Abstract
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 (PIP2) after oxaliplatin treatment. Inhibition of the PLC pathway can reverse the decreased TRPM8 activity as well as the decreased PIP2-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.
Highlights
Oxaliplatin is a first-line cytostatic and the major component of the widely usedFOLFOX regimen for the treatment of advanced colorectal cancer [1]
We first investigated whether the activity of the transient receptor potential melastatin 8 (TRPM8) channel was altered in response to oxaliplatin treatment
Using the TRPM8 specific agonist menthol (100 μM, 30 s), we observed that the TRPM8 channel activity was significantly reduced in oxaliplatin-treated animals after 24 h when compared with vehicle-treated animals (p = 0.0006, Figure 1A,B)
Summary
Oxaliplatin is a first-line cytostatic and the major component of the widely usedFOLFOX regimen for the treatment of advanced colorectal cancer [1]. 90% of the treated patients oxaliplatin causes neurotoxicity and acute pain that already begins several hours after treatment and that is characterized by cold allodynia [2,3]. Apart from these transient effects, in up to 80% of the patients oxaliplatin causes a long-term distal sensory neuropathy that can persist lifelong [4,5]. Several studies suggest that oxaliplatin treatment rapidly causes damage to the peripheral nervous system by inducing synthesis of reactive oxygen species (ROS), mitochondrial dysfunction and altered activity of neuronal ion channels [8,9,10,11]
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