Functional Roles of Presynaptic Opioid Receptors

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.