Evaluation of the Terpenes β‐caryophyllene, α‐terpineol, and γ‐terpinene in the Mouse Chronic Constriction Injury Model of Neuropathic Pain: Possible Cannabinoid Receptor Involvement

Abstract

Pain is one of the most common reasons to seek medical attention and chronic pain is a worldwide epidemic. Anecdotal reports suggest cannabis may be an effective analgesic. As cannabis contains the terpenes α-terpineol, β-caryophyllene, and γ-terpinene we hypothesized these terpenes would produce analgesia in a mouse model of neuropathic pain. We used the chronic constriction injury of the sciatic nerve mouse model, which produces mechanical allodynia, assessed via the von Frey assay, as well as thermal hyperalgesia assessed via the hotplate assay. Each terpene produced dose-related reversal of mechanical allodynia and thermal hyperalgesia. Thermal hyperalgesia displayed higher sensitivity to the effects of each terpene than mechanical allodynia and the rank order potency of the terpenes were α-terpineol > β-caryophyllene > γ-terpinene. To examine the involvement of cannabinoid receptors, we also tested each terpene in neuropathic mice lacking either functional cannabinoid type 1 receptors (CB1R (-/-)) or cannabinoid type 2 receptors (CB2R (-/-)). Compared to wild type mice, CB1R (-/-) mice treated with α-terpineol displayed a 2.91-fold shift in potency to reverse mechanical allodynia, and in CB2R (-/-) mice a 11.73-fold shift was observed. Similarly, β-caryophyllene-induced reversal of mechanical allodynia underwent a 1.80-fold shift in potency in CB2R (-/-) mice and γ-terpinene-induced reversal underwent a 1.24-fold shift in potency in CB1R (-/-) mice. Each terpene produced a subset of physiological effects from the cannabinoid tetrad assay. These findings suggest that α-terpineol, β-caryophyllene, and γ-terpinene may have differential cannabinoid receptor activity and a pharmacological profile that may yield new efficacious analgesics.