Division of Cancer Pathophysiology, National Cancer Research Institute, Tokyo 104-0045, Japan.
Emergency Life-Saving Technique Academy of Tokyo (ELSTA TOKYO), Hachioji-shi, Tokyo 192-0364, Japan.
Int J Mol Sci. 2019 Jul 3;20(13):3271. doi: 10.3390/ijms20133271.
Carboplatin, an anticancer drug, often causes chemotherapy-induced peripheral neuropathy (PN). Transient receptor potential ankyrin 1 (TRPA1), a non-selective cation channel, is a polymodal nociceptor expressed in sensory neurons. TRPA1 is not only involved in pain transmission, but also in allodynia or hyperalgesia development. However, the effects of TRPA1 on carboplatin-induced PN is unclear. We revealed that carboplatin induced mechanical allodynia and cold hyperalgesia, and the pains observed in carboplatin-induced PN models were significantly suppressed by the TRPA1 antagonist HC-030031 without a change in the level of TRPA1 protein. In cells expressing human TRPA, carboplatin had no effects on changes in intracellular Ca concentration ([Ca]); however, carboplatin pretreatment enhanced the increase in [Ca] induced by the TRPA1 agonist, allyl isothiocyanate (AITC). These effects were suppressed by an inhibitor of protein kinase A (PKA). The PKA activator forskolin enhanced AITC-induced increase in [Ca] and carboplatin itself increased intracellular cyclic adenosine monophosphate (cAMP) levels. Moreover, inhibition of A-kinase anchoring protein (AKAP) significantly decreased the carboplatin-induced enhancement of [Ca] induced by AITC and improved carboplatin-induced mechanical allodynia and cold hyperalgesia. These results suggested that carboplatin induced mechanical allodynia and cold hyperalgesia by increasing sensitivity to TRPA1 via the cAMP-PKA-AKAP pathway.
顺铂是一种抗癌药物，常引起化疗引起的周围神经病（PN）。瞬时受体电位锚蛋白 1（TRPA1）是一种非选择性阳离子通道，是感觉神经元中表达的多模式伤害感受器。TRPA1 不仅参与疼痛传递，还参与痛觉过敏或痛觉过敏的发展。然而，TRPA1 对顺铂引起的 PN 的影响尚不清楚。我们发现顺铂诱导机械性痛觉过敏和冷超敏反应，而在顺铂诱导的 PN 模型中观察到的疼痛明显被 TRPA1 拮抗剂 HC-030031 抑制，而 TRPA1 蛋白水平没有变化。在表达人 TRPA 的细胞中，顺铂对细胞内 Ca 浓度变化（[Ca]）没有影响；然而，顺铂预处理增强了 TRPA1 激动剂丙烯基异硫氰酸酯（AITC）诱导的[Ca]增加。这些作用被蛋白激酶 A（PKA）抑制剂抑制。PKA 激活剂 forskolin 增强了 AITC 诱导的[Ca]增加，而顺铂本身增加了细胞内环腺苷酸单磷酸（cAMP）水平。此外，A-激酶锚定蛋白（AKAP）的抑制显著降低了 AITC 诱导的顺铂诱导的[Ca]增加，并改善了顺铂诱导的机械性痛觉过敏和冷超敏反应。这些结果表明，顺铂通过增加对 TRPA1 的敏感性，通过 cAMP-PKA-AKAP 途径诱导机械性痛觉过敏和冷超敏反应。
