Cannflavins isolated from Cannabis sativa impede Caenorhabditis elegans response to noxious heat.

Cannflavins, flavonoids abundantly present in Cannabis sativa, possess a distinct chemical structure comprising a vanillyl group. Notably, the capsaicin structure also contains a vanillyl group, which is considered essential for interacting with the vanilloid receptor. The vanilloid receptor plays a crucial role in the perception of pain, heat, and inflammation and mediates the analgesic effects of capsaicin. Therefore, we postulated that prolonged exposure to cannflavin A (Can A) and cannflavin B (Can B) would provoke vanilloid receptor desensitization and hinder nocifensive responses to noxious thermal stimuli. C. elegans wild-type (N2) and mutants were exposed to Can A and Can B solutions for 60 min and then aliquoted on Petri dishes divided into quadrants for thermal stimulation. We then determined the thermal avoidance index for each C. elegans experimental group. Proteomics was performed to identify proteins and pathways associated with Can A or B treatment. Prolonged exposure to Can A and Can B hindered heat avoidance (32-35 °C) in C. elegans. No antinociceptive effect was observed 6 h post Can A or B exposure. Proteomics and Reactome pathway enrichment analyses identified hierarchical differences between Can A- and B-treated nematodes. However, both treatments were related to eukaryotic translation initiation (R-CEL-72613) and metabolic processes strongly associated with pain development. Our study aids in characterizing the pharmacological activity of cannflavins isolated from Cannabis sativa and outlines a possible application as pain therapy.

Cannabidiol and Tetrahydrocannabinol Antinociceptive Activity is Mediated by Distinct Receptors in Caenorhabditis elegans.

Cannabis has gained popularity in recent years as a substitute treatment for pain following the risks of typical treatments uncovered by the opioid crisis. The active ingredients frequently associated with pain-relieving effects are the phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), but their effectiveness and mechanisms of action are still under research. In this study, we used Caenorhabditis elegans, an ideal model organism for the study of nociception that expresses mammal ortholog cannabinoid (NPR-19 and NPR-32) and vanilloid (OSM-9 and OCR-2) receptors. Here, we evaluated the antinociceptive activity of THC and CBD, identifying receptor targets and several metabolic pathways activated following exposure to these molecules. The thermal avoidance index was used to phenotype each tested C. elegans experimental group. The data revealed for the first time that THC and CBD decreases the nocifensive response of C. elegans to noxious heat (32-35 °C). The effect was reversed 6 h post- CBD exposure but not for THC. Further investigations using specific mutants revealed CBD and THC are targeting different systems, namely the vanilloid and cannabinoid systems, respectively. Proteomic analysis revealed differences following Reactome pathways and gene ontology biological process database enrichment analyses between CBD or THC-treated nematodes and provided insights into potential targets for future drug development.