Opioids acting at the mu opioid receptor (MOR) remain the gold standard for moderate to severe pain relief, but serious side effects, particularly abuse liability, limit their use. The opioid epidemic has grown steadily in the past two decades, resulting in 130 deaths per day. Medications for treatment of opioid use disorder (OUD), particularly methadone and buprenorphine, have been helpful, but also have limitations. In addition to issues of compliance, they have reinforcing effects themselves, contributing to the need for close regulation. In this program, we will test modifications of a core pharmacophore of endomorphin analogs that has been shown to provide pain relief comparable to morphine while exhibiting reduction of several side effects, including abuse liability. In this program we will synthesize and screen glycosylated analogs of endomorphin with the goal of enhancing the blood-brain-barrier penetration and oral activity of the compounds. We will test them for antinociception and their ability to block the rewarding effects of morphine. The goal of these studies is to provide proof-of-concept that novel endomorphin analogs can provide 1.) Effective treatment of pain without rewarding properties, reducing the initiation of OUD and 2.) Effective blockade of opioid-induced reward, providing the basis for a novel medication for treatment of OUD.