β-Caryophyllene inhibits monoacylglycerol lipase activity and increases 2-arachidonoyl glycerol levels in vivo: a new mechanism of endocannabinoid-mediated analgesia?
Mol Pharmacol. 2024 Jan 9:MOLPHARM-AR-2023-000668. doi: 10.1124/molpharm.123.000668. Online ahead of print.
ABSTRACT
Introduction. The mechanisms of BCP-induced analgesia are not well studied. Here, we tested the efficacy of BCP in an acute post-surgical pain model and evaluated its effect on the endocannabinoid system. Methods. Efficacy of BCP was tested in an acute postsurgical pain model. Rats were treated with vehicle, 10, 25, 50, and 75 mg/kg BCP. Paw withdrawal responses (PWR) to mechanical stimuli were evaluated using von Frey filaments. Results. Endocannabinoids including 2-arachidonoylglycerol (2-AG) were also evaluated in plasma and tissues using an HPLC-MS-based approach. Monoacylglycerol lipase (MAGL) activity was evaluated in vitro as well as ex vivo. We observed a dose-dependent and time-dependent alleviation of hyperalgesia in incised paws up to 85% of the baseline value at 30 minutes after administration of BCP. We also observed dose-dependent increase in the 2-AG levels of about 3-fold after administration of BCP as compared to vehicle controls. Incubations of spinal cord tissue homogenates from BCP-treated rats with isotope-labeled 2-arachidonoylglycerol-d8 revealed a significantly reduced formation of the isotope-labeled MAGL product 2-AG-d8 as compared to vehicle controls indicating MAGL enzyme inhibition. In vitro MAGL enzyme activity assessment using 2-AG as the substrate revealed an IC of 15.8 µM for MAGL inhibition using BCP. Conclusion. These data showed that BCP inhibits MAGL activity in vitro and in vivo causing 2-AG levels to rise. Since the endocannabinoid 2-AG is a CB1 and CB2 receptor agonist, we propose the 2-AG-mediated cannabinoid receptor activation may contribute to BCP’s mechanism of analgesia. Significance Statement In contrast to opioids or cannabinoids, BCP consumption is relatively safe and is approved the FDA as a flavoring agent, which can be used in cosmetic and food additives. BCP is a potent anti-inflammatory agent which showed excellent anti-hyperalgesic properties in this study of acute pain. Based on this BCP might be a valuable alternative to opioids. We show an additive mechanism (monoacylglycerol lipase inhibition) by which BCP might indirectly alter CB2 receptor activity and exhibit its pharmacological properties.
PMID:38195158 | DOI:10.1124/molpharm.123.000668