RT Journal Article
SR Electronic
T1 Opioid Antagonism in Humans: A Primer on Optimal Dose and Timing for Central Mu-Opioid Receptor Blockade
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.25.481943
DO 10.1101/2022.02.25.481943
A1 Martin Trøstheim
A1 Marie Eikemo
A1 Jan Haaker
A1 J. James Frost
A1 Siri Leknes
YR 2022
UL http://biorxiv.org/content/early/2022/08/02/2022.02.25.481943.abstract
AB 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 minutes), 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 minutes. 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.Competing Interest StatementThe authors have declared no competing interest.