HC-030031, a TRPA1 Selective Antagonist, Attenuates Inflammatory- and Neuropathy-Induced Mechanical Hypersensitivity

作者：Samer R. Eid, Eric D. Crown, Eric L. Moore, Hongyu Annie Liang, Kar-Chan Choong, Shelley Dima, Darrell A. Henze, Stefanie A. Kane, Mark O. Urban · 发表于：Molecular Pain · 年份：2008 · DOI：10.1186/1744-8069-4-48 · 被引用次数：454 · 研究领域：Ion Channels and Receptors、Pain Mechanisms and Treatments、Ion channel regulation and function

BACKGROUND: Safe and effective treatment for chronic inflammatory and neuropathic pain remains a key unmet medical need for many patients. The recent discovery and description of the transient receptor potential family of receptors including TRPV1 and TRPA1 has provided a number of potential new therapeutic targets for treating chronic pain. Recent reports have suggested that TRPA1 may play an important role in acute formalin and CFA induced pain. The current study was designed to further explore the therapeutic potential of pharmacological TRPA1 antagonism to treat inflammatory and neuropathic pain. RESULTS: The in vitro potencies of HC-030031 versus cinnamaldehyde or allyl isothiocyanate (AITC or Mustard oil)-induced TRPA1 activation were 4.9 +/- 0.1 and 7.5 +/- 0.2 microM respectively (IC50). These findings were similar to the previously reported IC50 of 6.2 microM against AITC activation of TRPA1 1. In the rat, oral administration of HC-030031 reduced AITC-induced nocifensive behaviors at a dose of 100 mg/kg. Moreover, oral HC-030031 (100 mg/kg) significantly reversed mechanical hypersensitivity in the more chronic models of Complete Freunds Adjuvant (CFA)-induced inflammatory pain and the spinal nerve ligation model of neuropathic pain. CONCLUSION: Using oral administration of the selective TRPA1 antagonist HC-030031, our results demonstrated that TRPA1 plays an important role in the mechanisms responsible for mechanical hypersensitivity observed in inflammatory and neur...