The antinociceptive effects of selective TRPV1 antagonist RCI002 against chemotherapy-induced peripheral neuropathy.

Abstract

e15111 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect experienced by cancer patients receiving chemotherapy. Recent reports showed that transient receptor potential (TRP) channels are involved in paclitaxel- or oxaliplatin-induced neuropathic pain. TRP vanilloid 1 (TRPV1) may contribute to the development of mechanical allodynia and thermal hyperalgesia after cisplatin or oxaliplatin treatment. Moreover, paclitaxel-induced behavioral hypersensitivity is prevented and reversed by administration of TRPV1 antagonists. RCI002 is a potent and selective TRPV1 antagonist, blocking capsaicin activation of the target, with a little affect pH or heat activation. We found that RCI002 relieves neuropathic pain by inhibiting TRPV1, an important nociceptor involved in pain signal transduction, and does not cause thermoregulation, a problem with existing TRPV1 antagonists. In this study, Calcium imaging and patch clamp were employed to examine effects of RCI002 on mouse dorsal root ganglion (DRG) neurons and HEK293t cells expressing TRPV1. We also investigated RCI002 associated paclitaxel-induced peripheral neuropathic pain using a rat model. Methods: Dorsal root ganglion (DRG) neurons and TRPV1-transfected human embryonic kidney-derived (HEK) 293 cells were used for calcium imaging or whole-cell patch-clamp recording. CIPN was induced by intraperitoneal administration of paclitaxel 2 mg/kg for 4 consecutive days using adult male Sprague-Dawley rats. RCI002 were administered intraperitoneal and the paw withdrawal thresholds were measured using von Frey filaments. Results: We previously showed that RCI002, a novel TRPV1 antagonist that could be referred to as a new class of TRPV1 modulators that produce a significant analgesic effect formalin-induced behavior and improved mechanical allodynia undergoing spinal nerve ligation(SNL) in rats without hyperthermic effect. In the present study, The selective TRPV1 inhibitor RCI002 impaired capsaicin-induced calcium influx in DRG neurons. hTRPV1 expressed in HEK293 cells mediated a hemin-induced calcium influx which was blocked by RCI002. Behavioral assessment using the von Frey filaments. SD rat that received paclitaxel developed mechanical hypersensitivity to Von Frey filament stimulations of their hindpaws. Paclitaxel-induced hypersensitivity inhibited by TRPV1 antagonist RCI002(RCI002 EC50 = 0.85mg/kg). RCI002 significantly increased the paw withdrawal threshold more than pregabalin in CIPN rats(Pregabalin EC50 = 14.77mg/kg). Conclusions: Our findings suggest that RCI002 may be a promising approach to reduce paclitaxel-induced hyperexcitability and thereby to reduce neuropathy pain.