Nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor, a non-opioid branch of the opioid receptor family, shows structural similarities to traditional opioid receptors but binds opioid with very poor affinity. This receptor has been implicated in many physiological functions including pain regulation. This study quantitatively investigated the effect of (-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1 -yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111), a novel non-peptide ligand of NOP receptor, on the native NOP receptors in the midbrain ventrolateral periaqueductal gray (vlPAG), a crucial region for pain regulation. SB-612111 concentration-dependently antagonized N/OFQ-induced G-protein coupled inwardly rectifying K(+) (GIRK) current in vlPAG neurons. The IC(50) value of SB-612111 estimated from dose-response curves is 87.7±1.2nM. SB-612111 had no intrinsic agonistic activity and did not affect the GIRK current induced by [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin, a mu-opioid receptor agonist, when tested at concentrations of up to 1μM. It is concluded that SB-612111 is a pure, potent and selective antagonist of NOP receptors that mediate GIRK channel activation in the vlPAG neurons.
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