Investigation of in vivo efficacy of G-protein biased mu opioid receptor agonists.

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PROJECT SUMMARY Typical mu-opioid receptor (MOR) agonists (e.g., oxycodone, fentanyl) are efficacious analgesics for the treatment of moderate to severe pain. However, the therapeutic window of typical MOR agonists for pain management is limited by their unwanted side effects such as respiratory depression and abuse liability. The limitations of typical MOR agonists have prompted the development of novel MOR agonists (e.g., PZM-21, SR- 17018) with more favorable safety profiles. However, the mechanism by which these novel agonists produce their more desirable behavioral effects is still unknown. One body of evidence indicates that the compounds exhibit improved side-effect profiles due to G-protein signaling bias. However, more recent work has challenged this position with evidence indicating that these novel agonists are merely partial agonists at the MOR. Thus, the results from in vitro investigations into mechanisms are conflicting and in vivo studies are lacking. The purpose of this proposal is to investigate a series of G-protein biased MOR agonists in preclinical models of therapeutic and side effects, and under experimental conditions designed to differentiate typical from partial MOR agonists. Under these conditions, typical MOR agonists produce maximal magnitude of effects, and partial MOR agonists produce sub-maximal magnitude of effects. Specifically, Aim 1 will measure the magnitude of analgesia produced by novel MOR agonists in comparison to typical and partial MOR agonists under different levels of thermal nociceptive stimulation in a hot-plate assay. Aim 2 will measure the magnitude of respiratory depression produced by novel MOR agonists, in comparison to typical and partial MOR agonists in a whole-body plethysmography assay. Aim 3 will compare the maximum breakpoint (indicator of abuse liability) mediated by typical, partial, and novel MOR agonists in a self-administration assay under increasing levels of operant challenge provided by a progressive-ratio schedule of reinforcement. Based on the profile of behavioral effects engendered by the novel MOR agonists, we will be able to determine which in vitro position is most closely recapitulated in vivo. Ultimately, our findings from these three aims will inform the development of opioid-based therapeutics with more favorable safety profiles and wider therapeutic windows. To accomplish these aims, the training plan was described in this proposal, and, it will be carried out at the Jackson campus of the University of Mississippi Medical Center. The applicant will be receiving scientific training and professional development from the sponsor, the sponsor's collaborators, the Program In Neuroscience, and the School of Graduate Studies in the Health Sciences.