Functional roles of presynaptic opioid receptors

尽管阿片类药物是治疗严重疼痛的最有效方法，但它因其一系列有害的副作用而臭名昭著，如呼吸抑制，这是阿片类药物过量导致死亡的主要原因。死亡率在2022年达到历史最高水平，预计到2029年将有100-200万人死于阿片类药物过量。阿片类药物的镇痛和呼吸抑制作用都是通过Mu阿片受体介导的。能够区分触发止痛的u阿片受体上的作用和引起呼吸抑制的作用，将优化阿片类药物的疼痛治疗。有一些证据表明，u-阿片受体根据它们在神经元上的位置而产生不同的影响：无论是突触前还是突触后。镇痛通过突触前受体和突触后受体诱导，而呼吸抑制可能优先由突触后受体诱导。最近的研究表明，突触前阿片受体和突触后阿片受体也有不同的运输特征，因为突触前受体比静态突触后受体更具流动性。突触前和突触后受体的这种不同的流动性可能允许它们在功能影响上的差异。我们假设具有不同结合特性的激动剂(例如，On-Rate，Off-Rate)将在突触前和突触后受体之间表现出不同的强度(即时空偏差)。该项目旨在确定开发阿片受体激动剂所需的药效学参数，该激动剂将在没有呼吸抑制风险的情况下产生有效的镇痛作用。这将通过各种实验方法进行研究。将设计一个计算模型，以确定阿片激动剂和受体的配体-受体结合和流动性如何影响受体反应，以及这种差异是否表明存在任何形式的时空偏差。通过激活突触前受体和突触后受体对具有不同结合特性的药物的反应，将利用脑片电生理学来确定神经元活动的差异。最后，行为模型将被用来确定表现出时空偏差的阿片激动剂在止痛或呼吸抑制方面是否具有不同的效力。证明这种偏向的存在可以提供一条特定靶向突触前阿片受体的途径，从而在没有高死亡率的情况下诱导镇痛。

Despite being the most effective treatment for severe pain, opioids are notorious for their litany of unwanted side effects such as respiratory depression, the leading cause of death in opioid overdose. Mortality rates reached an all-time high in 2022, with 1-2 million people predicted to have died of opioid overdose by 2029. Both the analgesic and respiratory depressant effects of opioids are mediated through mu opioid receptors. Being able to differentiate between the actions at the mu opioid receptor that trigger analgesia and those which elicit respiratory depression would optimise opioid-based pain treatment. There is some evidence that mu-opioid receptors elicit different effects depending on where they are located on neurons: whether pre- or post-synaptically. With analgesia being induced through both pre- and post-synaptic receptors whereas respiratory depression may be preferentially induced by post-synaptic receptors. Recent research suggests that pre- and post-synaptic opioid receptors also have different trafficking profiles as presynaptic receptors are far more mobile than their static postsynaptic counterparts. This differential mobility of pre- and postsynaptic receptors may allow for the divergence in their functional impact. We hypothesise that agonists with different binding characteristics (eg. on-rate, off-rate) will exhibit different potencies between pre- and post-synaptic receptors (i.e. spatiotemporal bias). This could potentially lead to novel, potent analgesics being developed with reduced respiratory depressant effects.This project aims to determine the pharmacodynamic parameters required to develop an opioid receptor agonist that will elicit potent analgesia without the risk of respiratory depression. This will be investigated through a variety of experimental methods. A computational model will be devised to determine how ligand-receptor binding and mobility of opioid agonists and receptors impact receptor response and if this difference indicates any form of spatiotemporal bias. Differences in neuronal activity through activation of presynaptic vs postsynaptic receptors in response to drugs with different binding characteristics will be established using brain-slice electrophysiology. Finally behavioural models will be used to determine if opioid agonists exhibiting spatiotemporal bias have different potencies in analgesia or respiratory depression. Demonstrating the presence of such a bias could provide a route to specifically target presynaptic mu opioid receptors to elicit analgesia without the high mortality rates.