The G2A receptor (GPR132) contributes to oxaliplatin-induced mechanical pain hypersensitivity

Stephan W Hohmann,Sorin Tunaru,Gerd Geisslinger,Seungkyu Lee,Stefan Offermanns,Klaus Scholich,Carlo Angioni,Clifford J Woolf,Marco Sisignano

doi:10.1038/s41598-017-00591-0

Abstract

Chemotherapy-induced peripheral neuropathic pain (CIPN) is a common and severe debilitating side effect of many widely used cytostatics. However, there is no approved pharmacological treatment for CIPN available. Among other substances, oxaliplatin causes CIPN in up to 80% of treated patients. Here, we report the involvement of the G-protein coupled receptor G2A (GPR132) in oxaliplatin-induced neuropathic pain in mice. We found that mice deficient in the G2A-receptor show decreased mechanical hypersensitivity after oxaliplatin treatment. Lipid ligands of G2A were found in increased concentrations in the sciatic nerve and dorsal root ganglia of oxaliplatin treated mice. Calcium imaging and patch-clamp experiments show that G2A activation sensitizes the ligand-gated ion channel TRPV1 in sensory neurons via activation of PKC. Based on these findings, we conclude that targeting G2A may be a promising approach to reduce oxaliplatin-induced TRPV1-sensitization and the hyperexcitability of sensory neurons and thereby to reduce pain in patients treated with this chemotherapeutic agent.

Highlights

Chemotherapy-induced peripheral neuropathic pain (CIPN) is a severe adverse event of cytostatic drugs during cancer therapy
Incubation with 9-hydroxyoctadecadienoic acids (HODEs) (200 nM, 120 s) before the second stimulus leads to an increased calcium flux compared to the first stimulus (Δratio)
Data are presented as mean ± SEM with n = 44–99 neurons per concentration; **p < 0.01 one-way ANOVA with Bonferroni post-hoc test. (C) 13-HODE (200 nM, 120 s) does not increase the Δratio of TRPV1-dependent calcium flux in DRG neurons (n = 30–83). (D) Sample trace of whole-cell voltage clamp measurement of DRG neurons treated with capsaicin

Summary

Introduction

Chemotherapy-induced peripheral neuropathic pain (CIPN) is a severe adverse event of cytostatic drugs during cancer therapy. Under pathophysiological conditions TRP channels are sensitized, which causes a reduction of their activation threshold and thereby increased sensitivity to painful (hyperalgesia) or normally non-painful (allodynia) stimuli[7] These sensitization effects on TRP channels can be mediated by the activation of G-protein coupled receptors (GPCRs). Increased sensitization of TRPV1, TRPA1 and TRPV4 have been demonstrated to contribute to mechanical hypersensitivity and cold allodynia in chemotherapy-induced peripheral neuropathic pain[10,11,12]. Treatment with cytostatics, such as oxaliplatin, induces sensitization mechanisms in the peripheral nervous system, leading to increased activity of peripheral sensory neurons and increased pain perception[1]. We hypothesize that treatment with oxaliplatin induces G2A-expression in peripheral sensory neurons and thereby contributes to sensitization of nociceptive neurons and subsequently to oxaliplatin-induced neuropathic pain

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Conclusion