The Effects of URB597 in a Model of Cisplatin-Induced Hyperalgesia

Objectives: Cisplatin is a widely used chemotherapeutic drug with dose-limiting side effects such as peripheral neuropathy, neurotoxicity, and neuropathic pain. These detrimental effects are attenuated by the endocannabinoid anandamide (AEA), which is rapidly degraded in the body. AEA degradation is inhibited by the synthetic compound URB597. The goal of this study was to evaluate the behavioral and neuromorphological changes in URB597-treated mice in a model of cisplatin-induced hyperalgesia.

Methods: Adult, male mice (n=12) were divided into equal groups and treated with cisplatin alone, cisplatin + URB597, or vehicle alone. A von Frey monofilament of 0.6 g was administered ten times to the plantar surface of each hind paw and sudden withdrawal responses were counted. At the end of the experiment, mice were perfused and peripheral nerve tissue was collected for immunohistochemical analysis. Tissues were incubated in primary antibodies rabbit anti-ATF-3 and mouse anti-OX-42 and total number of affected neurons was recorded.

Results: There were no differences in the number of withdrawal responses in mice treated with vehicle (t = 1.241, p = 1.0, Bonferroni test) or cisplatin+URB597 (t = 2.009, p = 0.331, Bonferroni t-test). Cisplatin-treated mice exhibited a greater number of withdrawal responses compared to vehicle-treated and cisplatin+URB597-treated mice beginning after the fourth injection (t = 4.544, p < .001, two-way ANOVA). Immunohistochemical analysis indicated a difference in the number of ATF-3 labeled cells between cisplatin-treated tissue and vehicle-treated tissue (Q = 3.968, p < .05, Dunn’s multiple comparisons test) and between cisplatin-treated tissue and cisplatin+URB597-treated tissue (Q = 3.480, p < .05). No differences were observed between cisplatin+URB597-treated tissue and vehicle-treated tissue (Q = 0.796).

Conclusions: These studies demonstrate that URB597 attenuates cisplatin-produced neuropathic pain and neurotoxicity. These and future studies on URB597 may enable its use in clinical settings.

Supported by the UMSOD Summer Fellowship program