Terpenes from Cannabis sativa Induce Antinociception in Mouse Chronic Neuropathic Pain via Activation of Spinal Cord Adenosine A2A Receptors.
Terpenes from Cannabis sativa Induce Antinociception in Mouse Chronic Neuropathic Pain via Activation of Spinal Cord Adenosine A2A Receptors.
复制标题
大麻中的萜烯通过激活脊髓腺苷 A2A 受体诱导小鼠慢性神经性疼痛的镇痛作用。
DOI：
10.1101/2023.03.28.534594
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Streicher,JohnM
中科院分区：
文献类型：
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作者：
Schwarz,AbigailM;Keresztes,Attila;Bui,Thai;Hecksel,RyanJ;Peña,Adrian;Lent,Brianna;Gao,Zhan-Guo;Gamez-Rivera,Martín;Seekins,CalebA;Chou,Kerry;Appel,TaylorL;Jacobson,KennethA;Al-Obeidi,FahadA;Streicher,JohnM
萜烯是一种小的碳氢化合物，可以赋予许多植物香气和味道，包括大麻。许多研究表明，萜类化合物可以在人类和动物的各种疼痛状态下产生止痛作用。然而，这些研究在方法上是有限的，几乎没有建立起作用机制。在我们以前的工作中，我们证明了萜类化合物香叶醇、芳樟醇、β-品烯、α-胡萝卜烯和β-石竹烯通过多个受体靶点产生拟大麻的行为效应。因此，我们扩展了这项工作，以探索这些大麻萜类化合物缓解慢性疼痛的疗效和机制。我们首先通过向化疗诱导的周围神经病变(CIPN)或脂多糖诱导的炎性疼痛的雄性和雌性CD-1小鼠注射萜类化合物(200 mg/kg，ip)来测试其抗伤害效应，发现这些萜类化合物产生的效果与10 mg/kg吗啡或3.2 mg/kg WIN55,212大致相同。我们进一步发现，在条件性位置偏爱的测量中，所有的萜类都没有产生奖赏，而低剂量的萜类(100 mg/kg)与吗啡(3.2 mg/kg)联合使用比单独使用更能产生更强的抗伤害作用。然后，我们使用腺苷A2a受体(A2AR)选择性拮抗剂伊特拉德林(3.2 mg/kg，ip)和脊髓特异性CRISPR敲除A2AR来确定该受体是CIPN中萜类抗伤害性感受的机制。体外cAMP和结合研究以及计算机模拟研究进一步表明，这些萜类化合物是A2AR激动剂。总之，这些研究确定了大麻萜烯类化合物是治疗慢性神经病理性疼痛的潜在药物，并确定了脊髓中这种活性的受体机制。
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 efficacy and mechanism of these Cannabis terpenes in relieving chronic pain. We first tested for antinociceptive efficacy by injecting terpenes (200 mg/kg, IP) into male and female CD-1 mice with chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal efficacy 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 in the spinal cord for this activity.