Cannabis terpenes produced strong pain-relieving effects in mice with chemotherapy-induced peripheral neuropathy and inflammatory pain. Researchers tested geraniol, linalool, β-pinene, α-humulene and β-caryophyllene and found that, at the tested dose, their antinociceptive effects were roughly comparable to 10 mg/kg morphine or 3.2 mg/kg of the synthetic cannabinoid WIN55,212.
The terpenes also enhanced morphine’s pain-relieving effect when the two were given together at lower doses, while none of the terpenes produced reward in the conditioned-place-preference test. In the neuropathic pain model, blocking the adenosine A2A receptor significantly reduced the pain-relieving effect of every terpene tested.
Spinal-cord-specific A2A receptor knockdown further supported that mechanism, while laboratory and computer modeling suggested the terpenes can act as A2A receptor agonists. The authors concluded that Cannabis terpenes may represent potential therapeutics for chronic neuropathic pain and identified a specific receptor pathway through which that activity occurs.
“Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa .
A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action.
In our previous work, we showed that the terpenes geraniol, linalool, β-pinene, α-humulene, and β-caryophyllene produced cannabimimetic behavioral effects via multiple receptor targets. We thus expanded this work to explore the potential antinociception and mechanism of these Cannabis terpenes in a mouse model of chronic pain.
We first tested for antinociception by injecting terpenes (200 mg/kg, IP) into male and female CD-1 mice with mouse models of chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal antinociception to 10 mg/kg morphine or 3.2 mg/kg WIN55,212.
We further found that none of the terpenes produced reward as measured by conditioned place preference, while low doses of terpene (100 mg/kg) combined with morphine (3.2 mg/kg) produced enhanced antinociception vs either alone. We then used the adenosine A 2A receptor (A 2A R) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord-specific CRISPR knockdown of the A 2A R to identify this receptor as the mechanism for terpene antinociception in CIPN. In vitro cAMP and binding studies and in silico modeling studies further suggested that the terpenes act as A 2A R agonists.
Together these studies identify Cannabis terpenes as potential therapeutics for chronic neuropathic pain and identify a receptor mechanism for this activity.”
