Department of Diagnostic Physics, Oslo University Hospital, Oslo, Norway.
Department of Psychology, University of Oslo, Oslo, Norway.
Neuropsychopharmacology. 2023 Jan;48(2):299-307. doi: 10.1038/s41386-022-01416-z. Epub 2022 Aug 17.
Non-human animal studies outline precise mechanisms of central mu-opioid regulation of pain, stress, affiliation and reward processing. In humans, pharmacological blockade with non-selective opioid antagonists such as naloxone and naltrexone is typically used to assess involvement of the mu-opioid system in such processing. However, robust estimates of the opioid receptor blockade achieved by opioid antagonists are missing. Dose and timing schedules are highly variable and often based on single studies. Here, we provide a detailed analysis of central opioid receptor blockade after opioid antagonism based on existing positron emission tomography data. We also create models for estimating opioid receptor blockade with intravenous naloxone and oral naltrexone. We find that common doses of intravenous naloxone (0.10-0.15 mg/kg) and oral naltrexone (50 mg) are more than sufficient to produce full blockade of central MOR (>90% receptor occupancy) for the duration of a typical experimental session (~60 min), presumably due to initial super saturation of receptors. Simulations indicate that these doses also produce high KOR blockade (78-100%) and some DOR blockade (10% with naltrexone and 48-74% with naloxone). Lower doses (e.g., 0.01 mg/kg intravenous naloxone) are estimated to produce less DOR and KOR blockade while still achieving a high level of MOR blockade for ~30 min. The models and simulations form the basis of two novel web applications for detailed planning and evaluation of experiments with opioid antagonists. These tools and recommendations enable selection of appropriate antagonists, doses and assessment time points, and determination of the achieved receptor blockade in previous studies.
非人类动物研究概述了中央 μ 阿片类药物调节疼痛、应激、依恋和奖励处理的精确机制。在人类中，通常使用非选择性阿片受体拮抗剂（如纳洛酮和纳曲酮）的药理学阻断来评估 μ 阿片系统在这些处理中的参与。然而，阿片受体拮抗剂实现的阿片受体阻断的可靠估计值却缺失了。剂量和时间安排高度可变，并且通常基于单项研究。在这里，我们根据现有的正电子发射断层扫描数据，对阿片受体拮抗后中枢阿片受体阻断进行了详细分析。我们还创建了静脉内纳洛酮和口服纳曲酮估计阿片受体阻断的模型。我们发现，常见剂量的静脉内纳洛酮（0.10-0.15mg/kg）和口服纳曲酮（50mg）足以在典型的实验过程中（约 60 分钟）产生中枢 MOR 的完全阻断（>90%的受体占有率），可能是由于受体的初始超饱和。模拟表明，这些剂量还产生了高 KOR 阻断（78-100%）和一些 DOR 阻断（纳曲酮为 10%，纳洛酮为 48-74%）。较低剂量（例如，静脉内纳洛酮 0.01mg/kg）估计会产生较低的 DOR 和 KOR 阻断，同时仍能在约 30 分钟内实现高 MOR 阻断。这些模型和模拟构成了两个新的网络应用程序的基础，用于详细规划和评估阿片受体拮抗剂的实验。这些工具和建议可以帮助选择适当的拮抗剂、剂量和评估时间点，并确定之前研究中实现的受体阻断。
