Thermo-Sensitive TRP Channels: Novel Targets for Treating Chemotherapy-Induced Peripheral Pain

Abstract

Abnormal Ca²⁺ channel physiology, expression levels, and hypersensitivity to heat have been implicated in several pain states following treatment with chemotherapeutic agents. As members of the Ca²⁺ permeable transient receptor potential (TRP), five of the channels (TRPV1-4 and TRPM2) are activated by different heat temperatures, and two of the channels (TRPA1 and TRPM8) are activated by cold temperature. Accumulating evidences indicates that antagonists of TRPA1 and TRPM8 may protect against cisplatin, oxaliplatin, and paclitaxel-induced mitochondrial oxidative stress, inflammation, cold allodynia, and hyperalgesia. TRPV1 was responsible from the cisplatin-induced heat hyperalgesia and mechanical allodynia in the sensory neurons. TRPA1, TRPM8, and TRPV2 protein expression levels were mostly increased in the dorsal root (DRG) and trigeminal ganglia by these treatments. There is a debate on direct or oxaliplatin-induced oxidative cold stress dependent TRPA1 and TRPV4 activation in the DRG. Involvement of molecular pathways such as cysteine groups, glutathione metabolism, anandamide, cAMP, lipopolysaccharide, proteinase-activated receptor 2, and mitogen-activated protein kinase were also indicated in the oxaliplatin and paclitaxel-induced cold allodynia. In this review, we summarized results of five temperature-regulated TRP channels (TRPA1, TRPM8, TRPV1, TRPV2, and TRPV4) as novel targets for treating chemotherapy-induced peripheral pain.

Keywords: allodynia; chemotherapeutic agents; hyperalgesia; oxidative stress; thermo sensitive TRP channels.

Figure 1

Possible effects of cisplatin, oxaliplatin, and paclitaxel on thermo-TRP channels (TRPA1, TRPM8, TRPV1, TRPV2, and TRPV4) in the DRG neurons. Three chemotherapeutic agents (cisplatin, oxaliplatin, and paclitaxel) induce severe peripheral pain adverse effect in treatment of cancer patients. Reports on chemotherapy-induced pain in peripheral nerves were focused on five thermo-TRP channels (TRPA1, TRPM8, TRPV1, TRPV2, and TRPV4), because their expression levels are mostly high in the peripheral neurons. Activation of the five thermo-TRP channels by the cisplatin, oxaliplatin and paclitaxel lead to changes on levels of channel expression, channel sensitization, nociceptive behaviors, oxidative stress, mechanical, heat and cold hypersensitivity (Anand et al., ; Ta et al., ; Hara et al., 2013). In addition, the levels are induced by activation of some secondary molecular mechanisms such as glutathione (GSH) (Lee et al., 2017), proteinase-activated receptor 2 (PAR2) (Tian et al., 2015), cAMP (Anand et al., 2010), and Toll-like receptor 4 (TLR4) signaling (Meseguer et al., 2014).

Figure 2

Possible molecular pathways of cisplatin, oxaliplatin and paclitaxel on oxidative stress-dependent TRPA1 and TRPV4 activation in the DRG neurons. Cysteine groups are main target of oxidative stress in cellular membranes and membrane of TRPA1 has rich content of cysteine groups (Takahashi et al., 2011). TRPA1 and TRPV4 are oxidative stress-sensitive Ca²⁺-permeable channels. The cisplatin, oxaliplatin, and paclitaxel can results in augmented TRPA1 and TRPV4, leading to Ca²⁺ influx through direct channel activation or excessive production of oxidative stress and induction of apoptosis through depolarization of mitochondrial membranes. Overload Ca²⁺ influxes induce pain through substance P (SP) and excitatory amino acid production. Glutathione (GSH) is synthetized from cysteine redox cycle. Protective role of GSH on TRPA1 and TRPV4 through oxaliplatin and paclitaxel-induced oxidative stress in DRG neuron was reported (Materazzi et al., 2012). The molecular pathway may be a cause of chemotherapy-induced peripheral pain and this subject warrants further investigation.