Brain and Mind Centre, The University of Sydney, 94 Mallet Street, Camperdown, Sydney, NSW, 2050, Australia.
Faculty of Science, School of Psychology, The University of Sydney, Sydney, NSW, 2006, Australia.
Psychopharmacology (Berl). 2024 Aug;241(8):1705-1717. doi: 10.1007/s00213-024-06591-z. Epub 2024 Apr 27.
RATIONALE/OBJECTIVES: Targeting cannabinoid receptor type 1 (CB1R) has shown promise for treating opioid withdrawal symptoms. This study aimed to investigate the efficacy of a specific CB1R negative allosteric modulator (NAM), Org27569, in reducing both naloxone-precipitated and protracted withdrawal symptoms in oxycodone-dependent mice.
Mice received escalating doses of oxycodone (9-33 mg/kg IP) or saline twice daily for 9 days, followed by a final dose of oxycodone (33 mg/kg) or saline in the morning of day 9. In one cohort, the impact of Org27569 (3, 10, and 30 mg/kg) on naloxone (10 mg/kg IP) precipitated withdrawal symptoms was assessed. In another cohort, Org27569 (3 mg/kg) effects on the acquisition of conditioned place aversion to naloxone (0.6 mg/kg) precipitated opioid withdrawal, on behaviour following a 7-9-day abstinence period, and on naloxone (0.6 mg/kg) precipitated withdrawal-induced escape behaviour in a novel assay were assessed.
Although Org27569 decreased opioid withdrawal-induced jumping at doses of 10 and 30 mg/kg, these effects were confounded by reduced locomotion. At all doses tested, Org27569 had a modest inhibitory effect on gastrointestinal motility. At the lower dose of 3 mg/kg, which was not confounded by locomotor effects, Org27569 did not impact naloxone-precipitated withdrawal-induced jumping, acquisition of oxycodone withdrawal-induced conditioned place aversion, or naloxone-precipitated withdrawal-induced escape behaviour in a novel assay. A clear protracted opioid withdrawal phenotype was not observed in assays of anxiety-like or social behaviour.
Org27569 effects on negative affective-like symptoms were confounded by locomotor effects and effects on gastrointestinal motility were not opioid withdrawal specific. Further studies are needed in a model that produces a more pronounced protracted withdrawal syndrome.
靶向大麻素受体 1（CB1R）已显示出治疗阿片类药物戒断症状的潜力。本研究旨在研究一种特定的 CB1R 负变构调节剂（NAM），Org27569，在减少纳洛酮诱发和延长阿片类药物依赖小鼠戒断症状方面的疗效。
小鼠每天两次接受递增剂量的羟考酮（9-33mg/kg IP）或生理盐水，共 9 天，然后在第 9 天的早上给予最后一次羟考酮（33mg/kg）或生理盐水。在一个队列中，评估 Org27569（3、10 和 30mg/kg）对纳洛酮（10mg/kg IP）诱发的戒断症状的影响。在另一个队列中，评估 Org27569（3mg/kg）对纳洛酮（0.6mg/kg）诱发的阿片类药物戒断引起的条件性位置厌恶的获得、7-9 天戒断期后的行为以及纳洛酮（0.6mg/kg）诱发的新型试验中戒断引起的逃避行为的影响。
尽管 Org27569 降低了 10 和 30mg/kg 剂量下的阿片类药物戒断引起的跳跃，但这些影响因运动减少而变得复杂。在所有测试的剂量下，Org27569 对胃肠道动力都有适度的抑制作用。在较低剂量的 3mg/kg 下，运动效应没有混淆，Org27569 不影响纳洛酮诱发的戒断引起的跳跃、羟考酮戒断引起的条件性位置厌恶的获得或纳洛酮诱发的新型试验中的戒断引起的逃避行为。在焦虑样或社会行为的测定中，未观察到明显的延长阿片类药物戒断表型。
Org27569 对负性情感样症状的影响因运动效应而复杂化，而对胃肠道动力的影响与阿片类药物戒断无关。需要在产生更明显的延长戒断综合征的模型中进行进一步的研究。
