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

Eur J Pharmacol. 2008 Jan 28;579(1-3):110-5. doi: 10.1016/j.ejphar.2007.10.006. Epub 2007 Oct 11.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • (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