Eid Samer R, Crown Eric D, Moore Eric L, Liang Hongyu A, Choong Kar-Chan, Dima Shelley, Henze Darrell A, Kane Stefanie A, Urban Mark O
Department of Pain Research, Neuroscience Drug Discovery, Merck Research Laboratories, West Point, Philadelphia, USA.
Mol Pain. 2008 Oct 27;4:48. doi: 10.1186/1744-8069-4-48.
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.
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.
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 neuropathic pain models. These findings suggested that TRPA1 antagonism may be a suitable new approach for the development of a potent and selective therapeutic agent to treat both inflammatory and neuropathic pain.
对于许多患者而言，安全有效的慢性炎症性和神经性疼痛治疗方法仍是一项关键的未满足医疗需求。包括TRPV1和TRPA1在内的瞬时受体电位受体家族的最新发现和描述为治疗慢性疼痛提供了一些潜在的新治疗靶点。最近的报告表明，TRPA1可能在急性福尔马林和CFA诱导的疼痛中起重要作用。本研究旨在进一步探索药理学上TRPA1拮抗作用治疗炎症性和神经性疼痛的治疗潜力。
HC-030031对肉桂醛或异硫氰酸烯丙酯（AITC或芥子油）诱导的TRPA1激活的体外效价分别为4.9±0.1和7.5±0.2微摩尔（IC50）。这些发现与先前报道的针对AITC激活TRPA1的IC50为6.2微摩尔相似。在大鼠中，口服HC-030031剂量为100毫克/千克时可减少AITC诱导的伤害性反应行为。此外，口服HC-030031（100毫克/千克）在完全弗氏佐剂（CFA）诱导的炎症性疼痛的更慢性模型和神经性疼痛的脊神经结扎模型中显著逆转了机械性超敏反应。
通过口服选择性TRPA1拮抗剂HC-030031，我们的结果表明TRPA1在炎症性和神经性疼痛模型中观察到的机械性超敏反应机制中起重要作用。这些发现表明，TRPA1拮抗作用可能是开发一种有效且选择性治疗剂以治疗炎症性和神经性疼痛的合适新方法。
