TRPM3 as novel target to alleviate acute oxaliplatin-induced peripheral neuropathic pain

Abstract

ABSTRACTChemotherapy-induced peripheral neuropathic pain (CIPNP) is an adverse effect observed in up to 80% of cancer patients upon treatment with cytostatic drugs including paclitaxel and oxaliplatin. CIPNP can be so severe that it limits dose and choice of chemotherapy, and has a significant negative consequences on the quality of life of survivors. Current treatments for CIPNP are limited and unsatisfactory. TRPM3 is a Ca2+-permeable ion channel functionally expressed in peripheral sensory neurons involved in the detection of thermal stimuli. Here, we focus on the possible involvement of TRPM3 in acute oxaliplatin-induced mechanical allodynia and cold hypersensitivity. In vitro calcium microfluorimetry and whole-cell patch-clamp experiments showed that TRPM3 is functionally upregulated in both heterologous and homologous expression systems after acute (24h) oxaliplatin treatment, while direct application of oxaliplatin was without effect. In vivo behavioral studies using an acute oxaliplatin model for CIPNP showed the development of cold and mechano-hypersensitivity in control mice, which was lacking in TRPM3 deficient mice. In addition, the levels of pERK, a marker for neuronal activity, were significantly reduced in DRG neurons derived from TRPM3 deficient mice compared to control after oxaliplatin administration. Moreover, intraperitoneal injection of a TRPM3 antagonist, isosakuranetin, effectively reduced the oxaliplatin-induced pain behavior in response to cold and mechanical stimulation in mice with an acute form of oxaliplatin-induced peripheral neuropathy. In summary, TRPM3 thus represents a potential new target for the treatment of neuropathic pain in patients undergoing chemotherapy.