Plant Cannabinoids Activate Pain-Sensing Ion Channels Beyond the Known CB1 and CB2 Receptors | Research

The takeaway

Six plant cannabinoids activated TRPA1 channels (with CBC being the most potent at nanomolar concentrations) and blocked TRPM8 cold-sensing channels, revealing non-cannabinoid-receptor mechanisms for pain modulation.

Read this if you want to understand how cannabis compounds might relieve pain through mechanisms beyond the traditional cannabinoid receptors.

CBC activated pain-sensing TRPA1 channels at just 60 nanomolar, the most potent of all cannabinoids tested

What the researchers found

Researchers tested six plant cannabinoids (CBD, THC, CBD acid, THC acid, cannabichromene/CBC, and cannabigerol/CBG) on two ion channels involved in pain sensing: TRPA1 and TRPM8.

All six cannabinoids activated TRPA1 channels (which detect chemical irritants and contribute to inflammatory pain). CBC was by far the most potent, with an EC50 of just 60 nanomolar, making it more potent than mustard oil, the standard TRPA1 activator. CBG and CBD acid were the least potent.

For TRPM8 (the cold-sensing channel linked to menthol and icilin sensitivity), all cannabinoids except CBC blocked the channel's activation. CBD, CBG, THC, and THC acid were equipotent blockers at 70-160 nanomolar.

These findings demonstrated that cannabinoids interact with ion channels completely separate from the CB1 and CB2 cannabinoid receptors, potentially explaining some of cannabis's pain-relieving and anti-cancer effects.

Why it matters

This study revealed that plant cannabinoids act on pain-related ion channels (TRP channels) at very low concentrations, independent of the traditional CB1/CB2 receptor system. This provides a molecular explanation for some of cannabis's analgesic effects that couldn't be explained by cannabinoid receptor activity alone.

The numbers in context

TRPA1 activation: CBC EC50 = 60 nM (most potent), CBG/CBD acid EC50 = 3.4-12 micromolar. TRPM8 blockade: CBD, CBG, THC, THC acid IC50 = 70-160 nM. CBC did not block TRPM8.

How the study worked

Researchers used HEK-293 cells overexpressing TRPA1 or TRPM8 channels and measured intracellular calcium responses. Results were confirmed in rat dorsal root ganglia (DRG) sensory neurons that naturally express these channels. Six phytocannabinoids were tested across concentration ranges.

What this study cannot tell us

Cell line overexpression systems may not reflect natural channel density or behavior. DRG neuron results showed lower potency than the cell line results. The study examined isolated channels, not the complex pain processing of whole organisms.

How to read the evidence

This is a well-designed in vitro study with confirmation in primary neurons, providing moderate mechanistic evidence for cannabinoid-TRP channel interactions.

When this study was published

Published in 2008. TRP channels are now widely recognized as cannabinoid targets, and this study is frequently cited in the cannabinoid pharmacology literature.

The bigger picture

This study expanded the understanding of how cannabinoids work beyond CB1 and CB2 receptors. TRP channels are now recognized as important cannabinoid targets, and this has influenced drug development efforts targeting these channels for pain and other conditions.

Questions still open

Could CBC-based preparations be developed as TRPA1-targeted pain medications? Does TRPM8 blockade by cannabinoids explain any of cannabis's subjective effects? Do these TRP channel interactions contribute to cannabis's anti-cancer properties?

Common questions

What is CBC?

Cannabichromene (CBC) is a non-psychoactive cannabinoid found in cannabis. It's less well-known than THC or CBD but was the most potent activator of TRPA1 pain channels in this study.

What are TRP channels?

Transient receptor potential (TRP) channels are ion channels that detect temperature, chemicals, and pressure. TRPA1 senses irritants and contributes to inflammatory pain; TRPM8 senses cold and is activated by menthol.

Read the original research

Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8.

The Journal of pharmacology and experimental therapeutics, 325(3), 1007-15

View on PubMed ↗Publisher’s paper ↗

Citation

De Petrocellis, Luciano; Vellani, Vittorio; Schiano-Moriello, Aniello; Marini, Pietro; Magherini, Pier Cosimo; Orlando, Pierangelo; Di Marzo, Vincenzo. (2008). Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8.. The Journal of pharmacology and experimental therapeutics, 325(3), 1007-15. https://doi.org/10.1124/jpet.107.134809