Project Summary Mu opioid receptor (MOR) agonists are the most effective treatments for moderate to severe acute pain, but their high abuse liability and risk for lethal overdose have exacted a significant toll on public health in recent years. Our program of study has investigated the feasibility of combining MOR agonists with kappa opioid receptor (KOR) agonists to deter abuse and enhance pain-decreasing effects. Our findings from Project Period 1 of this program indicate that the atypical KOR agonist, nalfurafine, decreases oxycodone’s abuse-related effects and enhances analgesia, but nalfurafine also produced significant sedative effects on its own. Recently, new KOR agonists have been developed that are reported to produce even fewer of the adverse behavioral effects that are typical of the KOR-agonist class. These atypical KOR agonists have been described as “G-protein biased” due to their greater potency to activate G-protein signaling relative to other pathways at the KOR. Our preliminary data indicate that the biased KOR agonist, triazole 1.1, is more therapeutically selective than nalfurafine. However, it is unknown if the positive characteristics observed with triazole 1.1 are due to G-protein bias or other potential mechanisms peculiar to the structural class. The overall goal of this renewal application is to systematically investigate combinations of oxycodone with new atypical KOR agonists that are reported to be G-protein biased from different structural classes to determine if reported signaling bias is associated with increased therapeutic selectivity (decreased abuse potential; enhanced antinociception) and reduced KOR-mediated “side effects”. To accomplish this goal, we will use complementary animal models (rhesus monkeys and rats) and rigorous quantitative pharmacology to determine if the atypical KOR agonists can reduce oxycodone’s abuse- related effects (Specific Aim 1), augment oxycodone’s pain-decreasing effects (Aim 2), and produce fewer side effects when combined with oxycodone (Aim 3). We will relate the relative potencies of the various KOR agonists to produce therapeutic and unwanted side effects to identify optimal leads for future development of therapeutics that activate MORs and KORs (dual-acting molecules; drug combinations). The studies proposed in this renewal will positively impact public health by laying the groundwork for the development of non-addictive pain medications that will retain the high treatment efficacy of current prescription opioids.