Lysophospholipids Contribute to Oxaliplatin-Induced Acute Peripheral Pain

Abstract

Oxaliplatin, a platinum-based chemotherapeutic drug, which is used as first-line treatment for some types of colorectal carcinoma, causes peripheral neuropathic pain in patients. In addition, an acute peripheral pain syndrome develop in almost 90% of patients immediately after oxaliplatin treatment, which is poorly understood mechanistically but correlates with incidence and severity of the later-occurring neuropathy. Here we investigated the effects of acute oxaliplatin treatment in a murine model, showing that male and female mice develop mechanical hypersensitivity 24 h after oxaliplatin treatment. Interestingly, we found that the levels of several lipids were significantly altered in nervous tissue during oxaliplatin-induced acute pain. Specifically, the linoleic acid metabolite 9,10-EpOME (epoxide of linoleic acid) as well as the lysophospholipids lysophosphatidylcholine (LPC) 18:1 and LPC 16:0 were significantly increased 24 h after oxaliplatin treatment in sciatic nerve, DRGs, or spinal cord tissue as revealed by untargeted and targeted lipidomics. In contrast, inflammatory markers including cytokines and chemokines, ROS markers, and growth factors are unchanged in the respective nervous system tissues. Importantly, LPC 18:1 and LPC 16:0 can induce Ca 21 transients in primary sensory neurons, and we identify LPC 18:1 as a previously unknown endogenous activator of the ligand-gated calcium channels transient receptor potential V1 and M8 (transient receptor potential vanilloid 1 and transient receptor potential melastatin 8) in primary sensory neurons using both pharmacological inhibition and genetic knockout. Additionally, a peripheral LPC 18:1 injection was sufficient to induce mechanical hypersensitivity in naive mice. Hence, targeting signaling lipid pathways may ameliorate oxaliplatin-induced acute peripheral pain and the subsequent long-lasting neuropathy.

Pain Control by Targeting Oxidized Phospholipids: Functions, Mechanisms, Perspectives

“…In sterile inflammation, evoked by physical burn as well as UVB-mediated sunburn, derivates of oxidized linoleic acid increase (43,44). Lysophosphatidic acid 18:1 and lysophosphatidyl choline 16:0 and 18:1, additional metabolites deriving from phosphatidylcholine precursors, mediate neuropathic pain (45)(46)(47)(48). In a mouse model of chronic inflammation, oxidized linoleic acid-derived mediators increase in the central nervous system (49).…”

Oxaliplatin Causes Transient Changes in TRPM8 Channel Activity

“…Previously, we showed that oxaliplatin induced mechanical hypersensitivity 24 h after treatment [ 20 ]. For the current study, we first investigated whether the activity of the TRPM8 channel was altered in response to oxaliplatin treatment.…”

“…Viable neurons were identified by a short KCl stimulation at the end of each measurement, causing depolarization and activation of voltage-gated calcium channels. Previously, we could observe that the mRNA expressions of TRPV1 and TRPA1 were unchanged after oxaliplatin treatment [ 20 ]. We next investigated the mRNA expression levels of several other ion channels that have previously been connected with oxaliplatin-induced hypersensitivity [ 14 ].…”

“…Here, we investigate the activity of the ligand-gated calcium channels TRPV1, TRPA1, TRM8, TRPM3 and the purinergic receptor P2X3, a nucleotide-gated calcium-channel that is expressed in sensory neurons and that is known to contribute to chronic pain [ 19 ]. We found that the activity of TRPM8 but not of the other calcium channels was transiently increased 1 h after oxaliplatin treatment and decreased 24 h after oxaliplatin treatment, a timepoint at which mice show mechanical hypersensitivity [ 20 ]. This altered TRPM8 activity was not related to changes in the channel‘s gene expression.…”

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

“…As expected, this kind of response was lower in TRPM8 knockout (KO) mice. Lysophosphatidylcholine (LPC) 18:1 and LPC 16:0, which are over-expressed in oxaliplatin-induced peripheral neuropathy, have been identified as endogenous activators of TRPV1 and TRPM8 channels, suggesting that the modulation of lipid pathways could also serve to alleviate this neuropathy [142].…”