Cui M, Honore P, Zhong C, Gauvin D, Mikusa J, Hernandez G, Chandran P, Gomtsyan A, Brown B, Bayburt E K, Marsh K, Bianchi B, McDonald H, Niforatos W, Neelands T R, Moreland R B, Decker M W, Lee C-H, Sullivan J P, Faltynek C R
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6123, USA.
J Neurosci. 2006 Sep 13;26(37):9385-93. doi: 10.1523/JNEUROSCI.1246-06.2006.
Vanilloid receptor type 1 (TRPV1) is a ligand-gated nonselective cation channel that is considered to be an important integrator of various pain stimuli such as endogenous lipids, capsaicin, heat, and low pH. In addition to expression in primary afferents, TRPV1 is also expressed in the CNS. To test the hypothesis that the CNS plays a differential role in the effect of TRPV1 antagonists in various types of pain, the analgesic effects of two TRPV1 antagonists with similar in vitro potency but different CNS penetration were compared in vivo. Oral administration of either A-784168 (1-[3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine-4-carboxamide) (good CNS penetration) or A-795614 (N-1H-indazol-4-yl-N'-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea) (poor CNS penetration) blocked capsaicin-induced acute pain with the same potency. In complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, oral administration of either compound blocked thermal hyperalgesia with similar potency. Furthermore, intraplantar or intrathecal administration of A-784168 blocked CFA-induced thermal hyperalgesia, suggesting that both peripheral and CNS TRPV1 receptors may play a role in inflammatory thermal hyperalgesia. The effects of the two TRPV1 antagonists were further assessed in models presumably mediated by central sensitization, including CFA- and capsaicin-induced mechanical allodynia and osteoarthritic pain. In these models, the potency of the two compounds was similar after intrathecal administration. However, when administered orally, A-784168, with good CNS penetration, was much more potent than A-795614. Together, these results demonstrate that TRPV1 receptors in the CNS play an important role in pain mediated by central sensitization. In addition, these results demonstrate that significant CNS penetration is necessary for a TRPV1 antagonist to produce broad-spectrum analgesia.
1型香草酸受体（TRPV1）是一种配体门控的非选择性阳离子通道，被认为是多种疼痛刺激（如内源性脂质、辣椒素、热和低pH值）的重要整合器。除了在初级传入神经中表达外，TRPV1在中枢神经系统（CNS）中也有表达。为了验证中枢神经系统在TRPV1拮抗剂对各种类型疼痛的作用中发挥不同作用这一假设，我们在体内比较了两种体外效力相似但中枢神经系统穿透力不同的TRPV1拮抗剂的镇痛效果。口服A-784168（1-[3-（三氟甲基）吡啶-2-基]-N-[4-（三氟甲基磺酰基）苯基]-1,2,3,6-四氢吡啶-4-甲酰胺）（中枢神经系统穿透力良好）或A-795614（N-1H-吲唑-4-基-N'-[（1R）-5-哌啶-1-基-2,3-二氢-1H-茚-1-基]脲）（中枢神经系统穿透力差）以相同效力阻断辣椒素诱导的急性疼痛。在完全弗氏佐剂（CFA）诱导的慢性炎性疼痛中，口服这两种化合物中的任何一种都以相似效力阻断热痛觉过敏。此外，足底内或鞘内注射A-784168可阻断CFA诱导的热痛觉过敏，这表明外周和中枢神经系统的TRPV1受体可能在炎性热痛觉过敏中起作用。在可能由中枢敏化介导的模型中，包括CFA和辣椒素诱导的机械性异常性疼痛和骨关节炎疼痛，进一步评估了这两种TRPV1拮抗剂的作用。在这些模型中，鞘内注射后这两种化合物的效力相似。然而，口服给药时，中枢神经系统穿透力良好的A-784168比A-795614效力强得多。总之，这些结果表明中枢神经系统中的TRPV1受体在中枢敏化介导的疼痛中起重要作用。此外，这些结果表明TRPV1拮抗剂产生广谱镇痛作用需要显著的中枢神经系统穿透力。
