Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, N1G2W1, Canada.
Institute of Drug Research, Medical Facility, Hebrew University of Jerusalem, Jerusalem, Israel.
Psychopharmacology (Berl). 2020 Sep;237(9):2621-2631. doi: 10.1007/s00213-020-05559-z. Epub 2020 Jun 2.
When acutely administered intraperitoneally, the non-psychoactive cannabinoid cannabidiol (CBD), its acidic precursor cannabidiolic acid (CBDA) and a stable methyl ester of CBDA (HU-580) reduce lithium chloride (LiCl)-induced conditioned gaping in male rats (a selective preclinical model of acute nausea) via activation of the serotonin 1A (5-HT) receptor.
To utilise these compounds to manage nausea in the clinic, we must determine if their effectiveness is maintained when injected subcutaneously (s.c) and when repeatedly administered. First, we compared the effectiveness of each of these compounds to reduce conditioned gaping following repeated (7-day) and acute (1-day) pretreatments and whether these anti-nausea effects were mediated by the 5-HT receptor. Next, we assessed whether the effectiveness of these compounds can be maintained when administered prior to each of 4 conditioning trials (once per week). We also evaluated the ability of repeated CBD (7 days) to reduce LiCl-induced vomiting in Suncus murinus. Finally, we examined whether acute CBD was equally effective in male and female rats.
Both acute and repeated (7 day) s.c. administrations of CBD (5 mg/kg), CBDA (1 μg/kg) and HU-580 (1 μg/kg) similarly reduced LiCl-induced conditioned gaping, and these effects were blocked by 5HT receptor antagonism. When administered over 4 weekly conditioning trials, the anti-nausea effectiveness of each of these compounds was also maintained. Repeated CBD (5 mg/kg, s.c.) maintained its anti-emetic efficacy in S. murinus. Acute CBD (5 and 20 mg/kg, s.c.) administration reduced LiCl-induced conditioned gaping similarly in male and female rats.
When administered repeatedly (7 days), CBD, CBDA and HU-580 did not lose efficacy in reducing nausea and continued to act via agonism of the 5-HT receptor. When administered across 4 weekly conditioning trials, they maintained their effectiveness in reducing LiCl-induced nausea. Repeated CBD also reduced vomiting in shrews. Finally, CBD's anti-nausea effects were similar in male and female rats. This suggests that these cannabinoids may be useful anti-nausea and anti-emetic treatments for chronic conditions, without the development of tolerance.
当腹腔内急性给予非精神活性大麻素大麻二酚 (CBD)、其酸性前体大麻二酚酸 (CBDA) 和 CBDA 的稳定甲酯 (HU-580) 时，它们会通过激活 5-羟色胺 1A（5-HT）受体，减少雄性大鼠的氯化锂 (LiCl) 诱导的条件性张口（一种选择性的急性恶心临床前模型）。
为了将这些化合物用于临床治疗恶心，我们必须确定它们在皮下注射 (s.c) 时和反复给药时的有效性是否保持不变。首先，我们比较了这些化合物在反复（7 天）和急性（1 天）预处理后减少条件性张口的效果，以及这些抗恶心作用是否通过 5-HT 受体介导。接下来，我们评估了在 4 次条件试验（每周一次）之前给予这些化合物是否可以维持其有效性。我们还评估了反复给予 CBD（7 天）是否可以减少沙鼠的 LiCl 诱导呕吐。最后，我们检查了急性 CBD 在雄性和雌性大鼠中的效果是否相同。
急性和反复（7 天）s.c.给予 CBD（5 mg/kg）、CBDA（1 μg/kg）和 HU-580（1 μg/kg）同样减少了 LiCl 诱导的条件性张口，这些作用被 5-HT 受体拮抗作用阻断。当在每周 4 次的条件试验中给予这些化合物时，它们的抗恶心作用也得到了维持。反复给予 CBD（5 mg/kg，s.c.）在沙鼠中保持其抗呕吐作用。急性 CBD（5 和 20 mg/kg，s.c.）在雄性和雌性大鼠中减少 LiCl 诱导的条件性张口的效果相似。
当反复给予（7 天）时，CBD、CBDA 和 HU-580 在减少恶心方面并未失去效力，并继续通过 5-HT 受体激动作用发挥作用。当在 4 次每周的条件试验中给予时，它们在减少 LiCl 诱导的恶心方面保持有效。反复给予 CBD 还减少了沙鼠的呕吐。最后，CBD 的抗恶心作用在雄性和雌性大鼠中相似。这表明这些大麻素可能是用于治疗慢性疾病的有用的止吐和止恶心治疗药物，而不会产生耐受性。
