Fentanyl Overdose Deaths: Underlying Mechanisms

在过去的5年里，英国和美国的急性阿片类药物过量死亡人数都有所上升。一个新的危险是非法芬太尼(芬太尼及其结构类似物)出现在毒品领域。在美国，芬太尼导致的死亡已经达到流行水平(2016年超过2万人)，现在超过了海洛因或羟考酮等处方阿片类药物的死亡人数。在英国和欧洲，最近发生了几起令人震惊的芬太尼相关死亡事件。我们研究的目的是确定为什么芬太尼是如此致命的药物。阿片类药物过量死亡主要是由于呼吸抑制。在大脑中，芬太尼与u阿片受体(MOPr)相互作用产生呼吸抑制，是一种极其有效的阿片类药物，是吗啡的50-100倍。可能导致芬太尼过量死亡的因素是-作为高度有效的药物，即使是服用数量上的一个小错误也可能导致严重的呼吸抑制。-芬太尼对呼吸的抑制不太容易被拮抗剂纳洛酮逆转。-静脉注射芬太尼会导致呼吸肌僵硬(称为木胸综合征)，使呼吸变得更加困难。为了促进开发有效的干预措施来对抗芬太尼过量，我们需要充分了解为什么这些药物如此有效，它们如何抑制呼吸，为什么它们对纳洛酮逆转耐药，以及芬太尼是否对其他阿片类药物表现出较少的交叉耐受性。我们建议研究芬太尼与MOPr相互作用的几个新方面。(I)芬太尼如何与MOPr结合并激活MOPr。我们假设较高的脂类导致芬太尼的质膜关联更大，-未结合的芬太尼可以非常迅速地与MOPr重新结合以重新激活它，而其他阿片激动剂不会迅速与受体重新结合，而是在重新结合发生之前从受体附近扩散出去。-芬太尼可以通过疏水途径和亲水途径直接从膜脂进入MOPr的结合口袋。这种新的性质将增强芬太尼在体内抑制呼吸的激动剂效力，并使其不太容易被纳洛酮逆转。我们将测定芬太尼在磷脂单分子层中的分配系数，利用新的荧光技术研究药物与受体的快速结合和解离动力学，并利用MOPr蛋白的晶体结构进行高级分子动力学模拟配体与受体的相互作用。(Ii)肌肉僵硬对芬太尼呼吸抑制的贡献。我们将使用阿片类药物诱导的呼吸抑制的小鼠模型来研究呼吸肌僵硬对芬太尼衍生物呼吸抑制的贡献。(Iii)亲脂拮抗剂逆转芬太尼。我们将研究高亲脂性MOPr拮抗剂是否比纳洛酮更容易逆转芬太尼呼吸抑制。(Iv)耐受性突破。我们将确定“顶层”使用芬太尼是否可以打破长期使用海洛因或长期使用美沙酮或丁丙诺啡的阿片类药物替代治疗所产生的呼吸抑制耐受性。我们假设，使芬太尼更有效的过程及其诱导呼吸肌僵硬的能力可能会降低它们对其他阿片类药物的交叉耐受程度。我们研究的重要性是它解决了当前的一个主要国际健康问题--由于芬太尼类阿片类药物而导致的过量死亡人数上升。

Over the past 5 years acute opioid overdose deaths have risen both in the UK and the USA. A new danger is the emergence on the drug scene of illicit fentanyls (fentanyl and its structural analogues). In the USA deaths due to fentanyls have reached epidemic levels (over 20,000 in 2016) and now exceed those involving either heroin or prescription opioids such as oxycodone. In the UK and Europe there have recently been several alarming outbreaks of fentanyl-related deaths. The purpose of our research is to determine why fentanyls are such deadly drugs. Opioid overdose deaths are due primarily to respiratory depression. In the brain fentanyl interacts with the mu opioid receptor (MOPr) to produce respiratory depression and is an extremely potent opioid, being 50 - 100 times more potent than morphine. Factors that likely contribute to fentanyl overdose deaths are- being highly potent drugs, even a small error in the amount taken could lead to profound respiratory depression. - respiratory depression by fentanyls is less readily reversible by the antagonist naloxone.- on intravenous administration fentanyl can induce respiratory muscle rigidity (referred to as 'wooden chest' syndrome) making it even more difficult to breathe.To facilitate the development of effective interventions to combat fentanyl overdose we need to understand fully why these drugs are so potent, how they depress respiration, why they are resistant to naloxone reversal and whether fentanyls exhibit less cross tolerance to other opioid drugs.We propose to study several novel facets of the interactions of fentanyls with MOPr.(i) How fentanyls bind to and activate MOPrWe hypothesise that - higher lipophilicity results in greater plasma membrane association of fentanyls, - on unbinding fentanyls can very rapidly re-associate with MOPr to reactivate it whereas other opioid agonists do not rapidly re-bind to the receptor but diffuse away from the vicinity of the receptors before re-binding can occur. - fentanyls can access the binding pocket of MOPr directly from the membrane lipid through a hydrophobic pathway as well as via a hydrophilic aqueous pathway.Such novel properties would enhance the in vivo agonist potency of fentanyls to depress respiration and render them less susceptible to reversal by naloxone. We will determine the partition coefficient of fentanyls into phospholipid monolayers, utilise novel fluorescence technologies to study rapid drug-receptor association and dissociation kinetics, and perform advanced molecular dynamic simulations of ligand-receptor interaction using the crystal structure of the MOPr protein. (ii) Contribution of muscle rigidity to respiratory depression by fentanyls. We will use a mouse model of opioid-induced respiratory depression to examine the contribution of respiratory muscle rigidity to respiratory depression by fentanyl derivatives.(iii) Reversal of fentanyls by lipophilic antagonists. We will examine whether highly lipophilic MOPr antagonists more readily reverse fentanyl respiratory depression than naloxone.(iv) Tolerance breakthrough. We will determine whether 'on top' use of the fentanyls can break through the tolerance to respiratory depression that has been induced by prolonged heroin use or from prolonged opioid substitution therapy with methadone or buprenorphine. We hypothesise that the processes which make the fentanyls more potent and their abilities to induce respiratory muscle rigidity may reduce the degree of cross tolerance they exhibit to other opioids.The importance of our research is that it addresses a current major international health problem - the rise in overdose deaths due to the fentanyl class of opioid drugs.