Opioid analgesics, such as morphine, mediate their effects through activation of mu opioid receptors (MOR). As G protein-coupled receptors (GPCR), MOR signals through heterotrimeric G proteins and engages βarrestins. As multifaceted scaffolding proteins, βarrestins can engage with the receptor and either prevent activation of certain pathways (desensitization) or promote further downstream signaling by recruiting diverse signaling partners. There is substantial preclinical evidence in βarrestin2-KO mice that suggests that MOR may be negatively regulated by βarrestin2 in pathways promoting analgesia while MOR may utilize barrestin2 in pathways leading to certain side effects including tolerance, constipation and respiratory suppression. In this presentation, we discuss the utilization of new small molecule MOR agonists that have been developed at Scripps Florida that induce MOR signaling towards G protein pathways and away from βarrestin2 recruitment. These “G protein biased” agonists are potent and long lasting in promoting antinociception and have a highly diminished side effect profile in mice. These findings support the strengthening hypothesis that biased GPCR agonists can serve to harness desirable efficacy while diminishing adverse drug events. Moreover, we propose that "G biased" MOR agonists may be promising for widening the clinical therapeutic window for obtaining pain relief without side effects. Supported by NIH/NIDA grant 1R01DA033073 to LMB & TDB.

Harnessing ligand-directed signaling to improve pain therapeutics

249th National Meeting (2015)

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