent discharge post treatment expressed as a percentage inhibition of x2 control distensions immediately prior to drug or vehicle treatment. Changes are expressed as a mean ± sem and statistically compared before and after drug administration using one way ANOVA and Dunnett’s post hoc test vs vehicle group or paired Student’s t-test as appropriate (significant difference, p<0.05).

Consistent splanchnic afferent fibre responses to repeat phasic distension of the colon were obtained, which were not significantly different before and up to 40min after administration of vehicle (0.01%DMSO; p=0.47 n=5). Administration of ICI 204,448 elicited a time and concentration dependent inhibition of afferent responses to distension which was greatest 30-40min following drug administration (IC50=372 nM: inhibition of distension 9.14 ± 2.54% at 0.1µM n=3, 11.02 ± 3.31% at 0.3µM n=5, 21.71 ± 2.72% at 1.0µM n=6 p<0.05, 21.47 ± 4.95% at 10.0µM n=4 p<0.05).

The data generated demonstrates that administration of the selective KOR agonist IC204,448 elicits a significant inhibition of the colonic sensory nerve response to high threshold phasic distension.