Terpene blends from Cannabis sativa are cannabimimetic and antinociceptive in a mouse chronic neuropathic pain model via activation of adenosine A2a receptors

Abstract

An increase in the use of medicinal Cannabis for pain management has spurred research into the understudied bioactive compounds in Cannabis, such as terpenes. In our previous work, we showed that isolated and purified terpenes were cannabimimetic and also relieved chemotherapy-induced peripheral neuropathy (CIPN) pain via activation of Adenosine A_2a Receptors (A_2aR) in the spinal cord. However, terpenes are most often consumed by the public as complex extracts and mixtures, not purified individual terpenes, and whether this cannabimimetic and antinociceptive activity holds true in terpene extracts and blends is not clear. In this study, we thus extracted terpene blends from three distinct Cannabis chemovars and assessed these blends in male and female CD-1 mice for their cannabimimetic activity in the tetrad assay and pain-relieving properties in a CIPN model. Each terpene blend was unique in the relative amounts of different terpenes extracted. Though each blend was unique, each similarly elicited cannabimimetic behaviors of catalepsy, hyperlocomotion, and hypothermia, without tail flick analgesia. All three terpene blends effectively relieved CIPN, though the antinociception was more robust in male than in female mice. This antinociception was recapitulated by purified Myrcene but not D-Limonene. The A_2aR antagonist istradefylline blocked the pain-relieving effects of all three terpene blends, suggesting that the terpene blends act on A_2aR to relieve CIPN pain. Together, these findings suggest that terpene blends have similar pharmacological effects as purified single terpenes, and that observations made with single terpenes may be applicable to the complex terpene mixtures commonly consumed by the public.