QX-314 通过 TRPA1、TRPM8 和 TRPV1 通道的转运比较。
Comparison of the transport of QX-314 through TRPA1, TRPM8, and TRPV1 channels.
机构信息
Dentistry for Persons with Disability, Tokushima University Hospital, Tokushima, Japan.
出版信息
J Pain Res. 2013;6:223-30. doi: 10.2147/JPR.S41614. Epub 2013 Mar 16.
BACKGROUND
It has been demonstrated that N-ethyl-lidocaine (QX-314) can target the transient receptor protein vanilloid 1 (TRPV1) nociceptors when coadministered with capsaicin, resulting in a selective block of the nociceptors. Capsaicin is problematic in therapeutic use because it induces firing of nociceptors. The present study aimed to search for substitutes for capsaicin. We also examined the transportability of QX-314 into nociceptive neurons, through the pores of transient receptor potential ankyrin 1 (TRPA1), transient receptor potential melastatin-8 (TRPM8), and TRPV1.
METHODS
To investigate the effect on TRPA1, injections of a vehicle, allyl isothiocyanate (AITC), QX-314, or AITC/QX-314 were made into the hind paws of rats. The effects of menthol and capsaicin on the opening of TRPM8 and TRPV1 were also examined and compared with the potency of QX-314. To examine inhibition of the antinociceptive effect by capsaicin/ QX-314, capsazepine (50 μg/mL; 10 μL) was injected 30 minutes prior to capsaicin/QX-314 (10 μL) injection. Thermal sensitivity was investigated by the Hargreaves method. 5(6)-carboxyfluorescein (FAM)-conjugated QX-314 was used as a tracer to examine how many and which kind of dorsal root ganglia accumulate this molecule. QX-314-FAM, capsaicin/QX-314-FAM, AITC/QX-314-FAM, and menthol/QX-314-FAM were injected into the paw. Two weeks after injections, dorsal root ganglia were removed and sectioned with a cryostat.
RESULTS
The capsaicin/QX-314 group induced longer withdrawal-response latency at 60 to 300 minutes after injection than the control. Both menthol only and menthol/QX-314 injections showed analgesia 10 to 60 minutes after injection. No significant difference was seen between the capsazepine/capsaicin/QX-314 group and the vehicle group. The fluorescence in small- and medium-sized neurons was conspicuous in only the dorsal root ganglia injected with capsaicin/ QX-314-FAM.
CONCLUSION
These results indicate that TRPA1 and TRPM8 are ineffective in the transport of QX-314 compared with TRPV1.
背景
已证实，当与辣椒素联合使用时，N-乙基-利多卡因（QX-314）可以靶向瞬时受体蛋白香草素 1（TRPV1）伤害感受器，从而选择性地阻断伤害感受器。辣椒素在治疗用途中存在问题，因为它会引起伤害感受器的发射。本研究旨在寻找辣椒素的替代品。我们还研究了 QX-314 通过瞬时受体电位锚蛋白 1（TRPA1）、瞬时受体电位 melastatin-8（TRPM8）和 TRPV1 进入伤害感受器神经元的可运输性。
方法
为了研究对 TRPA1 的影响，向大鼠的后爪注射溶剂、丙烯基异硫氰酸酯（AITC）、QX-314 或 AITC/QX-314。还研究并比较了薄荷醇和辣椒素对 TRPM8 和 TRPV1 开放的作用，以及与 QX-314 的效力。为了研究辣椒素/QX-314 抑制抗伤害作用，在注射辣椒素/QX-314（10 μL）前 30 分钟注射辣椒素/QX-314（50 μg/mL；10 μL）。通过 Hargreaves 法研究热敏感性。使用 5（6）-羧基荧光素（FAM）缀合的 QX-314 作为示踪剂，研究有多少和哪种类型的背根神经节积聚这种分子。将 QX-314-FAM、辣椒素/QX-314-FAM、AITC/QX-314-FAM 和薄荷醇/QX-314-FAM 注射到爪子中。注射后 2 周，取出背根神经节并用冷冻切片机切片。
结果
与对照组相比，辣椒素/QX-314 组在注射后 60 至 300 分钟时引起更长的退缩反应潜伏期。仅薄荷醇和薄荷醇/QX-314 注射在注射后 10 至 60 分钟表现出镇痛作用。与辣椒素/QX-314 组和载体组相比，无显著差异。仅在注射辣椒素/QX-314-FAM 的背根神经节中，中小神经元的荧光明显。
结论
这些结果表明，与 TRPV1 相比，TRPA1 和 TRPM8 对 QX-314 的转运作用无效。
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