Ex vivo study of human visceral nociceptors
ObjectiveThe 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.DesignElectrophysiologic...
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| Published in | Gut Vol. 67; no. 1; pp. 86 - 96 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
BMJ Publishing Group LTD
01.01.2018
BMJ Publishing Group |
| Series | Original article |
| Subjects | |
| Online Access | Get full text |
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| Abstract | ObjectiveThe 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.DesignElectrophysiological (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.ResultsTwo 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.ConclusionsFunctionally distinct subpopulations of human visceral afferents can be demonstrated and could provide a platform technology to further study nociception in human tissue. |
|---|---|
| AbstractList | 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 (TRPV
4
) 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 TRPV
4
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. OBJECTIVEThe 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. DESIGNElectrophysiological (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. RESULTSTwo 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. CONCLUSIONSFunctionally distinct subpopulations of human visceral afferents can be demonstrated and could provide a platform technology to further study nociception in human tissue. 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. 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 (TRPV ) modulation on mechanical responses. 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 TRPV 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. Functionally distinct subpopulations of human visceral afferents can be demonstrated and could provide a platform technology to further study nociception in human tissue. ObjectiveThe 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.DesignElectrophysiological (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.ResultsTwo 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.ConclusionsFunctionally distinct subpopulations of human visceral afferents can be demonstrated and could provide a platform technology to further study nociception in human tissue. 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. |
| Author | McGuire, Cian Kung, Victor Chan, Christopher Reed, David Knowles, Charles H Aziz, Qasim Bulmer, David C Boundouki, George Blackshaw, L Ashley Broad, John Hockley, James R F Cibert-Goton, Vincent Peiris, Madusha Sanger, Gareth J Ahmed, Shafi Thaha, Mohamed A |
| AuthorAffiliation | 2 Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London , London , UK 1 National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London , London , UK |
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| Author_xml | – sequence: 1 givenname: Cian surname: McGuire fullname: McGuire, Cian email: d.bulmer@qmul.ac.uk organization: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 2 givenname: George surname: Boundouki fullname: Boundouki, George email: d.bulmer@qmul.ac.uk organization: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 3 givenname: James R F surname: Hockley fullname: Hockley, James R F email: d.bulmer@qmul.ac.uk organization: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 4 givenname: David surname: Reed fullname: Reed, David email: d.bulmer@qmul.ac.uk organization: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 5 givenname: Vincent surname: Cibert-Goton fullname: Cibert-Goton, Vincent email: d.bulmer@qmul.ac.uk organization: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 6 givenname: Madusha surname: Peiris fullname: Peiris, Madusha email: d.bulmer@qmul.ac.uk organization: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 7 givenname: Victor surname: Kung fullname: Kung, Victor email: d.bulmer@qmul.ac.uk organization: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 8 givenname: John surname: Broad fullname: Broad, John email: d.bulmer@qmul.ac.uk organization: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 9 givenname: Qasim surname: Aziz fullname: Aziz, Qasim email: d.bulmer@qmul.ac.uk organization: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 10 givenname: Christopher surname: Chan fullname: Chan, Christopher email: d.bulmer@qmul.ac.uk organization: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 11 givenname: Shafi surname: Ahmed fullname: Ahmed, Shafi email: d.bulmer@qmul.ac.uk organization: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 12 givenname: Mohamed A surname: Thaha fullname: Thaha, Mohamed A email: d.bulmer@qmul.ac.uk organization: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 13 givenname: Gareth J surname: Sanger fullname: Sanger, Gareth J email: d.bulmer@qmul.ac.uk organization: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 14 givenname: L Ashley surname: Blackshaw fullname: Blackshaw, L Ashley email: d.bulmer@qmul.ac.uk organization: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 15 givenname: Charles H surname: Knowles fullname: Knowles, Charles H email: d.bulmer@qmul.ac.uk organization: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 16 givenname: David C surname: Bulmer fullname: Bulmer, David C email: d.bulmer@qmul.ac.uk organization: National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK |
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| Keywords | VISCERAL NOCICEPTION NEUROGASTROENTEROLOGY VISCERAL SENSITIVITY ABDOMINAL PAIN ELECTROPHYSIOLOGY |
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| PublicationDecade | 2010 |
| PublicationPlace | England |
| PublicationPlace_xml | – name: England – name: London – name: BMA House, Tavistock Square, London, WC1H 9JR |
| PublicationSeriesTitle | Original article |
| PublicationTitle | Gut |
| PublicationTitleAlternate | Gut |
| PublicationYear | 2018 |
| Publisher | BMJ Publishing Group LTD BMJ Publishing Group |
| Publisher_xml | – name: BMJ Publishing Group LTD – name: BMJ Publishing Group |
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| Snippet | ObjectiveThe development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible... The development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible methodology to... Objective The development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible... Objective The development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible... OBJECTIVEThe development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible... |
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| SubjectTerms | Abdomen Adenosine Triphosphate - pharmacology Analgesics Anti-Inflammatory Agents, Non-Steroidal - pharmacology Bradykinin Bradykinin - analogs & derivatives Bradykinin - pharmacology Bradykinin Receptor Antagonists - pharmacology Disease Drug development Drug Evaluation, Preclinical - methods Gastrointestinal Agents - pharmacology Humans Indoles - pharmacology Intestines - drug effects Intestines - innervation Irritable bowel syndrome Morpholines - pharmacology Neurogastroenterology Nociceptors Nociceptors - drug effects Nociceptors - physiology Pain Pain perception Physical Stimulation - methods Pyrroles - pharmacology Rodents Sensory neurons Serotonin Receptor Agonists - pharmacology Studies Subpopulations Tissue Culture Techniques Transient receptor potential proteins TRPV Cation Channels - antagonists & inhibitors |
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| Title | Ex vivo study of human visceral nociceptors |
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