Antinociceptive Effect of Memantine and Morphine on Vincristine-induced Peripheral Neuropathy in Rats

Abstract

Background: Vincristine-induced peripheral neuropathy is a major dose limiting side effect and thus effective therapeutic strategy is required. In this study, we investigated the antinociceptive effect of memantine and morphine on a vincristine-induced peripheral neuropathy model in rats.

Methods: Male Sprague-Dawley rats weighing 220-240 g were used in all experiments. Rats subsequently received daily intraperitoneal injections of either vincristine sulfate (0.1 ml/kg/day) or saline (0.1 ml/kg/day) over 12 days, immediately following behavioral testing. For assessment of mechanical allodynia, mechanical stimuli using von Frey filament was applied to the paw to measure withdrawal threshold. The effects of N-methyl-D-aspartate receptors antagonist (memantine; 2.5, 5, 10 mg/kg intraperitoneal), opioid agonist (morphine; 2.5, 5, 10 mg/kg intraperitoneal) and vehicle (saline) on vicristine-induced neuropathy were evaluated.

Results: Mechanical allodynia developed over the course of ten daily injections of vincristine relative to groups receiving saline at the same time. Morphine abolished the reduction in paw withdrawal threshold compared to vehicle and produced dose-responsiveness. Only the highest dose of memantine (10 mg/kg) was able to increase paw withdrawal threshold compared to vehicle.

Conclusions: Systemic morphine and memantine have an antinociceptive effect on the vincristine-induced peripheral neuropathy model in rats. These results suggest morphine and memantine may be an alternative approach for the treatment of vincristine-induced peripheral neuropathic pain.

Keywords: antinociception; memantine; morphine; neuropathic pain; vincristine.

Fig. 1

Time course of hind paw withdrawal response to von Frey filaments after vincristine treatment. Data are presented as withdrawal threshold. Each line represents mean ± SEM of 8 rats. BL: baseline withdrawal threshold measured before vincristine treatment. Significant differences between saline (control) and vincristine treatment are indicated. ^*P < 0.05, ^†P < 0.01.

Fig. 2

Effects of intraperitoneal memantine for hindpaw withdrawal response to von Frey filaments after vincristine treatment. Data are presented as withdrawal threshold or percent of maximal possible effect (%MPE). Each line represents mean ± SEM of 6-7 rats. BL: baseline withdrawal threshold measured before vincristine treatment. Control data were measured immediately before intraperitoneal delivery of drug. Compared with vehicle (saline). ^*P < 0.01.

Fig. 3

Effects of intraperitoneal morphine for hindpaw withdrawal response to von Frey filaments after vincristine treatment. Data are presented as withdrawal threshold or percent of maximal possible effect (%MPE). Each line represents mean ± SEM of 6-7 rats. BL: baseline withdrawal threshold measured before vincristine treatment. Control data were measured immediately before intraperitoneal delivery of drug. Intraperitoneal morphine produced a dose-dependent increase in withdrawal threshold. Compared with vehicle (saline). ^*P < 0.05, ^†P < 0.01.