Inhibition of inflammatory pain and cough by a novel charged sodium
channel blocker
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.