The Therapeutic Potentialof Nociceptin/Orphanin FQReceptor Agonists as Analgesics without Abuse Liability

摘要

Although mu opioid (MOP) receptor agonists are the most commonly used analgesics for the treatment of moderate to severe pain in the clinic, the side effects of MOP agonists such as abuse liability limit their value as a medication. Research to identify novel analgesics without adverse effects is pivotal to advance the health care of humans. The nociceptin/orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, mediates distinctive actions in nonhuman primates which suggests the possibility that activity at this receptor may result in strong analgesia in the absence of virtually all of the side effects associated with MOP agonists. The present review highlights the recent progress of pharmacological studies of NOP-related ligands in primates. Selective NOP agonists, either peptidic or nonpeptidic, produce full analgesia in various assays in primates, when delivered systemically or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers, indicating a lack of abuse liability. Given that NOP agonists have low abuse liability and that coactivation ofNOP and MOP receptors produces synergistic antinociception, it isworth developing bifunctional NOP/MOP ligands. The outcomes of thesestudies and recent developments provide new perspectives to establisha translational bridge for understanding the biobehavioral functionsof NOP receptors in primates and for facilitating the developmentof NOP-related ligands as a new generation of analgesics without abuseliability in humans.