PT  - JOURNAL ARTICLE
AU  - Cian McGuire
AU  - George Boundouki
AU  - James R F Hockley
AU  - David Reed
AU  - Vincent Cibert-Goton
AU  - Madusha Peiris
AU  - Victor Kung
AU  - John Broad
AU  - Qasim Aziz
AU  - Christopher Chan
AU  - Shafi Ahmed
AU  - Mohamed A Thaha
AU  - Gareth J Sanger
AU  - L Ashley Blackshaw
AU  - Charles H Knowles
AU  - David C Bulmer
TI  - Ex vivo study of human visceral nociceptors
AID  - 10.1136/gutjnl-2016-311629
DP  - 2018 Jan 01
TA  - Gut
PG  - 86--96
VI  - 67
IP  - 1
4099  - http://gut.bmj.com/content/67/1/86.short
4100  - http://gut.bmj.com/content/67/1/86.full
SO  - Gut2018 Jan 01; 67
AB  - Objective The development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible methodology to study visceral nociception in human tissue that could aid future target identification and drug evaluation.Design Electrophysiological (single unit) responses of visceral afferents to mechanical (von Frey hair (VFH) and stretch) and chemical (bradykinin and ATP) stimuli were examined. Thus, serosal afferents (putative nociceptors) were used to investigate the effect of tegaserod, and transient receptor potential channel, vanilloid 4 (TRPV4) modulation on mechanical responses.Results Two distinct afferent fibre populations, serosal (n=23) and muscular (n=21), were distinguished based on their differences in sensitivity to VFH probing and tissue stretch. Serosal units displayed sensitivity to key algesic mediators, bradykinin (6/14 units tested) and ATP (4/10), consistent with a role as polymodal nociceptors, while muscular afferents are largely insensitive to bradykinin (0/11) and ATP (1/10). Serosal nociceptor mechanosensitivity was attenuated by tegaserod (−20.8±6.9%, n=6, p<0.05), a treatment for IBS, or application of HC067047 (−34.9±10.0%, n=7, p<0.05), a TRPV4 antagonist, highlighting the utility of the preparation to examine the mechanistic action of existing drugs or novel analgesics. Repeated application of bradykinin or ATP produced consistent afferent responses following desensitisation to the first application, demonstrating their utility as test stimuli to evaluate analgesic activity.Conclusions Functionally distinct subpopulations of human visceral afferents can be demonstrated and could provide a platform technology to further study nociception in human tissue.