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The Analgesic Potential of Terpenes in Neuropathic Pain: A Mouse Model

Published: 22/03/2024

Pain is reported as the most common reason for seeking medical attention worldwide. Furthermore, chronic pain has become a global epidemic affecting approximately 1 in 10 adults each year. Chronic neuropathic pain can be caused by injury or compression of nerves and can often be described as burning, pins and needles, or electric-shock-type pain. Despite such a high prevalence, there are limited treatment options for chronic neuropathic pain at present.

Cannabis and Chronic Pain

The use of cannabis for medicinal purposes can be traced back thousands of years to ancient Japanese and Chinese civilisations. Today, chronic pain remains the most commonly reported reason for medical cannabis use worldwide. In recent decades, research into various compounds isolated from the cannabis plant has provided promising insights into the way cannabinoids and terpenes interact with components of the endocannabinoid system which are involved in pain signalling and processing. While cannabinoids such as cannabidiol (CBD) and tetrahydrocannabinol (THC) remain among the most researched cannabis compounds, terpenes are also increasingly studied within the context of inflammation and pain.

Terpenes are aromatic polymer compounds found in a large number of plants. In a recent animal study of chronic neuropathic pain, researchers aimed to “systematically compare the effects of α-terpineol, β-caryophyllene, and γ-terpinene in the chronic constriction injury (CCI) neuropathic pain model and a test of acute antinociception, as well as for their potential to produce further CB1 receptor-mediated effects that could limit therapeutic potential.”

Design and Methods of the Study

The researchers used the chronic constriction injury (CCI) of the sciatic nerve mouse model to produce mechanical allodynia (a painful sensation caused by innocuous stimuli), assessed via the von Frey assay, as well as thermal hyperalgesia assessed via the hotplate assay. To examine the involvement of cannabinoid receptors (CB1R and CB2R) in the analgesic effects of terpenes, each terpene was tested in mice lacking functional CB1R or CB2R after CCI surgery.

A total of 192 mice were used across all experiments and were randomly assigned to either CCI or control group. A total of 78 male and female CB1R, CB2R, and matched wild-type control mice were used in CCI experiments. Surgery for the chronic constriction of the sciatic nerve was performed in mice who lacked CB1R and CB2R. Sham surgery, identical to CCI surgery but without loose nerve ligation was performed in the control group. After surgery, mechanical allodynia and thermal hyperalgesia were assessed, and responses were compared to pre-surgery thresholds. In the CCI experiments, mice were tested with a compound or vehicle between 5 and 18 days after surgery.

Results of the Study

All three terpenes were seen to produce a dose-related and time-dependent reversal of CCI-induced mechanical allodynia and thermal hyperalgesia in both male and female mice. α-terpineol, β-caryophyllene, and γ-terpinene showed slightly greater potency in the reversal of thermal hyperalgesia compared with mechanical allodynia.

The terpenes also demonstrated a dose-dependent reversal of CCI-induced mechanical allodynia in both CB1R and CB2R mice. The results indicated that both CB1R and CB2R play a role in the capacity of α-terpineol to reverse CCI-induced mechanical allodynia. It was also confirmed that β-caryophyllene has activity as a CB2R agonist. However, the findings of the study indicate that CB1R, but not CB2R, may play a functional role in γ-terpinene biological activity.

The researchers also examined each terpene for their effects against acute pain transmission, hypolocomotion, and hypothermia. They found that α-terpineol significantly lowered locomotion at the two highest doses tested; however, it did not produce an appreciable reduction in pain signalling in response to a painful heat sensation in the absence of CCI and did not decrease body temperature. Both β-caryophyllene and γ-terpinene produced small but significant effects in response to a painful heat stimulus in the absence of CCI, as well as decreases in body temperature and locomotion. This suggests that each terpene may possess cannabinoid receptor activity; however, they also likely act at other receptors to exert physiological and biological activity


The results of this study indicate that α-terpineol, β-caryophyllene, and γ-terpinene may have cannabinoid receptor activity which is relevant in the context of chronic neuropathic pain. All three terpenes demonstrated a strong dose-dependent reversal of mechanical allodynia and thermal hyperalgesia. This suggests a potential therapeutic role for terpenes in neuropathic pain; however, more research is needed.

The researchers conclude that further studies examining these terpenes in “different models of neuropathic pain, additional determination of specific receptor signalling pathways, as well as different routes of administration and dosing paradigms are needed.”

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