RT Journal Article
SR Electronic
T1 Comparison of the Anti-nociceptive and Anti-Rewarding Profiles of Novel Bifunctional Nociceptin/Orphanin FQ Receptor (NOPr)-Mu Opioid Receptor (MOPr) Ligands: Implications for Therapeutic Applications
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.109.157446
DO 10.1124/jpet.109.157446
A1 Lawrence R. Toll
A1 Taline V Khroyan
A1 Willma Polgar
A1 Faming Jiang
A1 Cris Olsen
A1 Nurulain T. Zaveri
YR 2009
UL http://jpet.aspetjournals.org/content/early/2009/09/22/jpet.109.157446.abstract
AB The nociceptin receptor, NOPr, a member of the opioid receptor family, is a target for the treatment of pain and drug abuse. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide for NOPr, not only modulates opioid antinociception, but also blocks the rewarding effects of several abused drugs, such as morphine, cocaine and amphetamine. We hypothesized that NOPr agonists, with bifunctional activity at the mu-opioid receptor (MOPr), may function as non-addicting analgesics or as drug abuse medications. Bifunctional small-molecule NOPr agonists possessing different selectivities and efficacies at MOPr were evaluated in an acute thermal antinociception assay, and for their ability to induce conditioned place preference (CPP) and their effect on morphine-induced CPP. SR14150, a high-affinity NOPr partial agonist, with low MOPr affinity and efficacy, produced analgesia that was naloxone-reversible. SR14150 did not induce CPP alone, nor did it attenuate morphine-induced CPP. SR16507, which has high affinity for both NOPr and MOPr, full agonist activity at NOPr and partial agonist activity at MOPr, was also a potent analgesic and produced CPP alone, but also modestly attenuated morphine CPP. SR16835, a NOPr full agonist and low-affinity MOPr partial agonist, was not antinociceptive, did not produce CPP alone, but attenuated morphine CPP. Our results suggest that NOPr full agonist activity is required to modulate opioid-induced reward whereas a bifunctional NOPr/MOPr partial agonist profile may be suitable as a non-addicting analgesic. The opioid-modulating effects of the NOPr ligands may be effectively utilized to produce better medications for treatment of drug abuse and pain.The American Society for Pharmacology and Experimental Therapeutics