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156. Visceral and somatic pain modalities reveal NaV1.7-independent visceral nociceptive pathways.

Author

Hockley, James R. F., González‐Cano, Rafael, McMurray, Sheridan, Tejada‐Giraldez, Miguel A., McGuire, Cian, Torres, Antonio, Wilbrey, Anna L., Cibert‐Goton, Vincent, Nieto, Francisco R., Pitcher, Thomas, Knowles, Charles H., Baeyens, José Manuel, Wood, John N., Winchester, Wendy J., Bulmer, David C., Cendán, Cruz Miguel, and McMurray, Gordon

Subjects
VISCERAL pain, SODIUM channels, DELETION mutation, CYCLOPHOSPHAMIDE, MESSENGER RNA
Abstract

Key points Voltage-gated sodium channels play a fundamental role in determining neuronal excitability., Specifically, voltage-gated sodium channel subtype NaV1.7 is required for sensing acute and inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown., Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for NaV1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling., These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality-specific manner and help to direct drug discovery efforts towards novel visceral analgesics., Abstract Voltage-gated sodium channel NaV1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of NaV1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific NaV1.7 knockout mouse (NaV1.7Nav1.8) and selective small-molecule NaV1.7 antagonist PF-5198007. NaV1.7Nav1.8 mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both NaV1.7Nav1.8 and littermate controls. Loss, or blockade, of NaV1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of NaV1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel α subunits revealed NaV1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of NaV1.7 (in NaV1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective NaV1.7 antagonist PF-5198007. Our data demonstrate that NaV1.7 (in NaV1.8-expressing neurons) contributes to defined pain pathways in a modality-dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of NaV1.7 alone in the viscera may be insufficient in targeting chronic visceral pain. [ABSTRACT FROM AUTHOR]

Published
2017
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165. Function and dysfunction of the colon and anorectum in adults : Working team report of the Swedish Motility Group (SMoG)

Author

Karling, Pontus, Abrahamsson, Hasse, Dolk, Anders, Hallböök, Olof, Hellström, Per M., Knowles, Charles H, Kjellström, Lars, Lindberg, Greger, Lindfors, Per-Johan, Nyhlin, Henry, Ohlsson, Bodil, Schmidt, Peter T, Sjölund, Kristina, Sjövall, Henrik, Walter, Susanne, Karling, Pontus, Abrahamsson, Hasse, Dolk, Anders, Hallböök, Olof, Hellström, Per M., Knowles, Charles H, Kjellström, Lars, Lindberg, Greger, Lindfors, Per-Johan, Nyhlin, Henry, Ohlsson, Bodil, Schmidt, Peter T, Sjölund, Kristina, Sjövall, Henrik, and Walter, Susanne

Abstract

Symptoms of fecal incontinence and constipation are common in the general population. These can, however, be unreliably reported and are poorly discriminatory for underlying pathophysiology. Furthermore, both symptoms may coexist. In the elderly, fecal impaction always must be excluded. For patients with constipation, colon transit studies, anorectal manometry and defecography may help to identify patients with slow-transit constipation and/or pelvic floor dysfunction. The best documented medical treatments for constipation are the macrogols, lactulose and isphagula. Evolving drugs include lubiprostone, which enhances colonic secretion by activating chloride channels. Surgery is restricted for a highly selected group of patients with severe slow-transit constipation and for those with large rectoceles that demonstrably cause rectal evacuatory impairment. For patients with fecal incontinence that does not resolve on antidiarrheal treatment, functional and structural evaluation with anorectal manometry and endoanal ultrasound or magnetic resonance (MR) of the anal canal may help to guide management. Sacral nerve stimulation is a rapidly evolving alternative when other treatments such as biofeedback and direct sphincter repair have failed. Advances in understanding the pathophysiology as a guide to treatment of patients with constipation and fecal incontinence is a continuing important goal for translational research. The content of this article is a summary of presentations given by the authors at the Fourth Meeting of the Swedish Motility Group, held in Gothenburg in April 2007.

Published
2009
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173. 257 Anatomical Sensory Nerve Markers in Human Gut

Author

McGuire, Cian, primary, Harrington, Andrea M., additional, Hubball, Andy, additional, McPhail, Hilary, additional, Peiris, Madusha, additional, Bulmer, David C., additional, Knowles, Charles H., additional, and Blackshaw, L. Ashley, additional

Published
2013
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177. Prostaglandin E2 mediates acid-induced heartburn in healthy volunteers

Author

Kondo, Takashi, primary, Oshima, Tadayuki, additional, Tomita, Toshihiko, additional, Fukui, Hirokazu, additional, Watari, Jiro, additional, Okada, Hiroki, additional, Kikuchi, Shojiro, additional, Sasako, Mitsuru, additional, Matsumoto, Takayuki, additional, Knowles, Charles H., additional, and Miwa, Hiroto, additional

Published
2013
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178. Diagnostic accuracy study of anorectal manometry for diagnosis of dyssynergic defecation.

Author

Grossi, Ugo, Carrington, Emma V., Bharucha, Adil E., Horrocks, Emma J., Scott, S. Mark, and Knowles, Charles H.

