title: 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.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chia-Ju
authors.initials: CJ
authors.lastname: Kuo
authors.forename: Yan-Yu
authors.initials: YY
authors.lastname: Liao
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo'
authors.forename: Lih-Chu
authors.initials: LC
authors.lastname: Chiou
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018847:Opioid Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010487:Periaqueductal Gray / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C479838:(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2); C498512:UFP-102; C000722285:Oprl1 protein, rat