A NOVEL FORM OF SPATIOTEMPORAL BIAS FOR MU OPIOID RECEPTORS

G protein-coupled receptors (GPCRs) are present on virtually all mammalian neurons where they affect excitability and neurotransmitter release. Mu-opioid receptors (MOPrs) are involved in numerous brain functions such as pain, reward and mood and are present on neurons in many different brain areas both pre- and post-synaptically. Pre-synaptic MOPrs diffuse along the membrane, in and out of the active zone [1], whereas post-synaptically MOPrs are largely static. We hypothesise that agonists with a slower off-rate at MOPrs (longer dwell-time) are more likely to successfully signal at pre-synaptic MOPrs than shorter dwell-time agonists, so would be ‘biased’ towards signalling through pre-synaptic receptors. Mathematical modelling of agonist-receptor signalling, based on [2] enabled determination of factors affecting potency receptors. Brain-slice electrophysiological recordings from mouse locus coeruleus neurons were performed to quantify potency of agonists with different dwell times at pre- and post-synaptic receptors.
Mathematical modelling showed dwell-time to be the most influential factor when comparing relative potencies at pre- and post-synaptic MOPrs. Using electrophysiology pre- and post-synaptic potencies of short (met-enkephalin and morphine) and longer (etorphine and carfentanil) dwell-time agonists were determined. Carfentanil and etorphine were found to be ~45x more potent than Met-Enkephalin or morphine at post-synaptic receptors and ~36,000x more potent at pre-synaptic receptors. Thus, longer dwell-time agonists were relatively ~1000x more potent at pre-synaptic MOPrs than shorter dwell-time agonists. This novel form of spatio-temporal bias may have profound implications on our understanding of MOPr signalling in the brain, and brain GPCRs in general.
References
1. doi:10.1016/j.neuron.2019.11.016
2. doi:10.1038/s41598-020-67844-3