Interaction of the synthetic cannabinoid WIN55212 with tramadol on nociceptive thresholds and core body temperature in a chemotherapy-induced peripheral neuropathy pain model

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant adverse effect of many anticancer drugs. Current strategies for the management of CIPN pain are still largely unmet. The aim of this study is to investigate the antinociceptive potential of combining tramadol with the synthetic cannabinoid WIN55212, and to evaluate their associated adverse effects, separately or in combination, in a CIPN rat model, and to investigate their ability to modulate the transient receptor potential vanilloid 1 (TRPV1) receptor activity. Von Frey filaments were used to determine the paw withdrawal threshold in adult male Sprague–Dawley rats (200–250 g) following intraperitoneal (i.p) injection of cisplatin. Single cell ratiometric calcium imaging was used to investigate WIN55212/tramadol combination ability to modulate the TRPV1 receptor activity. Both tramadol and WIN55212 produced dose-dependent antinociceptive effect when administered separately. The lower dose of tramadol (1 mg/kg) significantly enhanced the antinociceptive effects of WIN55212 without interfering with core body temperature. Mechanistically, capsaicin (100 nM) produced a robust increase in [Ca2+]i in dorsal root ganglia (DRG) neurons ex vivo. Capsaicin-evoked calcium responses were significantly reduced upon pre-incubation of DRG neurons with only the highest concentration of tramadol (10 µM), but not with WIN55212 at any concentration (0.1, 1 and 10 µM). However, combining sub-effective doses of WIN55212 (1 µM) and tramadol (0.1 µM) produced a significant inhibition of capsaicin-evoked calcium responses. Combining WIN55212 with tramadol shows better antinociceptive effects with no increased risk of hypothermia, and provides a potential pain management strategy for CIPN.