Yoo Ji Hoon, Borsodi Anna, Tóth Géza, Benyhe Sándor, Gaspar Robert, Matifas Audrey, Kieffer Brigitte L, Metaxas Athanasios, Kitchen Ian, Bailey Alexis
Faculty of Health and Medical Sciences, AY building, University of Surrey, Guildford, Surrey GU2 7XH UK; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, United States.
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvari krt 62, H-6726 Szeged, Hungary; Institute of Pharmacodynamics and Biopharmacy, University of Szeged, 6720 Zrinyi u. 9, Hungary.
Neurosci Lett. 2017 Mar 16;643:16-21. doi: 10.1016/j.neulet.2017.02.002. Epub 2017 Feb 10.
Oxymorphone, one of oxycodone's metabolic products, is a potent opioid receptor agonist which is thought to contribute to the analgesic effect of its parent compound and may have high potential abuse liability. Nonetheless, the in vivo pharmacological binding profile of this drug is still unclear. This study uses mice lacking mu (MOP), kappa (KOP) or delta (DOP) opioid receptors as well as mice lacking all three opioid receptors to provide full characterisation of oxymorphone binding sites in the brain. Saturation binding studies using [H]oxymorphone revealed high affinity binding sites in mouse brain displaying Kd of 1.7nM and Bmax of 147fmol/mg. Furthermore, we performed quantitative autoradiography binding studies using [H]oxymorphone in mouse brain. The distribution of [H]oxymorphone binding sites was found to be similar to the selective MOP agonist [H]DAMGO in the mouse brain. [H]Oxymorphone binding was completely abolished across the majority of the brain regions in mice lacking MOP as well as in mice lacking all three opioid receptors. DOP and KOP knockout mice retained [H]oxymorphone binding sites suggesting oxymorphone may not target DOP or KOP. These results confirm that the MOP, and not the DOP or the KOP is the main high affinity binding target for oxymorphone.
羟吗啡酮是羟考酮的代谢产物之一，是一种强效阿片受体激动剂，被认为有助于其母体化合物的镇痛作用，并且可能具有很高的滥用潜力。尽管如此，这种药物在体内的药理学结合情况仍不清楚。本研究使用缺乏μ（MOP）、κ（KOP）或δ（DOP）阿片受体的小鼠以及缺乏所有三种阿片受体的小鼠，以全面表征羟吗啡酮在大脑中的结合位点。使用[H]羟吗啡酮进行的饱和结合研究显示，小鼠大脑中存在高亲和力结合位点，其解离常数（Kd）为1.7nM，最大结合容量（Bmax）为147fmol/mg。此外，我们在小鼠大脑中使用[H]羟吗啡酮进行了定量放射自显影结合研究。发现[H]羟吗啡酮结合位点的分布与小鼠大脑中选择性MOP激动剂[H]DAMGO相似。在缺乏MOP的小鼠以及缺乏所有三种阿片受体的小鼠的大多数脑区中，[H]羟吗啡酮结合完全消失。DOP和KOP基因敲除小鼠保留了[H]羟吗啡酮结合位点，这表明羟吗啡酮可能不以DOP或KOP为靶点。这些结果证实，羟吗啡酮的主要高亲和力结合靶点是MOP，而不是DOP或KOP。
