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

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

doi:10.1038/s41598-017-00591-0

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

Sci Rep. 2017 Mar 27;7(1):446. doi: 10.1038/s41598-017-00591-0.

Authors

Stephan W Hohmann¹, Carlo Angioni¹, Sorin Tunaru², Seungkyu Lee³, Clifford J Woolf³, Stefan Offermanns², Gerd Geisslinger^{1

4}, Klaus Scholich¹, Marco Sisignano⁵

Affiliations

¹ Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital, Goethe-University, D-60590, Frankfurt am Main, Germany.
² Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany.
³ F. M. Kirby Neurobiology Center, Children's Hospital Boston, and Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA.
⁴ Fraunhofer Institute for Molecular Biology and Applied Ecology - Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt am Main, Germany.
⁵ Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital, Goethe-University, D-60590, Frankfurt am Main, Germany. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Cycle Proteins / deficiency
Cell Cycle Proteins / metabolism*
Cyclic AMP-Dependent Protein Kinases / metabolism
Enzyme Activation / drug effects
Ganglia, Spinal / drug effects
Ganglia, Spinal / pathology
Hyperalgesia / chemically induced*
Hyperalgesia / metabolism*
Hyperalgesia / pathology
Linoleic Acids, Conjugated
Mice, Inbred C57BL
Neuralgia / chemically induced*
Neuralgia / metabolism*
Neuralgia / pathology
Organoplatinum Compounds / adverse effects*
Oxaliplatin
Protein Kinase C / metabolism
Receptors, G-Protein-Coupled / deficiency
Receptors, G-Protein-Coupled / metabolism*
Sciatic Nerve / drug effects
Sciatic Nerve / pathology
Sensory Receptor Cells / metabolism
TRPV Cation Channels / deficiency
TRPV Cation Channels / metabolism

Substances

Cell Cycle Proteins
G2A receptor
Linoleic Acids, Conjugated
Organoplatinum Compounds
Receptors, G-Protein-Coupled
TRPV Cation Channels
TRPV1 protein, mouse
Oxaliplatin
9-hydroxy-10,12-octadecadienoic acid
Cyclic AMP-Dependent Protein Kinases
Protein Kinase C

Abstract

Publication types

MeSH terms

Substances

Grants and funding