Selective antagonism of TRPA1 produces limited efficacy in models of inflammatory- and neuropathic-induced mechanical hypersensitivity in rats. Mol Pain 2016;12
Date
12/03/2016Pubmed ID
27899696Pubmed Central ID
PMC5131813DOI
10.1177/1744806916677761Scopus ID
2-s2.0-85007432888 (requires institutional sign-in at Scopus site) 24 CitationsAbstract
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 NRAuthor
Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Action PotentialsAmines
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