Oxaliplatin, which is widely used as chemotherapy for certain solid cancers, frequently causes peripheral neuropathy. Commonly described neuropathic symptoms include aberrant sensations such as mechanical allodynia (hypersensitivity to normally innocuous stimuli). Although oxaliplatin neuropathy is a dose‐limiting toxicity, there are no established preventive strategies available at present. By screening several sets of small‐molecule chemical libraries (more than 3,000 compounds in total) using a newly established in vitro high‐throughput phenotypic assay, we identified fulvestrant, a clinically approved drug for the treatment of breast cancer in postmenopausal women, as having a protective effect on oxaliplatin‐induced neuronal damage. Furthermore, histological and behavioural analyses using a rat model of oxaliplatin neuropathy demonstrated the in vivo efficacy of fulvestrant to prevent oxaliplatin‐induced axonal degeneration of the sciatic nerve and mechanical allodynia. Furthermore, fulvestrant did not interfere with oxaliplatin‐induced cytotoxicity against cancer cells. Thus, our findings reveal a previously unrecognised pharmacological effect of fulvestrant to prevent oxaliplatin‐induced painful peripheral neuropathy without impairing its cytotoxicity against cancer cells and may represent a novel prophylactic option for patients receiving oxaliplatin chemotherapy.

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The G-protein-coupled receptor MrgprA3 (MAS-related GPR family member A3) is expressed specifically in a subpopulation of dorsal root ganglion (DRG) sensory neurons. Recently, MrgprA3 + DRG neurons are identified as itch-selective neurons. While MrgprA3 responds to the anti-malaria drug chloroquine and causes strong itch, chloroquine requires high concentrations to activate MrgprA3 and also displays non-selective effects. Therefore, it is necessary to accurately evaluate the ability of MrgprA3 to cause itch sensation. In this study, we screened a series of small molecule compounds to search for agonists that activate MrgprA3 by high-throughput Ca 2+ imaging. We identified papaverine, an opium alkaloid, that specifically evoked Ca 2+ responses in cells expressing MrgprA3. Papaverine also increased Ca 2+ level in primary cultured DRG neurons that were responded to chloroquine. Furthermore, we found that intradermal injection of papaverine to the cheek produced scratching behavior but not wiping behavior in mice. Papaverine-evoked scratching was resistant to the histamine H1 receptor antagonist chlorpheniramine. We further found that intradermal papaverine caused phosphorylation of extracellular signalregulated kinases (ERK) in the superficial dorsal horn. Finally, we showed that mice lacking gastrin-releasing peptide receptors (GRPR) that are required for itch transmission in the spinal cord exhibited reduction of the papaverineevoked scratching compared with wild-type mice. In this study, we found that papaverine potently activates MrgprA3 and may cause itch sensation via activation of MrgprA3.