Myrcene and terpene regulation of TRPV1

Abstract

Nociceptive Transient Receptor Potential channels such as TRPV1 are targets for treating pain. Both antagonism and agonism of TRP channels can promote analgesia, through inactivation and chronic desensitization. Since plant-derived mixtures of cannabinoids and the Cannabis component myrcene have been suggested as pain therapeutics, we screened terpenes found in Cannabis for activity at TRPV1. We used inducible expression of TRPV1 to examine TRPV1-dependency of terpene-induced calcium flux responses. Terpenes contribute differentially to calcium fluxes via TRPV1 induced by Cannabis-mimetic cannabinoid/terpenoid mixtures. Myrcene dominates the TRPV1-mediated calcium responses seen with terpenoid mixtures. Myrcene-induced calcium influx is inhibited by the TRPV1 inhibitor capsazepine and Myrcene elicits TRPV1 currents in the wholecell patch-clamp configuration. TRPV1 currents are highly sensitive to internal calcium. When Myrcene currents are evoked, they are distinct from capsaicin responses on the basis of I max and their lack of shift to a pore-dilated state. Myrcene pre-application and residency at TRPV1 appears to negatively impact subsequent responses to TRPV1 ligands such as Cannabidiol, indicating allosteric modulation and possible competition by Myrcene. Molecular docking studies suggest a non-covalent interaction site for Myrcene in TRPV1 and identifies key residues that form partially overlapping Myrcene and Cannabidiol binding sites. We identify several non-Cannabis plantderived sources of Myrcene and other compounds targeting nociceptive TRPs using a data mining approach focused on analgesics suggested by non-Western Traditional Medical Systems. These data establish TRPV1 as a target of Myrcene and suggest the therapeutic potential of analgesic formulations containing Myrcene.

Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Actions of Phytocannabinoids or Endocannabinoids on TRPA1 and TRPV1 Channels

“…However, that the phytocannabinoids failed to activate hTRPV1 here is contrary to the existing literature. 16,25,35,36 For example, CBD has been shown to be a TRPV1 channel agonist with potencies between 1 and 30 lM, but in our study CBD did not activate hTRPV1 cells at a 30 lM concentration. 16,25 There are numerous differences in assay conditions that may help explain the discrepant findings, including differences in expression levels of TRPV1, which may render other systems more sensitive to the effects of cannabinoids.…”

“…16,25 There are numerous differences in assay conditions that may help explain the discrepant findings, including differences in expression levels of TRPV1, which may render other systems more sensitive to the effects of cannabinoids. 16,25,35,36 Differences in the method utilized to measure changes in intracellular calcium, the temperature at which the experiments were performed, and the concentration of solvents might also contribute to the discordant findings. [37][38][39] The present study is limited to assessing terpenoid and cannabinoid interactions in a HEK cell tetracyclineregulated expression system.…”

Terpenes/Terpenoids in <b><i>Cannabis</i></b>: Are They Important?

“…Myrcene is simply the important monoterpene in the plant. Myrcene has antipsychotic, antioxidant, analgesic, anti-inflammatory, sedative, muscle relaxant, and anticancerogenic properties [53][54][55][56]. The most important sesquiterpene in the cannabis plant is probably β-caryophyllene.…”

A Review of Hemp as Food and Nutritional Supplement

“…41 In vitro studies also suggest that b-myrcene may be useful to treat pain through interaction with transient receptor potential cation channel subfamily V member 1 (TRPV1) channels. 42 Limonene may exert antiallergic activity.…”