[Nphe(1)]N/OFQ-(1-13)-NH(2) is a competitive and selective antagonist at nociceptin/orphanin FQ receptors mediating K(+) channel activation in rat periaqueductal gray slices.
A novel member of the opioid related receptor family, the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor was identified and demonstrated to be involved in many physiological functions including pain regulation. [Nphe(1)]N/OFQ-(1-13)-NH(2) (Nphe) is a novel peptide antagonist of NOP receptors, developed using peripheral preparations. We have quantitatively investigated the interaction of Nphe with N/OFQ, the endogenous ligand of NOP receptors, in the midbrain ventrolateral periaqueductal gray (PAG), a crucial brain region for N/OFQ-induced reversal of opioid analgesia, using the patch-clamp recording technique in brain slices. N/OFQ concentration-dependently activated an inwardly rectifying K(+) current in response to hyperpolarization ramps from -60 to -140 mV. Nphe concentration-dependently attenuated the K(+) current activated by N/OFQ without changing its reversal potential. The presence of Nphe right-shifted the concentration-response curve to N/OFQ in a parallel manner. The Schild plot analysis yielded a slope of 1.16 and a pA(2) value of 6.64 that is similar to those obtained in peripheral preparations. At concentrations up to 3 microM, Nphe affected neither the membrane current per se, nor the inwardly rectifying K(+) current activated by [D-Ala(2), N-Me-Phe(4),Gly-ol(5)]-enkephalin or baclofen, a mu-opioid and GABA(B) receptor agonist, respectively. It is concluded that Nphe acts as a pure, selective and competitive antagonist at native NOP receptors of ventrolateral PAG neurons.
Chiou
Lih-Chu
LC
Department of Pharmacology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd., Section 1, Taipei 100, Taiwan. lcchiou@ha.mc.ntu.edu.tw
Fan
Shu-Huai
SH
Guerrini
Remo
R
Caló
Girolamo
G
D000818:Animals; D004594:Electrophysiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009292:Narcotic Antagonists; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018847:Opioid Peptides / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology*; D010487:Periaqueductal Gray / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D015221:Potassium Channels / Q000819:agonists*; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor
D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010446:Peptide Fragments; D015221:Potassium Channels; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; C439964:nociceptin (1-13) amide; C000722285:Oprl1 protein, rat