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

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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 A2a receptors (A2aR). 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. 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 (0.32mg/kg, sc). After pain was established, the mice received 200mg/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 A2aR antagonist istradefylline (3.2mg/kg, ip) 10min before terpene, with mechanical sensitivity measured after. Hot plate pain testing was performed as a control. 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 A2aR in these pain models. Terpenes had no effect on hot plate latencies, ruling out non-specific motor effects. 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 A2aR furthers our knowledge of its importance in pain processing and as a target of terpene drugs.