The family of G protein-coupled receptors (GPCRs) contains more than 800 members, and are responsive to many different ligands in the body including amino acids and other small molecules, peptides, ions, hormones and even light. We are particularly interested in the opioid receptors, GPCRs that are activated by endogenous peptides such as the enkephalins and endorphins, and which are also the target of important drugs such as morphine.

Opioid drugs are of great therapeutic and societal importance, as they are used for the treatment of pain but are also abused by addicts. We study the pharmacology of µ and δ opioid receptors, from in silico Molecular Dynamics simulations which enable us to model opioid drug interactions with the receptor, through in vitro signalling assays in cells to experiments on opioid-induced respiratory depression. Our cell signalling assays involve measurements of ligand binding to opioid receptors, as well as opioid receptor coupling to G proteins and arrestins, and the phosphorylation and trafficking of the receptors.  In all our studies we strongly emphasise the ideas of basic pharmacology such as efficacy and ligand kinetics to explore and explain the effects of opioid drugs.

One area of particular interest is that of ligand bias, where different agonists acting at a receptor are thought to induce distinct conformations of the receptor, leading to different downstream signalling effects and hence different effects in the organism. We are interested in exploring the nature of biased agonism at opioid receptors, and also in developing novel biased agonists for the µ and δ opioid receptors, to provide better, safer analgesic drugs with fewer adverse effects.

Another area of interest is that of opioid receptor desensitization, leading to tolerance to the effects of opioid agonist drugs, and loss of their effectiveness. The molecular mechanisms involved include receptor phosphorylation by GPCR kinases (GRKs) and arrestin binding to the receptor, but importantly other kinases are involved in opioid receptor regulation, such as protein kinase C. We are currently exploring these mechanisms in order to understand them fully.