• Yan-Yu Liao, Cynthia Wei-Sheng Lee, Ing-Kang Ho, and Lih-Chu Chiou.
• Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1 Jen-Ai Road, Taipei, Taiwan.
• Life Sci. 2012 Feb 13; 90 (7-8): 306-12.

AimThe nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor was reported to be functionally heterogeneous. We investigated if [Tyr(10)]N/OFQ(1-11), a peptide ligand reported to selectively bind to the high affinity site of (125)I-[Tyr(14)]N/OFQ in rodent brains, can be a tool for revealing the NOP receptor heterogeneity. We have previously founded an NOP receptor subset insensitive to Ro 64-6198 and (+)-5a Compound, two non-peptide NOP agonists, in rat ventrolateral periaqueductal gray (vlPAG) neurons. Here, we examined if [Tyr(10)]N/OFQ(1-11) differentiated (+)-5a Compound-sensitive and -insensitive vlPAG neurons. Certain mu-opioid (MOP) receptor ligands highly competing with [Tyr(10)]N/OFQ(1-11) in binding studies also showed high affinity at expressed heteromeric NOP-MOP receptors. We also examined if [Tyr(10)]N/OFQ(1-11) distinguished heteromeric NOP-MOP receptors from homomeric NOP receptors.Main MethodsThe NOP receptor activity was evaluated by G-protein coupled inwardly rectifying potassium (GIRK) currents in rat vlPAG slices, and by inhibition of cAMP accumulation in HEK293 cells expressing NOP receptors or co-expressing NOP and MOP receptors.Key FindingsIn vlPAG neurons, [Tyr(10)]N/OFQ(1-11), like N/OFQ, induced GIRK currents through NOP receptors. It was less potent (EC(50): 8.98μM) but equi-efficacious as N/OFQ. [Tyr(10)]N/OFQ(1-11) displayed different pharmacological profiles as (+)-5a Compound, and was effective in both (+)-5a Compound-sensitive and -insensitive neurons. In NOP-expressing HEK293 cells and NOP- and MOP-co-expressing cells, [Tyr(10)]N/OFQ(1-11) displayed similar concentration-response curves in decreasing cAMP accumulation.Significance[Tyr(10)]N/OFQ(1-11) is an NOP full agonist and less potent than N/OFQ. However, it can neither reveal the functional heterogeneity of NOP receptors in vlPAG neurons nor differentiate heteromeric NOP-MOP and homomeric NOP receptors.Copyright © 2011 Elsevier Inc. All rights reserved.

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