The NOP receptor, the fourth receptor in the opioid receptor family, is found throughout the brain and is involved in a variety
of CNS systems and pathways. The endogenous ligand for NOP receptors, nociceptin/orphanin FQ (now called N/OFQ), was originally
thought to increase a painful stimulus since intracerebroventricular (i.c.v.) administration of this heptadecapeptide led to a decrease in
tail-flick and hot-plate latency in mice. Further studies suggested that N/OFQ blocks opiate analgesia when administered i.c.v. but potentiates
opiate analgesia and has antinociceptive activity when administered intrathecally. I.c.v. administration of N/OFQ has other beneficial
actions including inhibition of reward induced by several different abused drugs, as well as anti-anxiety activity. Recent work has
demonstrated that individual small molecules that activate both NOP and mu receptors possess mu-mediated antinociceptive activity with
reduced reward, as determined by conditioned place preference tests. Furthermore, selective NOP receptor agonists appear to be active in
certain chronic pain models and reduce both drug craving and anxiety. NOP receptor antagonists may also have therapeutic benefits since
both peptide and small molecule antagonists have anti-depressant activity in two different animal models. Therefore, both selective NOP
receptor compounds and non-selective compounds, with both NOP receptor and mu opioid receptor activity, appear to have potential for
clinical use for several neurological and psychiatric disorders including acute and chronic pain, drug abuse, anxiety and depression.
Keywords: Nociceptin/orphanin FQ, NOP receptor, antinociception, drug abuse, anxiety, antidepressant, Parkinson’s disease.
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