The Antiallodynic Effect of Nefopam on Vincristine-Induced Neuropathy in Mice

Abstract

Background: Chemotherapy-induced neuropathic pain is a disabling condition following cancer treatment. Vincristine has more neurotoxicity than other vinca alkaloid agents. This study evaluated the correlation of different doses of nefopam with antiallodynic effects in a mouse vincristine neuropathy model.

Methods: A peripheral neuropathic mouse model was made by intraperitoneal injection of vincristine (0.1 mg/kg/day; 5-day-on, 2-day-off schedule over 12 days). After the development of allodynia, mice were injected intraperitoneally with 0.9% normal saline (NS group) or various doses (10, 30, 60 mg/kg) of nefopam (Nefopam group). We examined allodynia using von Frey hairs pre-administration and at 30, 60, 90, 120, 180, 240 mins, and 24 hrs after drug administration. We also measured the neurokinin-1 receptor concentrations in the spinal cord to confirm the antiallodynic effect of nefopam after drug administration.

Results: The peripheral neuropathic mouse model showed prominent mechanical allodynia. Intraperitoneal nefopam produced a clear dose-dependent increase in paw withdrawal threshold compared with pre-administration values and versus the NS group. The concentration of neurokinin-1 receptor was significantly decreased in the Nefopam group (P<0.05).

Conclusion: Intraperitoneally administered nefopam yielded a dose-dependent attenuation of mechanical allodynia and decreased neurokinin-1 receptor concentration, suggesting that the neurokinin-1 receptor is involved in the antiallodynic effects of nefopam in vincristine neuropathy.

Keywords: allodynia; mice; nefopam; neurokinin-1; neuropathy; vincristine.

Figure 1

Time course of the paw withdrawal response to mechanical stimuli during vincristine treatment. The results are expressed as mean ± standard error of mean (n=6, in each group). **P<0.01, ***P<0.001, ****P<0.0001 significantly different from the saline group.

Figure 2

Effects of intraperitoneal nefopam on mechanical stimuli. The paw withdrawal threshold was measured before (Pre) and after intraperitoneal administration of normal saline (NS) and nefopam 10 mg/kg (Nefopam10), nefopam 30 mg/kg (Nefopam30), and nefopam 60 mg/kg (Nefopam60). The results are expressed as mean ± standard error of mean (n=6 in each group). ‡P<0.05 between the NS group and other groups, †P<0.05 between the NS and nefopam10 group, *P<0.05 between nefopam30 and the NS, nefopam10 group, §P<0.05 nefopam60 vs other groups.

Figure 3

Effects of intraperitoneal nefopam on NK1 receptors after vincristine-induced neuropathy. Immunohistochemistry showed that NK1 receptor binding components were elevated in vincristine-induced neuropathic mice. (A) Representative spinal cord stained for NK1 receptor in a control mouse. (B) Representative spinal cord stained for NK1 receptor in a vincristine-induced neuropathic mouse. (C) Representative spinal cord stained for NK1 receptor in a vincristine-induced neuropathic mouse after 60 mg/kg nefopam treatment. (D) The percentage of NK1 receptors in the spinal cord was significantly lower in 60 mg/kg nefopam-injected mice (Nefopam) compared to saline-injected mice (Vincristine) in vincristine-induced neuropathic mouse models. *P<0.05, **P<0.01.