Pharmacological interactions between conventional and biased MOR agonists

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PROJECT SUMMARY Our laboratory focuses on understanding how different ligands can modulate the activity of the mu opioid receptor (MOR) and how differential activation may preserve or prevent physiological responses typically induced by drugs at this receptor. To this end, the Bohn lab has worked to develop diverse “biased” agonists that diverge from morphine and enkephalins by their ability to preferentially signal through G protein pathways over recruiting βarrestin2 to the receptor. Our preliminary studies suggest that SR-17018, our most G biased compound, does not induce respiratory suppression in mice, although it has the same potency as morphine in the hot plate nociception assay. Further, unlike morphine, which stimulates mouse running behavior, SR-17018 does not induce hyperactivity. When we treat mice with SR-17018 and morphine, we find that SR-17018 blocks morphine- induced hyperactivity. I will continue characterizing the behavioral responses using MOR agonists from βarrestin 2- and G protein-biased ligands, in a dose-response manner in the locomotor activity assay and respiratory suppression to fully understand the nature of this apparent competitive interaction. This proposal aims to attain training in behavioral and in vitro pharmacology to define opioid interactions at MOR in mice. I will gain training in execution and design of behavioral studies, acquisition of pharmacokinetic data, and evaluation of receptor signaling in brain regions. Further, my training will entail gaining understanding in fundamentals of GPCR pharmacological principles. I will use mouse models of drug reinforcement initially; my training in understanding addictive behaviors will be augmented by taking a formal course on the neurobiology of addiction and by participating in focused addiction research conferences outlined in the proposal. The studies resulting from this application will be used to identify possible benefits for adjuvant therapy to potentiate antinociception while decreasing the risk of adverse effects. These studies will shed light on the role and mechanism of biased agonism in mice towards the development of safer pain treatment and pharmaceuticals and will provide me the training that I need to continue my career path towards becoming an independent faculty researcher in addiction sciences.