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How do Terpenes Affect Pain Transmission?

Published: 22/11/2023

Cannabis Sativa is a complex plant containing hundreds of active components, including cannabinoids, terpenes, flavonoids and more. Medical cannabis research, primarily into cannabidiol (CBD) and tetrahydrocannabinol (THC) – the two most abundant cannabinoids – has increased in recent years into conditions such as chronic pain, fibromyalgia, and insomnia. However, cannabinoids are not the only cannabis compounds that are being investigated for potential therapeutic properties.

Terpenes, which are produced in small and varying amounts in Cannabis Sativa and many other plants have biological properties of their own. For example, some terpenes including limonene, phytol, borneol, terpineol, and caryophyllene, have already been found to affect pain transmission in pre-clinical models of chronic pain.

In many cases, the mechanisms associated with the effects of terpenes are not fully understood. Some studies have revealed that some terpenes are able to elicit some cannabimimetic effects via cannabinoid receptors while others do so independently of these receptors. For example, camphene and α-bisabolol have been seen to inhibit inflammatory and neuropathic pain transmission via Cav3.2 T-type calcium channels in mice. In ascertaining a mechanism of action, previous studies described terpene activity at CB1 or CB2 receptors, whilst others reported an absence of a modulatory effect of terpenes on endocannabinoids or phytocannabinoids in TRPV1 and TRPA1 transfected HEK cells.

The authors of a recent study from Imperial College London and Curaleaf International examined the potential antinociceptive effects of ten terpenes on capsaicin responses in an established model of neuronal hypersensitivity.

Design and Methods of the Study

Ten different terpenes (borneol, caryophyllene, limonene, α-phellandrene, phytol, α-pinene, nerolidol, terpinolene, myrcene and α-terpineol) were assessed for their effects on calcium influx in sensory neurons, and in modulating their responses to a noxious stimulus using capsaicin – an active ingredient found in chilli peppers that produces a burning-type pain sensation. The effects of capsaicin are specifically mediated via activation of the transient receptor potential vanilloid subtype 1 (TRPV1) channel expressed in small nociceptive primary sensory neurons of the dorsal root ganglia (DRG). The expression and sensitivity of TRPV1 is enhanced by the neurotrophic factors in rodent and human DRG neurons.

In the present study, the researchers used an in vitro model of neuronal hypersensitivity to determine the effects of terpenes on TRPV1 signalling in rat DRG neurons.

Results of the Study

After the establishment of a stable baseline, individual terpenes or 0.1% ethanol (vehicle) were applied at different concentrations (0.001, 0.01, 0.1, 1, 10 and 100 µM), followed five minutes later by 1 µM capsaicin.

None of the ten terpenes elicited calcium influx and baseline changes were rarely observed following application. In the presence of the terpenes, capsaicin responses were completely inhibited for 6-8 minutes in most capsaicin-sensitive neurons. This effect was not dose dependent.

The baseline remained unchanged for 6-8 minutes following the application of capsaicin; this was followed by increased calcium levels in a subset of capsaicin sensitive neurons. Some neurons demonstrated immediate capsaicin responses that were transient, followed by a second increase in calcium after 6-8 minutes, and very few neurons demonstrated similar responses to vehicle-treated controls. Except for borneol and limonene, a large proportion of capsaicin sensitive neurons showed complete inhibition in the presence of all terpenes.

The researchers examined the mechanism of the inhibitory effects of the terpenes. They found that the terpene-mediated capsaicin response inhibition is reversible.

Following washout of medium and 45-minute recovery, terpene application in calcium- and magnesium-free Hank’s Balanced Salt Solution and 200 µM egtazic acid, also resulted in delayed capsaicin responses. The findings suggest that the delayed capsaicin responses were due to calcium release from the endoplasmic reticulum, while calcium influx was completely blocked in the presence of terpenes in most capsaicin sensitive neurons.

The authors noted that terpene mediated TRPV1 inhibition did not involve CB1 or CB2 cannabinoid receptors, as both the CB1 antagonist SR141716 and the CB2 receptor antagonist AM630 did not change the inhibitory effects of the terpenes. This suggests that terpenes can mediate TRPV1 inhibitory effects independently of cannabinoid receptors.

Terpene inhibition of TRPV1 was reversed in the presence of a sodium/potassium (Na+/K+) ATPase inhibitor, indicating that the terpenes activated the Na+/K+ ATPase, an intrinsic enzyme in the plasma membrane, which is responsible for the coupled active transport of sodium and potassium in most eukaryotic cells. The terpene activation of the Na+/K+ ATPase could potentially lead to hyperpolarization and neuronal inhibition, which is likely to affect other receptors, such as TRPA1 and TRPM8.

The results presented in this study indicate that terpenes have similar effects of inhibiting neuronal activation by activating Na+/K+ ATPase. This is a novel finding that hasn’t previously been described in the literature.

To conclude, the findings of this study show that terpenes are inhibitors of pain signalling via Na+/K+ ATPase. The researchers suggest that future studies to assay Na+/K+ ATPase activation by terpenes should be useful in providing an estimate of their potency and efficacy in this setting.

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