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

AIMS: To test for the 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.

Neuropharmacological characterization of frutalin in mice: Evidence of an antidepressant-like effect mediated by the NMDA receptor/NO/cGMP pathway.

In this study we evaluated the effect of frutalin (FTL) on mouse behavior. Mice (n=6/group) were treated (i.p.) with FTL (0.25; 0.5 or 1mg/kg) or vehicle and submitted to several tests (hole-board/HBT, elevated plus maze/PMT, open field/OFT, tail suspension/TST, or forced swimming/FST). Yohimbine, ketamine, l-NAME, aminoguanidine, 7-NI, methylene blue, l-arginine or dl-serine was administered 30min before FTL (0.5mg/kg). To evaluate the subchronic effect, animals were injected with FTL or vehicle for 7days and submitted to the FST. Molecular docking was simulated using FTL against NOS and the NMDA receptor. No changes were observed in the HBT or the OFT. FTL (0.25mg/kg) increased the number of entries into enclosed arms in the PMT. FTL reduced immobility in the TST (0.25 and 0.5mg/kg) and the FST (0.25mg/kg; 0.5mg/kg). The effect of FTL was dependent on carbohydrate interaction and protein structure integrity and was reduced by ketamine, l-NAME, aminoguanidine, 7-NI and methylene blue, but not by l-arginine, yohimbine or dl-serine. The antidepressant-like effect remained after subchronic treatment. The molecular docking study revealed a strong interaction between FTL and NOS and NMDA. FTL was found to have an antidepressant-like effect mediated by the NMDA receptor/NO/cGMP pathway.

Acute and neuropathic orofacial antinociceptive effect of eucalyptol.

Terpenes have a wide range of pharmacological properties, including antinociceptive action. The anti-inflammatory and antinociceptive effects of eucalyptol are well established. The purpose of this study was to evaluate the antinociceptive effect of eucalyptol on acute and neuropathic orofacial pain in rodent models. Acute orofacial and corneal nociception was induced with formalin, capsaicin, glutamate and hypertonic saline in mice. In another series, animals were pretreated with capsazepine or ruthenium red to evaluate the involvement of TRPV1 receptors in the effect of eucalyptol. In a separate experiment, perinasal tissue levels of IL-1ß, TNF-α and IFN-γ were measured. Rats were pretreated with eucalyptol before induction of temporomandibular joint pain with formalin or mustard oil. In another experiment, rats were submitted to infraorbital nerve transection (IONX) to induce chronic pain, followed by induction of mechanical hypersensitivity using Von Frey hairs. Locomotor performance was evaluated with the open-field test, and molecular docking was conducted on the TRPV1 channel. Pretreatment with eucalyptol significantly reduced formalin-induced nociceptive behaviors in all mouse strains, but response was more homogenous in the Swiss strain. Eucalyptol produced antinociceptive effects in all tests. The effect was sensitive to capsazepine but not to ruthenium red. Moreover, eucalyptol significantly reduced IFN-γ levels. Matching the results of the experiment in vivo, the docking study indicated an interaction between eucalyptol and TRPV1. No locomotor activity changes were observed. Our study shows that eucalyptol may be a clinically relevant aid in the treatment of orofacial pain, possibly by acting as a TRPV1 channel antagonist.