title: Multiple roles for NaV1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease-derived stimuli.
abstract: Chronic visceral pain affects millions of individuals worldwide and remains poorly understood, with current therapeutic options constrained by gastrointestinal adverse effects. Visceral pain is strongly associated with inflammation and distension of the gut. Here we report that the voltage-gated sodium channel subtype NaV1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons. We show that NaV1.9 is required for normal mechanosensation, for direct excitation and for sensitization of mouse colonic afferents by mediators from inflammatory bowel disease tissues, and by noxious inflammatory mediators individually. Excitatory responses to ATP or PGE2 were substantially reduced in NaV1.9(-/-) mice. Deletion of NaV1.9 substantially attenuates excitation and subsequent mechanical hypersensitivity after application of inflammatory soup (IS) (bradykinin, ATP, histamine, PGE2, and 5HT) to visceral nociceptors located in the serosa and mesentery. Responses to mechanical stimulation of mesenteric afferents were also reduced by loss of NaV1.9, and there was a rightward shift in stimulus-response function to ramp colonic distension. By contrast, responses to rapid, high-intensity phasic distension of the colon are initially unaffected; however, run-down of responses to repeat phasic distension were exacerbated in NaV1.9(-/-) afferents. Finally colonic afferent activation by supernatants derived from inflamed human tissue was greatly reduced in NaV1.9(-/-) mice. These results demonstrate that NaV1.9 is required for persistence of responses to intense mechanical stimulation, contributes to inflammatory mechanical hypersensitivity, and is essential for activation by noxious inflammatory mediators, including those from diseased human bowel. These observations indicate that NaV1.9 represents a high-value target for development of visceral analgesics.
authors: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AJ, UK; 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 E1 2AT, UK.
authors: James R F
authors: JR
authors: Hockley
authors: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AJ, UK; 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 E1 2AT, UK.
authors: George
authors: G
authors: Boundouki
authors: 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 E1 2AT, UK.
authors: Vincent
authors: V
authors: Cibert-Goton
authors: 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 E1 2AT, UK.
authors: Cian
authors: C
authors: McGuire
authors: Centre for Neuroscience and Trauma, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors: Ping K
authors: PK
authors: Yip
authors: 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 E1 2AT, UK.
authors: Christopher
authors: C
authors: Chan
authors: 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 E1 2AT, UK.
authors: Michael
authors: M
authors: Tranter
authors: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.
authors: John N
authors: JN
authors: Wood
authors: Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN, UK.
authors: Mohammed A
authors: MA
authors: Nassar
authors: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AJ, UK; 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 E1 2AT, UK.
authors: L Ashley
authors: LA
authors: Blackshaw
authors: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AJ, UK.
authors: Qasim
authors: Q
authors: Aziz
authors: Centre for Neuroscience and Trauma, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors: Gregory J
authors: GJ
authors: Michael
authors: Centre for Neuroscience and Trauma, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors: Mark D
authors: MD
authors: Baker
authors: Neusentis (Pfizer Ltd), The Portway Building, Granta Science Park, Cambridge CB21 6GS, UK.
authors: Wendy J
authors: WJ
authors: Winchester
authors: 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 E1 2AT, UK.
authors: Charles H
authors: CH
authors: Knowles
authors: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AJ, UK; 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 E1 2AT, UK. Electronic address: d.bulmer@qmul.ac.uk.
authors: David C
authors: DC
authors: Bulmer
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D003106:Colon / Q000294:innervation* / Q000378:metabolism / Q000503:physiopathology; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism* / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D015212:Inflammatory Bowel Diseases / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D062558:NAV1.9 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D010812:Physical Stimulation; D017833:Visceral Afferents / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D055815:Young Adult
chemical_list: D062558:NAV1.9 Voltage-Gated Sodium Channel; C491885:Scn11a protein, mouse; D000255:Adenosine Triphosphate; D015232:Dinoprostone
keywords: Distal colon; Inflammatory bowel disease; Na(V)1.9; Nociceptor sensitivity; Noxious distension; Supernatants; Visceral hypersensitivity; Visceral pain; Voltage-gated sodium channel