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Inhibition of inflammatory pain and cough by a novel charged sodium channel blocker
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  • Ivan Tochitsky,
  • Sooyeon Jo,
  • Nick Andrews,
  • Masakazu Kotoda,
  • Benjamin Doyle,
  • Jaehoon Shim,
  • Sebastien Talbot,
  • Roberson David,
  • Jinbo Lee,
  • Louise Haste,
  • Stephen Jordan,
  • Bruce Levy,
  • Bruce Bean,
  • Clifford Woolf
Ivan Tochitsky
Boston Children's Hospital F M Kirby Neurobiology Center
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Sooyeon Jo
Harvard Medical School
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Nick Andrews
Boston Children's Hospital F M Kirby Neurobiology Center
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Masakazu Kotoda
Boston Children's Hospital F M Kirby Neurobiology Center
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Benjamin Doyle
Boston Children's Hospital F M Kirby Neurobiology Center
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Jaehoon Shim
Boston Children's Hospital F M Kirby Neurobiology Center
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Sebastien Talbot
Université de Montréal
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Roberson David
Boston Children's Hospital F M Kirby Neurobiology Center
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Jinbo Lee
Sage Partner International
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Louise Haste
Covance Inc.
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Stephen Jordan
Covance Inc.
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Bruce Levy
Brigham and Women's Hospital
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Bruce Bean
Harvard Medical School
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Clifford Woolf
Boston Children's Hospital F M Kirby Neurobiology Center
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Abstract

Background and Purpose: Many pain-triggering nociceptor neurons express TRPV1 or TRPA1, cation-selective channels with large pores that enable permeation of QX-314, a cationic analogue of lidocaine. Co-application of QX-314 with TRPV1 or TRPA1 activators can silence nociceptors. We now describe BW-031, a novel more potent cationic sodium channel inhibitor, test whether its application alone can inhibit the pain associated with tissue inflammation, and whether this strategy can also inhibit cough. Experimental Approach: We characterized BW-031 inhibition of sodium channels and tested BW-031 in three models of inflammatory pain: rat paw inflammation produced by Complete Freund’s Adjuvant injection or surgical incision and a mouse paw UV burn model. We also tested the ability of BW-031 to inhibit cough induced by inhalation of dilute citric acid in guinea pigs. Key Results: BW-031 inhibited Nav1.7 and Nav1.1 channels with ~6-fold greater potency than QX-314 when introduced inside cells and entered capsaicin-activated TRPV1 expressing sensory neurons. BW-031 inhibited inflammatory pain in all three models, producing more effective and longer-lasting inhibition of pain than QX-314 in the mouse UV burn model. BW-031 was also effective in reducing cough counts by 78-90% when applied intratracheally under isoflurane anesthesia or by aerosol inhalation in awake guinea pigs with airway inflammation produced by ovalbumin sensitization. Conclusion and Implications: BW-031 a novel cationic sodium channel inhibitor can be applied locally as a single agent to inhibit inflammatory pain and also effectively inhibits cough in a guinea pig model of nociceptor-activated cough, suggesting a new clinical approach to treating cough.

Peer review status:ACCEPTED

03 Feb 2021Submitted to British Journal of Pharmacology
04 Feb 2021Submission Checks Completed
04 Feb 2021Assigned to Editor
08 Feb 2021Reviewer(s) Assigned
23 Feb 2021Review(s) Completed, Editorial Evaluation Pending
02 Mar 2021Editorial Decision: Revise Minor
21 Apr 20211st Revision Received
23 Apr 2021Submission Checks Completed
23 Apr 2021Assigned to Editor
26 Apr 2021Review(s) Completed, Editorial Evaluation Pending
27 Apr 2021Editorial Decision: Accept