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 A2A receptor (A2AR) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord-specific CRISPR knockdown of the A2AR 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 A2AR agonists. Together these studies identify Cannabis terpenes as potential therapeutics for chronic neuropathic pain and identify a receptor mechanism for this activity.

中文翻译：

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大麻中的萜烯通过激活腺苷 A2A 受体，在慢性神经性疼痛小鼠模型中诱导镇痛作用。

萜烯是一种小型碳氢化合物，可为许多植物（包括大麻）赋予香气和味道。许多研究表明，萜烯可以缓解人类和动物各种疼痛状态下的疼痛。然而，这些研究在方法上受到限制，并且很少建立作用机制。在我们之前的工作中，我们表明萜烯香叶醇、芳樟醇、β-蒎烯、α-葎草烯和β-石竹烯通过多个受体靶点产生大麻模拟行为效应。因此，我们扩展了这项工作，以探索这些大麻萜烯在慢性疼痛小鼠模型中的潜在抗伤害作用和机制。我们首先通过向具有化疗引起的周围神经病变 (CIPN) 或脂多糖引起的炎症疼痛模型的雄性和雌性 CD-1 小鼠中注射萜烯 (200 mg/kg, IP) 来测试镇痛作用，发现萜烯产生的镇痛作用大致相同10 mg/kg 吗啡或 3.2 mg/kg WIN55,212 具有镇痛作用。我们进一步发现，根据条件性位置偏好测量，没有一种萜烯产生奖励，而低剂量的萜烯（100毫克/千克）与吗啡（3.2毫克/千克）联合使用，与单独使用任何一种相比，产生增强的镇痛作用。然后，我们使用腺苷 A2A 受体 (A2AR) 选择性拮抗剂伊曲茶碱 (3.2 mg/kg，IP) 和 A2AR 的脊髓特异性 CRISPR 敲低来确定该受体是 CIPN 中萜烯抗伤害的机制。体外 cAMP 和结合研究以及计算机模拟研究进一步表明萜烯可充当 A2AR 激动剂。这些研究共同确定了大麻萜烯作为慢性神经性疼痛的潜在治疗方法，并确定了这种活性的受体机制。