Myrcene and terpene regulation of TRPV1

C Jansen,L.M.N Shimoda,J.K Kawakami,L Ang,A.J Bacani,J.D Baker,C Badowski,M Speck,A.J Stokes,A.L Small-Howard,H Turner

doi:10.1080/19336950.2019.1654347

C Jansen, L.M.N Shimoda + Show 9 more

Open Access

https://doi.org/10.1080/19336950.2019.1654347

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Abstract

ABSTRACTNociceptive 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 whole-cell 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 Imax 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 plant-derived 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.

Highlights

Components of plant secondary metabolomes have been used in traditional and indigenous medical systems for pain management for centuries
This study evaluated terpenes found in C. sativa for their effectiveness in activation of TRPV1
We found that while mixtures of terpenes were effective in eliciting large calcium influxes in a TRPV1-expression system, most of this activity was accounted for by two compounds, Myrcene and Nerolidol

Summary

Introduction

Components of plant secondary metabolomes have been used in traditional and indigenous medical systems for pain management for centuries. Examples include Chinese Traditional Medical System formulations, Japanese Kampo, African systems, indigenous Pacific and Oceanic systems and Indian Ayurveda [1,2,3]. Numerous countries have pluralized medical systems where these therapies are integrated to varying degrees with Western medical approaches[4], and they form significant components of medical care in economically disadvantaged countries by necessity [3,5]. The general relegation of these pharmacopeias to the nutraceutical market in the West has led to the dominance of the debate around “medical” marijuana as the primary plant-based medicine currently under scrutiny in the US and other Western countries for its efficacy and safety [8,9,10,11]. Pain is one of the most common indications for the use of Cannabis medicinally[12], and there is data supporting its efficacy and its potential as an opioid-sparing approach [13,14,15,16,17,18]

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