Faculty Collaboration Database

Selective antagonism of TRPA1 produces limited efficacy in models of inflammatory- and neuropathic-induced mechanical hypersensitivity in rats. Mol Pain 2016;12

Date

12/03/2016

Pubmed ID

27899696

Pubmed Central ID

PMC5131813

DOI

10.1177/1744806916677761

Scopus ID

2-s2.0-85007432888 (requires institutional sign-in at Scopus site)   24 Citations

Abstract

The transient receptor potential ankyrin 1 (TRPA1) channel has been implicated in pathophysiological processes that include asthma, cough, and inflammatory pain. Agonists of TRPA1 such as mustard oil and its key component allyl isothiocyanate (AITC) cause pain and neurogenic inflammation in humans and rodents, and TRPA1 antagonists have been reported to be effective in rodent models of pain. In our pursuit of TRPA1 antagonists as potential therapeutics, we generated AMG0902, a potent (IC₉₀ of 300 nM against rat TRPA1), selective, brain penetrant (brain to plasma ratio of 0.2), and orally bioavailable small molecule TRPA1 antagonist. AMG0902 reduced mechanically evoked C-fiber action potential firing in a skin-nerve preparation from mice previously injected with complete Freund's adjuvant, supporting the role of TRPA1 in inflammatory mechanosensation. In vivo target coverage of TRPA1 by AMG0902 was demonstrated by the prevention of AITC-induced flinching/licking in rats. However, oral administration of AMG0902 to rats resulted in little to no efficacy in models of inflammatory, mechanically evoked hypersensitivity; and no efficacy was observed in a neuropathic pain model. Unbound plasma concentrations achieved in pain models were about 4-fold higher than the IC₉₀ concentration in the AITC target coverage model, suggesting that either greater target coverage is required for efficacy in the pain models studied or TRPA1 may not contribute significantly to the underlying mechanisms.

Author List

Lehto SG, Weyer AD, Youngblood BD, Zhang M, Yin R, Wang W, Teffera Y, Cooke M, Stucky CL, Schenkel L, Geuns-Meyer S, Moyer BD, Wild KD, Gavva NR

Author

Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Action Potentials
Amines
Analgesics
Animals
Anti-Inflammatory Agents, Non-Steroidal
CHO Cells
Cricetulus
Cyclohexanecarboxylic Acids
Exploratory Behavior
Freund's Adjuvant
Hyperalgesia
Inflammation
Male
Mice, Inbred C57BL
Mice, Knockout
Naproxen
Nerve Fibers, Unmyelinated
Pain Threshold
Rats
Rats, Sprague-Dawley
Sciatica
TRPA1 Cation Channel
TRPC Cation Channels
gamma-Aminobutyric Acid