Viphyllin(TM), a Standardized Black Pepper Seed Extract Exerts Antinociceptive Effects in Murine Pain Models via Activation of Cannabinoid Receptor CB2, Peroxisome Proliferator-Activated Receptor-Alpha and TRPV1 Ion Channels

PURPOSE: Plant-based natural products as anti-nociceptors have enormous potential as safer alternatives to conventional opiates and NSAIDS. Piper nigrum (black pepper) is one of the major culinary spices with medicinal attributes. METHODS: In the present study, the antinociceptive activity of a standardized black pepper seed extract (Viphyllin) containing not less than 30% β-caryophyllene (BCP) was evaluated using pain models in mice, namely acetic acid-induced writhing test, formalin-induced paw licking test, hot plate test and tail flick test. Further, the antagonists SR141716A (0.1 mg/kg i.p.), AM630 (5 mg/kg i.p.), capsazepine (0.1 mg/kg body weight i.p.), and GW6471 (1 mg/kg i.p.) were used to evaluate the involvement of cannabinoid receptors CB1 and CB2, TRPV1 ion channel and PPARα receptor, respectively. Molecular docking (AutoDock 4.2) was used to study the interaction of BCP with the agonist-binding sites of the selected pain receptors. RESULTS: Viphyllin at 10 mg, 25 mg and 50 mg/kg (i.p.) significantly inhibited the writhings in mice as compared to untreated control group (p < 0.001). Further, Viphyllin at 50 mg/kg showed strong antinociceptive effect in formalin-induced paw licking test (p < 0.05). Pretreatment of mice with AM630 significantly reversed the antinociceptive activity of Viphyllin in both early and late phases of formalin test (p < 0.05). Administration of Viphyllin markedly increased the latency time of mice in hot plate test (p < 0.001). Further, Viphyllin markedly increased the latency time of tail flick compared to control group from 30 min to 90 min after treatment. AM630, Capsazepine, and GW6471 abolished the analgesic effect of Viphyllin. These findings clearly suggest the involvement of CB2 receptor, TRPV1 ion channel and PPARα receptor activation in Viphyllin-mediated antinociceptive activity. Docking score predictions further supported the possible involvement of BCP in the antinociceptive mechanism of Viphyllin. CONCLUSION: In conclusion, Viphyllin could be a natural pain-relieving agent involving safer pain signaling mechanisms, unlike conventional opiates and NSAIDs.