Chronic effects of G protein-biased mu-opioid receptor agonists in the brain

G-protein coupled receptors (GPCRs) are the largest family of targets for approved drugs, with ~35%
of current drug treatments targeting GPCRs. However, very few of these are GPCR agonists - drugs
that directly activate the receptor. A primary reason for this is that chronic treatment with GPCR
agonists can lead to a progressive loss of drug response, known as tolerance. Drug tolerance hinders
the development of novel GPCR agonists as future drug treatments, and limits the clinical
effectiveness of current GPCR agonists.
The discovery of "biased agonists" at G protein-coupled receptors (GPCRs) has revolutionised the field.
Conventional GPCR agonists activate the receptor to cause cellular effect, but then the receptor is
desensitized. This desensitization is the predominant mechanism underlying drug tolerance. One
advantage of biased agonists is that they can allow GPCRs to signal to cause the desired cellular effect,
but the receptors then may evade the usual mechanisms leading to desensitization and tolerance.
Mu-opioid receptors (MOPrs) are one of the few types of GPCR where agonists are already used in the
clinic (eg. morphine for pain relief), as well as being abused on the street (eg. heroin). Tolerance is a
significant problem when these drugs are taken long-term. Novel biased agonists at MOPr have
recently been discovered, with some entering clinical trials, but, the long term effects of these drugs
are yet to be studied.
Although the field of biased GPCR agonists is relatively new, the supervisory team of researchers has
many years of experience in studying bias, desensitization and tolerance, particularly at MOPrs. For
the first time, we can now bring together in this application the necessary expertise, experimental
approaches and a number of novel biased mu-opioid receptor agonists to study tolerance to biased
MOPr agonists.
This project takes a co-ordinated transdisciplinary approach, using a combination of in vivo and ex vivo
techniques: behaviour, brain slice electrophysiology, phosphoproteomics. By studying the effects of
biased MOPr agonists at a cellular, receptor and whole-animal level we will uncover the mechanisms
by which biased agonists induce desensitization and tolerance.
This study is of profound importance for the future of biased agonists as novel and effective drugs, as
well as offering a truly translational neuroscience PhD project, using a range of different techniques.