Orofacial Antinociceptive Effect of Nifedipine in Rodents Is Mediated by TRPM3, TRPA1, and NMDA Processes

Aims: Totest forthe possible antinociceptive effect of nifedipine in rodent models of acute and chronic neuropathic orofacial pain and the possible involvement of TRP- and NMDA-related processes in this effect. Methods: Acute nociceptive behavior was induced by administering formalin, cinnamaldehyde, glutamate, capsaicin, or acidified saline to the upper lip or hypertonic saline to the cornea of Swiss mice. Acute nociceptive behavior was also induced by formalin injected into the TMJ or mustard oil injected into the masseter muscle of Wistar rats. The chronic pain model involved infraorbital nerve transection (IONX) in Wistar rats to induce mechanical hypersensitivity, which was assessed with von Frey hair stimulation of the upper lip. The effects of pretreatment with nifedipine or vehicle (control) were tested on the nociceptive behaviors. Docking experiments were also performed. Statistical analysis included one-way ANOVA followed by Tukey post hoc test and two-way ANOVA followed by Bonferroni post hoc test (statistical significance P < .05). Results: Nifedipine produced significant antinociceptive effects in all of the acute nociceptive behaviors except that induced by capsaicin. The antinociceptive effects were attenuated by NMDA, TRPA1, or TRPM3 receptor antagonists. The IONX animals developed facial mechanical hypersensitivity, which was significantly reduced by nifedipine. The docking experiments suggested that nifedipine may interact with TRPM3 and NMDA receptors. Conclusion: The present study has provided novel findings in a variety of acute and chronic orofacial pain models showing that nifedipine, a selective inhibitor of L-type Ca2+ channels, can suppress orofacial nociceptive behavior through NMDA, TRPA1, and TRPM3 receptor systems.