EFFECT OF DIFELIKAFALIN (CR845), A PERIPHERALLY ACTING Κ-OPIOID RECEPTOR AGONIST, ON CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY IN MICE

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse side effect of cytotoxic anticancer drugs. We have reported that CIPN development involves extracellular release of high mobility group box 1 (HMGB1), a nuclear protein, and activation of its membrane receptors including the receptor for advanced glycation end-products (RAGE), and that taxanes (e.g., paclitaxel and docetaxel) and platinum drugs (e.g., oxaliplatin) cause HMGB1 release from different cells, i.e., macrophages (Mφ) and non-Mφ cells, respectively. Given that opioids alleviate Mφ activity, we tested whether difelikefalin (CR845), a peripherally acting κ-opioid receptor agonist, would prevent CIPN in mice. Considering the recent evidence for androgen suppression of C-fiber excitability, we also examined the impact of castration on CIPN caused by docetaxel, which is used to treat castration-resistant prostate cancer (CRPC), and then evaluated the efficacy of CR845. Paclitaxel (4 mg/kg), oxaliplatin (1 mg/kg) or docetaxel (1 mg/ kg) was repeatedly administered i.p. to male mice to cause CIPN, as evaluated by von Frey test. Repeated administration of CR845 (0.1 mg/kg) prevented CIPN caused by paclitaxel, but not oxaliplatin, although CIPN by oxaliplatin was prevented by azeliragon (30 mg/kg), a RAGE inhibitor. The mice castrated by degarelix, a GnRH receptor antagonist, or orchiectomy showed CIPN after treatment with docetaxel even at subeffective doses, which was prevented by CR845. Collectively, CR845 is capable of preventing Mφ-dependent CIPN caused by taxanes. Androgen decline by castration is considered to aggravate CIPN caused by docetaxel, and CR845 is particularly useful to prevent severe CIPN in docetaxel-treated men with CRPC.