Subjects
MANOMETERS, DIAGNOSIS of defecation disorders, CONSTIPATION, WOMEN'S health, PROCTOLOGY, PATIENTS
Abstract

Objective The diagnostic accuracy of anorectal manometry (AM), which is necessary to diagnose functional defecatory disorders (FDD), is unknown. Using blinded analysis and standardised reporting of diagnostic accuracy, we evaluated whether AM could discriminate between asymptomatic controls and patients with functional constipation (FC). Design Derived line plots of anorectal pressure profiles during simulated defecation were independently analysed in random order by three expert observers blinded to health status in 85 women with FC and 85 age-matched asymptomatic healthy volunteers (HV). Using accepted criteria, these pressure profiles were characterised as normal (ie, increased rectal pressure coordinated with anal relaxation) or types I-IV dyssynergia. Interobserver agreement and diagnostic accuracy were determined. Results Blinded consensus-based assessment disclosed a normal pattern in 16/170 (9%) of all participants and only 11/85 (13%) HV. The combined frequency of dyssynergic patterns (I-IV) was very similar in FC (80/85 (94%)) and HV (74/85 (87%)). Type I dyssynergia ('paradoxical' contraction) was less prevalent in FC (17/85 (20%) than in HV (31/85 (36.5%), p=0.03). After statistical correction, only type IV dyssynergia was moderately useful for discriminating between FC (39/85 (46%)) and HV (17/85 (20%)) (p=0.001, positive predictive value=70.0%, positive likelihood ratio=2.3). Interobserver agreement was substantial or moderate for identifying a normal pattern, dyssynergia types I and IV, and FDD, and fair for types II and III. Conclusions While the interpretation of AM patterns is reproducible, nearly 90% of HV have a pattern that is currently regarded as 'abnormal' by AM. Hence, AM is of limited utility for distinguishing between FC and HV. [ABSTRACT FROM AUTHOR]

Published
2016
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179. Anterior resection syndrome

Author

Bryant, Catherine LC, primary, Lunniss, Peter J, additional, Knowles, Charles H, additional, Thaha, Mohamed A, additional, and Chan, Christopher LH, additional

Published
2012
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185. Genetics of human enteric neuropathies

Author

Panza, Emanuele, primary, Knowles, Charles H., additional, Graziano, Claudio, additional, Thapar, Nikhil, additional, Burns, Alan J., additional, Seri, Marco, additional, Stanghellini, Vincenzo, additional, and De Giorgio, Roberto, additional

Published
2012
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186. Ex vivo study of human visceral nociceptors

Author

McGuire, Cian, Boundouki, George, Hockley, James R F, Reed, David, Cibert-Goton, Vincent, Peiris, Madusha, Kung, Victor, Broad, John, Aziz, Qasim, Chan, Christopher, Ahmed, Shafi, Thaha, Mohamed A, Sanger, Gareth J, Blackshaw, L Ashley, Knowles, Charles H, and Bulmer, David C

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 TRPV4antagonist, 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.

Published
2018
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187. Sacral Neuromodulation: Standardized Electrode Placement Technique

Author

Matzel, Klaus E., Chartier‐Kastler, Emmanuel, Knowles, Charles H., Lehur, Paul A., Muñoz‐Duyos, Arantxa, Ratto, Carlo, Rydningen, Mona B., Sørensen, Michael, van Kerrebroeck, Philip, and de Wachter, Stefan

Abstract

Sacral neuromodulation (SNM) (sacral nerve stimulation SNS) has become an established therapy for functional disorders of the pelvic organs. Despite its overall success, the therapy fails in a proportion of patients. This may be partially due to inadequate electrode placement with suboptimal coupling of the electrode and nerve. Based on these assumptions the technique of sacral spinal neuromodulation has been redefined. All descriptions relate to the only currently available system licensed for all pelvic indications (Medtronic Interstim®). An international multidisciplinary working party of ten individuals highly experienced in performing SNM convened two meetings (including live operating) to standardize the implant procedure. This report addresses the main steps to optimal electrode lead placement in temporal sequence. Key elements of the electrode placement are radiological marking, the use of a curved stylet, the entry of the electrode into the sacral foramen and its progression through the foramen, its placement guided by a combination of a typical appearance in fluoroscopy and achieving specific motor/sensory responses with stimulation. The report describes quadripolar electrode placement and then either insertion of a connecting percutaneous extension lead or permanent implantation of the programmable device. Standardization of electrode placement may ensure close electrode proximity to the target nerve providing a higher likelihood for optimal effect with less energy consumption (better battery longevity), more programming options with more electrode contacts close to the nerve and reduced likelihood of side‐effects. The potentially better clinical outcome needs to be demonstrated.

Published
2017
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191. A Novel Phenotype of Glycogen Storage Disease Presenting as Gastrointestinal Neuromuscular Disease

Author

Martin, Joanne E., primary, Chowdhury, ATMDilshad H., additional, McElwaine, Suzanne, additional, Fikree, Asma, additional, Broad, John, additional, Knowles, Charles H., additional, Allen, Liz, additional, Bevan, Shaun, additional, Burt, Emma, additional, Hymas, Austin J., additional, Rowburrey, Philip J., additional, Sanger, Gareth J., additional, Rahman, Mohammed M., additional, Thomas, Alice A., additional, Yiannakou, Yan, additional, Cooper, Sheldon C., additional, Evagora, Christopher A., additional, Levey, Pauline M., additional, Cotter, Finbarr E., additional, Aziz, Qasim, additional, Elaine, Murphy, additional, Pickersgill, Richard W., additional, Bainbridge, Katie, additional, and Silk, David B., additional

Published
2011
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196. Esophageal Epithelial ASIC3 is Associated With Increase in Severity of Symptoms in Patients With Gastro-Esophageal Reflux Disease (GERD)

Author

Chua, Yang C., primary, Hubball, Andrew, additional, Peiris, Madusha, additional, Ng, Kee S., additional, Hughes, Sarah F., additional, Chin Aleong, Joanne, additional, Preston, Sean L., additional, Patel, Bijendra, additional, Chaudry, Asif, additional, Levey, Pauline M., additional, Martin, Joanne E., additional, Aziz, Qasim, additional, and Knowles, Charles H., additional

Published
2011
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