Optimization and pharmacological characterization of a refined cisplatin-induced rat model of peripheral neuropathic pain.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting side-effect of many front-line anticancer drugs. This study was designed to establish and pharmacologically characterize a refined rat model of cisplatin-induced CIPN. Adult male Sprague-Dawley rats received four (n=18) or five (n=18) single intraperitoneal bolus doses of cisplatin at 3 mg/kg, or saline (control group), once-weekly. Body weight and general health were assessed over a 49-day study period. von Frey filaments and the Hargreaves test were used to define the time course for the development of mechanical allodynia and thermal hypoalgesia in the hindpaws and for efficacy assessment of analgesic/adjuvant agents. The general health of rats administered four cisplatin doses was superior to that of rats administered five doses. Mechanical allodynia was fully developed (paw withdrawal thresholds≤6 g) in the bilateral hindpaws from day 32 to 49 for both cisplatin dosing regimens. They also showed significant thermal hypoalgesia in the bilateral hindpaws. In cisplatin-treated rats with paw withdrawal thresholds of up to 6 g, single bolus doses of gabapentin and morphine produced dose-dependent analgesia, whereas meloxicam and amitriptyline lacked efficacy. We have established and pharmacologically characterized a refined rat model of CIPN that is suitable for efficacy profiling of compounds from analgesic discovery programmes.