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. (250 words)