Zimmermann K, Leffler A, Fischer M M J, Messlinger K, Nau C, Reeh P W
Department of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nuremberg, Universitaetsstrasse 17, D-91054 Erlangen, Germany.
Neuroscience. 2005;135(4):1277-84. doi: 10.1016/j.neuroscience.2005.07.018. Epub 2005 Sep 13.
TRPV1 gene disruption results in a loss of capsaicin and proton responsiveness, but has minimal effects on heat-induced nocifensive behavior, suggesting that sensory transduction of heat is independent of TRPV1. TRPV3, another heat-activated ion channel but insensitive to capsaicin, was shown to be expressed in keratinocytes as well as in sensory neurons projecting to the skin. Recently, 2-aminoethoxydiphenyl borate was introduced as a TRPV3 agonist, but its selectivity was questioned by showing that it activated recombinant TRPV1 and TRPV2 as well. We used the isolated mouse skin-saphenous nerve preparation and whole-cell patch-clamping of cultured dorsal root ganglia neurons from TRPV1-/- and wildtype mice. We found no phenotypic differences between the heat responses of polymodal C-fibers, whereas cultured dorsal root ganglia neurons of TRPV1-/- hardly showed any heat-activated currents. Only C-fibers of wildtype but not TRPV1-/- mice were clearly sensitized to heat by 2-aminoethoxydiphenyl borate 10 and 100 microM; heat-activated current in wildtype neurons was only facilitated at 100 microM. Noxious heat-induced calcitonin gene-related peptide release showed clear deficits (<50%) in TRPV1 deficient skin, but the stimulated calcitonin gene-related peptide release from the isolated skull dura was unaffected. In both models, 2-aminoethoxydiphenyl borate was able to potentiate the heat response (46 degrees C, 5 min) in a concentration-dependent manner, again, only in wildtype but not TRPV1-/- mice, suggesting that TRPV2/3 are not involved in this sensitization to heat. The results further suggest that TRPV1 is not responsible for the normal heat response of native nociceptors but plays the essential role in thermal sensitization and a prominent one in controlling dermal calcitonin gene-related peptide release, i.e. neurogenic inflammation.
瞬时受体电位香草酸亚型1（TRPV1）基因缺失导致对辣椒素和质子反应性丧失，但对热诱导的伤害性反应影响极小，这表明热感觉转导独立于TRPV1。TRPV3是另一种热激活离子通道，但对辣椒素不敏感，已证实在角质形成细胞以及投射至皮肤的感觉神经元中表达。最近，2-氨基乙氧基二苯硼酸盐被用作TRPV3激动剂，但因其也能激活重组TRPV1和TRPV2，其选择性受到质疑。我们使用了分离的小鼠皮肤-隐神经标本以及对来自TRPV1基因敲除小鼠和野生型小鼠的培养背根神经节神经元进行全细胞膜片钳记录。我们发现多模式C纤维的热反应在表型上没有差异，而TRPV1基因敲除小鼠的培养背根神经节神经元几乎未显示出任何热激活电流。仅野生型小鼠而非TRPV1基因敲除小鼠的C纤维对10和100微摩尔的2-氨基乙氧基二苯硼酸盐明显热敏感；野生型神经元中的热激活电流仅在100微摩尔时增强。有害热诱导的降钙素基因相关肽释放显示在TRPV1缺陷皮肤中明显减少（<50%），但从分离的颅骨硬脑膜刺激释放的降钙素基因相关肽不受影响。在两个模型中，2-氨基乙氧基二苯硼酸盐均能够以浓度依赖方式增强热反应（46摄氏度，5分钟），同样，仅在野生型小鼠而非TRPV1基因敲除小鼠中如此，这表明TRPV2/3不参与这种对热的敏感化。结果进一步表明，TRPV1对天然伤害感受器的正常热反应无作用，但在热敏感化中起关键作用，且在控制皮肤降钙素基因相关肽释放即神经源性炎症中起重要作用。
