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

被引:97
作者
Ding, Huiping [1 ]
Kiguchi, Norikazu [1 ,2 ]
Yasuda, Dennis [3 ]
Daga, Pankaj R. [3 ]
Polgar, Willma E. [3 ]
Lu, James J. [3 ]
Czoty, Paul W. [1 ]
Kishioka, Shiroh [2 ]
Zaveri, Nurulain T. [3 ]
Ko, Mei-Chuan [1 ,4 ]
机构
[1] Wake Forest Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27157 USA
[2] Wakayama Med Univ, Dept Pharmacol, Wakayama, Japan
[3] Astraea Therapeut, Mountain View, CA 94043 USA
[4] WG Hefner Vet Affairs Med Ctr, Salisbury, NC 28144 USA
关键词
PROGRESSIVE-RATIO SCHEDULES; FQ PEPTIDE RECEPTORS; ABUSE LIABILITY; INDUCED HYPERALGESIA; UNITED-STATES; INDUCED ITCH; MORPHINE; LIGANDS; NOP; PAIN;
D O I
10.1126/scitranslmed.aar3483
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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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页数:11
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