Transient receptor potential channel involvement in antinociceptive effect of citral in orofacial acute and chronic pain models.

This study aimed to test for the possible antinociceptive effect of the naturally occurring terpene citral in rodent models of acute and chronic orofacial pain and to test for the possible involvement of transient receptor potential (TRP) channels in this effect. Acute nociceptive behavior was induced in one series of experiments by administering formalin, cinnamaldehyde, menthol or capsaicin to the upper lip. Nociceptive behavior was assessed by orofacial rubbing, and the effects of pre-treatment with citral (0.1, 0.3 or 1.0 mg/Kg) or vehicle (control) were tested on the behavior. Nociceptive behavior was also induced by formalin injected into the temporomandibular joint or mustard oil injected into the masseter muscle, preceded by citral or vehicle (control) treatment. The chronic pain model involved infraorbital nerve transection (IONX) that induced mechanical hypersensitivity which was assessed by von Frey hair stimulation of the upper lip. Motor activity was also evaluated. Docking experiments were performed using TRPV1 and TRPM8 channels. Citral but not vehicle produced significant (p<0.01, ANOVA) antinociception on all the acute nociceptive behaviors, and these effects were attenuated by TRPV1 antagonist capsazepine, TRPM3 antagonist mefenamic acid and by TRPM8 desensitization, but not by ruthenium red and TRPA1 antagonist HC-030031. The IONX animals developed facial mechanical hypersensitivity that was significantly reduced by citral but not by vehicle. The docking experiments revealed that citral may interact with TRPV1 and TRPM8 channels. These results indicate the potential use of citral as an inhibitor of orofacial nociception in both acute and chronic pain states through TRPV1, TRPM3 and TRPM8 channels. See also Figure 1(Fig. 1).

Botulinum toxin promotes orofacial antinociception by modulating TRPV1 and NMDA receptors in adult zebrafish.

The aim of the study was to evaluate the possible involvement of transient receptor potential (TRP) channels, Acid-sensing ion channels (ASIC) and N-Methyl-D-aspartate receptor (NMDAR) in the orofacial antinociceptive behaviour effect of botulinum toxin type A (BoNT/A) in adult zebrafish. Initially, the open field test was performed to evaluate the effect of BoNT/A on the locomotor activity of zebrafish. Subsequently, the animals were pretreated with BoNT/A (0.05U, 0.1U or 0.5U/masseter) and acute orofacial nociception was induced by cinnamaldehyde, capsaicin, menthol, acid saline or glutamate applied to the lip or masseter muscle. In another group of experiments, animals were pre-treated with capsazepine (TRPV1 antagonist) or ketamine (NMDAR antagonist) to investigate the mechanism of antinociception. The possible involvement of central C-fibre afferents was also investigated using capsaicin desensitized animals. A molecular docking study was performed to observe the in silico interaction of BoNT/A with TRPV1 and NMDA channels. Pretreatment with BoNT/A reduced the nociceptive behaviour induced by capsaicin and glutamate. Antinociception was effectively inhibited by capsazepine and ketamine, as well as by capsaicin-induced desensitization. Consistent with these in vivo findings, the molecular docking study indicated that BoNT/A can interact with TRPV1 and NMDAR. The results indicate the involvement of TRP and NMDAR mechanisms in the orofacial antinociceptive behaviour effect of BoNT/A. The results also confirm the pharmacological relevance of BoNT/A as an inhibitor of orofacial nociception behaviour.

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.