Select terpenes from Cannabis sativa are antinociceptive in mouse models of post-operative pain and fibromyalgia via adenosine A2a receptors.

Abstract

Background: Terpenes from Cannabis show promise for pain management. Our lab found that the terpenes geraniol, linalool, β-caryophyllene, and α-humulene relieve chemotherapy-induced peripheral neuropathy via Adenosine A_2a receptors (A_2aR). This suggests terpenes as potential non-opioid, non-cannabinoid therapeutics. In this study, we investigated post-operative and fibromyalgia pain, expanding potential terpene applications to different pain types.

Methods: Male and female CD-1 mice had their baseline mechanical sensitivity measured via von Frey filaments and underwent either paw incision surgery or reserpine-induced fibromyalgia (0.32 mg/kg, sc). After pain was established, the mice received 200 mg/kg ip of a terpene, and their mechanical sensitivity was measured over three hours. To determine the potential mechanism of action, mice were given the A_2aR antagonist istradefylline (3.2 mg/kg, ip) 10 min before terpene, with mechanical sensitivity measured after. Hot plate pain testing was performed as a control.

Results: Terpene treatment caused time-dependent elevation of the mechanical thresholds of the mice from both pain models, strongest for geraniol, then linalool or α-humulene, indicating that these four terpenes are anti-nociceptive in post-surgical and fibromyalgia pain. Pretreatment with istradefylline blocked antinociception, suggesting the terpenes act via the A_2aR in these pain models. Terpenes had no effect on hot plate latencies, ruling out non-specific motor effects.

Conclusions: These results demonstrate that the terpenes geraniol, linalool, β-caryophyllene, and α-humulene may be a viable medication for post-operative and fibromyalgia pain relief. Their mechanism of action via the A_2aR furthers our knowledge of its importance in pain processing and as a target of terpene drugs.