Research ArticlePain

A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates

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Science Translational Medicine  29 Aug 2018:
Vol. 10, Issue 456, eaar3483
DOI: 10.1126/scitranslmed.aar3483

A dual-targeting painkiller

Opioids are among the most effective treatments for severe pain. Their pain-relieving effects are mediated by activation of the mu opioid peptide (MOP) receptor. Unfortunately, selective MOP agonists induce diverse side effects, including respiratory depression, tolerance, hyperalgesia, and dependence. Recently, activation of the nociceptin/orphanin FQ peptide (NOP) receptor has been reported to enhance MOP agonist–induced analgesia without producing side effects. Now, Ding et al. have developed a bifunctional MOP/NOP agonist, called AT-121, that showed potent analgesic effects in nonhuman primates without inducing hyperalgesia, respiratory depression, or dependence. The results suggest that bifunctional MOP/NOP agonists might represent a safe and effective pharmacological tool for treating severe pain.


Misuse of prescription opioids, opioid addiction, and overdose underscore the urgent need for developing addiction-free effective medications for treating severe pain. Mu opioid peptide (MOP) receptor agonists provide very effective pain relief. However, severe side effects limit their use in the clinical setting. Agonists of the nociceptin/orphanin FQ peptide (NOP) receptor have been shown to modulate the antinociceptive and reinforcing effects of MOP agonists. We report the discovery and development of a bifunctional NOP/MOP receptor agonist, AT-121, which has partial agonist activity at both NOP and MOP receptors. AT-121 suppressed oxycodone’s reinforcing effects and exerted morphine-like analgesic effects in nonhuman primates. AT-121 treatment did not induce side effects commonly associated with opioids, such as respiratory depression, abuse potential, opioid-induced hyperalgesia, and physical dependence. Our results in nonhuman primates suggest that bifunctional NOP/MOP agonists with the appropriate balance of NOP and MOP agonist activity may provide a dual therapeutic action for safe and effective pain relief and treating prescription opioid abuse.

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