TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists
TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists
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DOI：
10.1523/jneurosci.1246-06.2006
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发表时间：
2006-09-13
影响因子：
5.3
通讯作者：
Faltynek, C. R.
中科院分区：
文献类型：
--
作者：
Cui, M.;Honore, P.;Faltynek, C. R.
1 型香草酸受体 (TRPV1) 是一种配体门控非选择性阳离子通道，被认为是内源性脂质、辣椒素、热和低 pH 等各种疼痛刺激的重要整合因子。除了在初级传入神经中表达外，TRPV1 还在中枢神经系统中表达。为了验证 CNS 在 TRPV1 拮抗剂对各种类型疼痛的作用中发挥不同作用的假设，我们比较了两种体外效力相似但 CNS 渗透不同的 TRPV1 拮抗剂的体内镇痛效果。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）（良好的中枢神经系统渗透性）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）（中枢神经系统渗透性差）以相同的效力阻断辣椒素引起的急性疼痛。在完全弗氏佐剂（CFA）诱导的慢性炎症性疼痛中，口服任何一种化合物都可以以相似的效力阻断热痛觉过敏。此外，足底内或鞘内施用 A-784168 可阻断 CFA 诱导的热痛觉过敏，表明外周和 CNS TRPV1 受体可能在炎症热痛觉过敏中发挥作用。在可能由中枢敏化介导的模型中进一步评估了两种 TRPV1 拮抗剂的作用，包括 CFA 和辣椒素诱导的机械异常性疼痛和骨关节炎疼痛。在这些模型中，鞘内给药后两种化合物的效力相似。然而，口服给药时，A-784168 具有良好的 CNS 渗透性，比 A-795614 更有效。总之，这些结果表明 CNS 中的 TRPV1 受体在中枢敏化介导的疼痛中发挥重要作用。此外，这些结果表明，TRPV1 拮抗剂必须具有显着的中枢神经系统渗透才能产生广谱镇痛作用。
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.