Pre-clinical evaluation of the efficacy of combined THC and CBDA to treat nausea, pain and anxiety in veterinary medicine

几千年来，大麻一直被用来治疗恶心、疼痛和焦虑。然而，直到20世纪60年代，耶路撒冷希伯来大学的科学家们才发现大麻中的精神活性成分，即δ -9-四氢大麻酚（THC）和其他非精神活性大麻素，大麻二酚（CBD）和大麻二酸（CBDA）。现在已知大麻植物含有60多种化学物质，它们的结构密切相关，被称为大麻素，但唯一能改变情绪的成分是四氢大麻酚。最近使用恶心大鼠模型的临床前研究表明，THC和CBD在减少毒素引起的急性恶心和预期性恶心方面都非常有效（正如化疗患者返回治疗诊所时所见）。它们在减轻炎症性疼痛方面也都很有效。四氢大麻酚在类焦虑行为的动物模型中产生剂量依赖效应，低剂量减少焦虑，高剂量增加焦虑。在动物模型中，CBD减少了不同剂量的焦虑，并已被证明可以逆转高剂量四氢大麻酚产生的焦虑。最近，在动物模型中，CBD的酸性前体CBDA被发现在减少急性和预期性恶心方面比CBD强近1000倍，而对一般运动活动水平没有任何影响；因此，CBDA在兽医学治疗恶心方面可能具有相当大的治疗潜力。然而，CBDA对炎症性疼痛或焦虑的影响尚未得到评估。四氢大麻酚和CBDA联合比值的治疗潜力尚未得到系统评价。本研究旨在评估四氢大麻酚和CBDA的组合比例（以及每种化合物单独）在啮齿动物模型中抑制急性和预期性恶心、炎症性疼痛和焦虑的能力。这些研究可能潜在地为兽药的开发提供临床前证据，以便在未来的伴侣动物临床试验中进行测试。

The cannabis plant has been used to treat nausea, pain and anxiety for thousand of years. However, it wasn't until the 1960's that scientists at the Hebrew University of Jerusalem discovered the psychoactive ingredient in cannabis, delta-9-tetrahydrocannabinol (THC) and other non-psychoactive cannabinoids, cannabidiol (CBD) and cannabidiolic acid (CBDA) in the plant. It is now known that the cannabis plant contains over 60 chemicals that have closely related structures, called cannabinoids, but the only mood altering consititutent is THC. Recent pre-clinical research using rat models of nausea has revealed that both THC and CBD are highly effective in reducing toxin-induced acute nausea and anticipatory nausea (as seen in chemotherapy patients when they return to the treatment clinic). They are also both effective in reducing inflammatory pain. THC produces a dose-dependent effect in animal models of anxiety-like behaviour, with low doses reducing anxiety and high doses increasing anxiety. CBD reduces anxiety across doses in animal models and has been shown to reverse the anxiety produced by high doses of THC. Most recently, the acidic precursor to CBD, CBDA that is in the plant before it is heated, has been found to be nearly 1000 times more potent than CBD in reducing acute and anticipatory nausea in animal models, without showing any effect on general motor activity level; therefore, CBDA may have considerable therapeutic potential in treating nausea in veterinary medicine. However, CBDA has not been evaluated for its effect on inflammatory pain or on anxiety. The therapeutic potential of combined ratios of THC and CBDA have not been systematically evaluated. The present studies aim to evaluate combined ratios of THC and CBDA (as well as each compound separately) in their ability to suppress acute and anticipatory nausea, inflammatory pain and anxiety in rodent models. These studies may potentially provide the pre-clinical evidence for the development of veterinary medicines to test in future clinical trials with companion animals.