Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe-University, 60590 Frankfurt am Main, Germany.
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
Int J Mol Sci. 2021 May 7;22(9):4962. doi: 10.3390/ijms22094962.
Oxaliplatin is a third-generation platinum-based anticancer drug that is widely used as first-line treatment for colorectal carcinoma. Patients treated with oxaliplatin develop an acute peripheral pain several hours after treatment, mostly characterized by cold allodynia as well as a long-term chronic neuropathy. These two phenomena seem to be causally connected. However, the underlying mechanisms that trigger the acute peripheral pain are still poorly understood. Here we show that the activity of the transient receptor potential melastatin 8 (TRPM8) channel but not the activity of any other member of the TRP channel family is transiently increased 1 h after oxaliplatin treatment and decreased 24 h after oxaliplatin treatment. Mechanistically, this is connected with activation of the phospholipase C (PLC) pathway and depletion of phosphatidylinositol 4,5-bisphosphate (PIP) after oxaliplatin treatment. Inhibition of the PLC pathway can reverse the decreased TRPM8 activity as well as the decreased PIP-concentrations after oxaliplatin treatment. In summary, these results point out transient changes in TRPM8 activity early after oxaliplatin treatment and a later occurring TRPM8 channel desensitization in primary sensory neurons. These mechanisms may explain the transient cold allodynia after oxaliplatin treatment and highlight an important role of TRPM8 in oxaliplatin-induced acute and neuropathic pain.
奥沙利铂是第三代铂类抗癌药物，广泛用于结直肠癌的一线治疗。接受奥沙利铂治疗的患者在治疗后数小时会出现急性外周疼痛，主要表现为冷感觉异常和长期慢性神经病变。这两种现象似乎存在因果关系。然而，触发急性外周疼痛的潜在机制仍知之甚少。在这里，我们发现奥沙利铂治疗后 1 小时，瞬时受体电位 melastatin 8（TRPM8）通道的活性短暂增加，奥沙利铂治疗后 24 小时活性降低。从机制上讲，这与奥沙利铂治疗后磷脂酶 C（PLC）途径的激活和磷脂酰肌醇 4,5-二磷酸（PIP）的耗竭有关。抑制 PLC 途径可以逆转奥沙利铂治疗后 TRPM8 活性的降低以及 PIP 浓度的降低。总之，这些结果指出了奥沙利铂治疗后 TRPM8 活性的短暂变化，以及随后发生的感觉神经元中 TRPM8 通道脱敏。这些机制可能解释了奥沙利铂治疗后的短暂冷感觉异常，并强调了 TRPM8 在奥沙利铂诱导的急性和神经性疼痛中的重要作用。
