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

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.

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.

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.

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.

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).