Quantitative study of [(pF)Phe4,Arg14,Lys15]nociceptin/orphanin FQ-NH2 (UFP-102) at NOP receptors in rat periaqueductal gray slices.

Abstract

The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor is a novel member of the opioid receptor family with little affinity for traditional opioids. This receptor and its endogenous ligand, N/OFQ, are widely distributed in the brain and are implicated in many physiological functions including pain regulation. [(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2) (UFP-102) is a newly developed peptide agonist of NOP receptors. In this study, we quantitatively investigated the effect of UFP-102 at native NOP receptors of the ventrolateral periaqueductal gray (PAG), a crucial midbrain area involved in pain regulation and enriched with NOP receptors, using blind patch-clamp whole-cell recording technique in rat brain slices. UFP-102, like N/OFQ, induced an outward current in ventrolateral PAG neurons and increased the membrane current elicited by a hyperpolarization ramp from -60 to -140 mV. The current induced by UFP-102 was characterized with inward rectification and had a reversal potential near the equilibrium potential of K(+) ions, indicating that UFP-102 activates G-protein coupled inwardly rectifying K(+) channels. The effect of UFP-102 was concentration-dependent with the maximal effect similar to that of N/OFQ. The EC(50) value was 11+/-2 nM, which is 5 fold lower than that of N/OFQ. The effect of UFP-102 was not affected by naloxone while competitively antagonized by UFP-101 ([Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2)), a potent NOP receptor antagonist, with a pA(2) value of 6.7. These results suggest that UFP-102 is a full agonist at the postsynaptic NOP receptors of the midbrain of rats and is 5 fold more potent than N/OFQ.

• Authors: Chia-Ju Kuo, Yan-Yu Liao, Remo Guerrini, Girolamo Calo', Lih-Chu Chiou
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 579 Issue 1-3 Pg. 110-5 (Jan 28 2008) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17976580 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (Nphe(1),Arg(14),Lys(15))N-OFQ NH(2)
• G Protein-Coupled Inwardly-Rectifying Potassium Channels
• Opioid Peptides
• Receptors, Opioid
• UFP-102
• nociceptin
• Nociceptin Receptor
• Oprl protein, rat

Topics

• Animals
• Dose-Response Relationship, Drug
• Electrophysiology
• G Protein-Coupled Inwardly-Rectifying Potassium Channels (drug effects, metabolism)
• In Vitro Techniques
• Neurons (drug effects, metabolism)
• Opioid Peptides (administration & dosage, pharmacology)
• Patch-Clamp Techniques
• Periaqueductal Gray (drug effects, metabolism)
• Rats
• Rats, Wistar
• Receptors, Opioid (agonists, metabolism)
• Nociceptin Receptor