Front and hind paw differential analgesic effects of amitriptyline gabapentin ibuprofen and URB937 on mechanical and cold sensitivity in cisplatin-induced neuropathy

摘要

Cisplatin is a widely used platinum-derived antineoplastic agent that frequently results in peripheral neuropathy. Therapeutic strategies for neuropathic pain are limited and characterized by variable efficacy and severe adverse effects. Clinical translation of novel analgesics has proven difficult with many agents demonstrating preclinical efficacy failing in clinical trials. Preclinical studies frequently assess pain behaviors in the hind paws; however, the front paws have a greater degree of the fine sensorimotor functions characteristically damaged by chemotherapy-induced neuropathy. This is the first study to assess pain responses in the front paws. Here, we test the hypothesis that mouse front paws exhibit pain-related alterations in mechanical and thermal (cold) sensitivity in a murine model of cisplatin-induced neuropathy and that pharmacological treatment with amitriptyline, gabapentin, ibuprofen, and URB937 normalize pain behaviors in the front and hind paws. Cold (acetone withdrawal latencies) and mechanical (von Frey withdrawal thresholds) sensitivity were significantly increased and decreased respectively in both the front and the hind paws following initiation of weekly systemic (intraperitoneal) cisplatin injections (5 mg/kg). For the hind paws, systemic administration of amitriptyline (30 mg/kg), gabapentin (100 mg/kg), ibuprofen (0–10 mg/kg), or URB937 (0–10 mg/kg) resulted in a decrease in acetone withdrawal latencies and increase in von Frey withdrawal thresholds with return to normal values at the highest doses tested. For the front paws, return to baseline values for the highest doses was found for cold allodynia but not mechanical allodynia, where the highest doses failed to return to baseline values. These results indicate that mouse front paws exhibit pain-related changes in cisplatin-induced neuropathy and that drug effects can vary based on testing stimulus and location. This suggests that front paw responses across multiple modalities provide reliable and accurate information about pain-related drug effects. Future studies should be aimed at elucidating the mechanisms underlying these differential effects.