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.2009 Dec;331(3):946-53.
doi: 10.1124/jpet.109.156711. Epub 2009 Aug 27.

Nociceptin/orphanin FQ receptor activation attenuates antinociception induced by mixed nociceptin/orphanin FQ/mu-opioid receptor agonists

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Nociceptin/orphanin FQ receptor activation attenuates antinociception induced by mixed nociceptin/orphanin FQ/mu-opioid receptor agonists

Taline V Khroyan et al. J Pharmacol Exp Ther.2009 Dec.

Abstract

Activation of brain nociceptin/orphanin FQ (NOP) receptors leads to attenuation of mu-opioid receptor (MOP receptor)-mediated antinociception. Buprenorphine, a high-affinity partial MOP receptor agonist also binds to NOP receptors with 80 nM affinity. The buprenorphine-induced inverted U-shaped dose-response curve for antinociception may be due to NOP receptor activation, given that, in the presence of the NOP receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J113397), or in NOP receptor knockout mice, buprenorphine has a steeper dose-response curve and acts as a full agonist. To further explore the involvement of the direct activation of NOP receptors by buprenorphine and other compounds that activate both NOP and MOP receptors, the antinociceptive effects of 1-(1-(2,3,3alpha,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one. (SR16435), 3-ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin-2-one (SR16507), buprenorphine, pentazocine, and morphine, compounds with varying levels of MOP and NOP receptor affinity and efficacy, were assessed in mice using the tail-flick assay. The ability of the selective NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) to potentiate antinociception induced by the above compounds was examined to investigate whether activation of NOP receptors leads to attenuation of MOP receptor-mediated antinociception. SB-612111 potentiated antinociception induced by buprenorphine and the other mixed NOP/MOP receptor agonists SR16435 and SR16507. However, SB-612111 had no effect on pentazocine or morphine antinociception, two compounds with no NOP receptor-binding affinity. These results further support the hypothesis that activation of NOP receptors can lead to attenuation of MOP receptor-mediated antinociception elicited by mixed NOP/MOP receptor compounds such as buprenorphine, SR16435, and SR16507 and that, although buprenorphine has low efficacy in vitro, it has significant NOP receptor agonist activity in vivo.

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Figures

Fig. 1.
Fig. 1.
Acute thermal antinociceptive effect of buprenorphine alone or coadministered with SB-612111 by use of the tail-flick assay at 10 min (A), 30 min (B), and 60 min (C) after injection. Data are mean %MPE (± S.E.M.). An asterisk (*) represents a significant difference from their respective vehicle controls, whereas a plus sign (+) represents a significant difference from buprenorphine alone (P < 0.05).
Fig. 2.
Fig. 2.
Acute thermal antinociceptive effect of mixed NOP receptor/MOP receptor partial agonist SR16435 alone or coadministered with SB-612111 by use of the tail-flick assay at 10 min (A), 30 min (B), and 60 min (C) after injection. Data are mean %MPE (± S.E.M.). An asterisk (*) represents a significant difference from their respective vehicle controls, whereas a plus sign (+) represents a significant difference from SR16435 alone (P < 0.05).
Fig. 3.
Fig. 3.
Acute thermal antinociceptive effect of mixed NOP receptor/MOP receptor full agonist SR16507 alone or coadministered with SB-612111 by use of the tail-flick assay at 10 min (A), 30 min (B), and 60 min (C) after injection. Data are mean %MPE (± S.E.M.). An asterisk (*) represents a significant difference from their respective vehicle controls, whereas a plus sign (+) represents a significant difference from SR16507 alone (P < 0.05).
Fig. 4.
Fig. 4.
Acute thermal antinociceptive effect of MOP receptor full agonist morphine (A, B) and partial agonist pentazocine (C, D) alone or coadministered with SB-612111 using the tail-flick assay at 30 and 60 min after injection. Data are mean %MPE (± S.E.M.). An asterisk (*) represents a significant difference from their respective vehicle controls (P < 0.05).
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