Terenius Lars, Oasa Sho, Sezgin Erdinc, Ma Yuelong, Horne David, Radmiković Mihajlo, Jovanović-Talisman Tijana, Martin-Fardon Remi, Vukojevic Vladana
Karolinska Institutet.
Karolinska Institute.
Res Sq. 2023 Jul 21:rs.3.rs-3091960. doi: 10.21203/rs.3.rs-3091960/v1.
Naltrexone (NTX), a homologue of the opiate antidote naloxone, is an orally active long-acting mu-opioid receptor (MOP) antagonist used in the treatment of opiate dependence. NTX is also found to relieve craving for alcohol and is one of the few FDA-approved drugs for alcohol use disorder (AUD). Reports that NTX blocks the actions of endogenous opioids released by alcohol are not convincing, suggesting that NTX interferes with alcohol actions by affecting opioid receptors. MOP and kappa-opioid receptor (KOP) are structurally related but functionally different. MOP is mainly located in interneurons activated by enkephalins while KOP is located in longer projections activated by dynorphins. While the actions of NTX on MOP are well established, the interaction with KOP and addiction is not well understood. We used sensitive fluorescence-based methods to study the influence of alcohol on KOP and the interaction between KOP and NTX. Here we report that alcohol interacts with KOP and its environment in the plasma membrane. These interactions are affected by NTX and are exerted both on KOP directly and on the plasma membrane (lipid) structures ("off-target"). The actions of NTX are stereospecific. Selective KOP antagonists, recently in early clinical trials for major depressive disorder, block the receptor but do not show the full action profile of NTX. The therapeutic effect of NTX treatment in AUD may be due to direct actions on KOP and the receptor environment.
纳曲酮（NTX）是阿片类解毒剂纳洛酮的同系物，是一种口服活性长效μ-阿片受体（MOP）拮抗剂，用于治疗阿片类药物依赖。人们还发现NTX可缓解对酒精的渴望，它是美国食品药品监督管理局（FDA）批准用于治疗酒精使用障碍（AUD）的少数药物之一。关于NTX阻断酒精释放的内源性阿片类物质作用的报道并不令人信服，这表明NTX通过影响阿片受体来干扰酒精的作用。MOP和κ-阿片受体（KOP）在结构上相关但功能不同。MOP主要位于由脑啡肽激活的中间神经元中，而KOP位于由强啡肽激活的较长投射中。虽然NTX对MOP的作用已得到充分证实，但其与KOP的相互作用及成瘾机制尚不清楚。我们使用基于敏感荧光的方法来研究酒精对KOP的影响以及KOP与NTX之间的相互作用。在此我们报告，酒精与KOP及其在质膜中的环境相互作用。这些相互作用受NTX影响，并且既直接作用于KOP，也作用于质膜（脂质）结构（“脱靶”）。NTX的作用具有立体特异性。选择性KOP拮抗剂最近在治疗重度抑郁症的早期临床试验中，可阻断该受体，但未显示出NTX的完整作用谱。NTX治疗AUD的疗效可能归因于其对KOP和受体环境的直接作用。
