Nociceptin/Orphanin FQ Receptor Activation Attenuates Antinociception Induced by Mixed Nociceptin/Orphanin FQ/ -Opioid Receptor Agonists

Activation of brain nociceptin/orphanin FQ (NOP) receptors leads to attenuation of -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 doseresponse 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-4piperidyl]-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(2,3,3 ,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin2-one. (SR16435), 3-ethyl-1-(1-(4-isopropylcyclohexyl)piperidin4-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 receptormediated antinociception. SB-612111 potentiated antinociception induced by buprenorphine and the other mixed NOP/MOP receptor agonists SR16435 and SR16507. However, SB612111 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 receptormediated 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. Buprenorphine is a potent analgesic that is widely used both in the clinic and in the laboratory because of its high therapeutic index. In analgesia experiments in rodents, buprenorphine has been demonstrated to have a very flat, or even an inverted U-shaped dose-response curve, under appropriate experimental conditions (Cowan et al., 1977; Lutfy et al., 2003). Buprenorphine is also approved as a medication for heroin abuse. Buprenorphine’s approval as an addiction medication was based on many years of preclinical experiments and clinical trials demonstrating that a daily dose of buprenorphine attenuates heroin abuse while maintaining the patient in a condition suitable for daily life (Jasinski et al., 1978). Because of its safety, buprenorphine has replaced This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA023281, DA14026] (to L.T. and N.Z., respectively). This work was presented in part at the International Narcotics Research Conference; 2000 Jul 13–18; Charleston, SC. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.109.156711. ABBREVIATIONS: MOP receptor, -opioid receptor; CHO cells, Chinese hamster ovary cells; N/OFQ, nociceptin/orphanin FQ; MPE, maximum possible effect, NOP receptor, nociceptin/orphanin FQ receptor; J113397, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3dihydro-2H-benzimidazol-2-one; SB-612111, ( )-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten5-ol; SR16507, 3-ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin-2-one; JTC-801, N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride; G418, (2R,3S,4R,5R,6S)-5-amino-6-[(1R,2S,3S,4R,6S)-4,6-diamino-3-[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl4-methylaminooxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-2-(1-hydroxyethyl)oxane-3,4-diol; Ro 64-6198, (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1Hphenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one; UFP-101, [Nphe,Arg,Lys]nociceptin-NH2; DAMGO, (2S)-2-[[2-[[(2R)-2-[[(2S)-2amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]acetyl]-methylamino]-N-(2-hydroxyethyl)-3-phenylpropanamide; GTP S, guanosine 5 -3-O-(thio)triphosphate; ANOVA, analysis of variance; CPP, conditioned place preference; SR16835, 1-(1-(2,3,3 ,4,5,6-hexahydro-1H-phenalen-1yl)piperidin-4-yl)-indolin-2-one. 0022-3565/09/3313-946–953$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 331, No. 3 Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics 156711/3529366 JPET 331:946–953, 2009 Printed in U.S.A. 946 at A PE T Jornals on July 9, 2017 jpet.asjournals.org D ow nladed from methadone maintenance in a large number of methadonemaintained addicts. Although it is not approved for the treatment of cocaine or alcohol abuse, buprenorphine has been shown to decrease the self-administration of both of those drugs as well in rodents, non-human primates, and people (Martin et al., 1983; Mello et al., 1989; June et al., 1998). However, the exact mechanism of this action is not known. Buprenorphine is a long-lasting, high-affinity opiate with partial agonist activity at MOP receptors (Lewis, 1985). It also has high affinity to the other opioid receptors, and is a partial agonist at -opioid receptors and an antagonist at -opioid receptors (Spagnolo et al., 2008). More recently, it was reported that buprenorphine also binds to the NOP receptors (Wnendt et al., 1999; Huang et al., 2001; Spagnolo et al., 2008). The affinity of buprenorphine for NOP receptors (Ki 80–100 nM) is not as high as its affinity for the other opioid receptors, at which the Ki is in the low nanomolar range (Toll et al., 1998). It is thought that the activity of buprenorphine at the NOP receptor contributes to its shallow dose-response curve for antinociception. NOP receptors, like the opioid receptors, are involved in a large number of central nervous system and peripheral actions. However, nociceptin/orphanin FQ (N/OFQ), the endogenous ligand for NOP receptors, in general does not have actions similar to the opioid peptides. In fact, when delivered intracerebroventricularly, N/OFQ is not analgesic, it blocks opioid analgesic activity (Meunier et al., 1995; Reinscheid et al., 1995), and it is not rewarding (Devine et al., 1996). Furthermore, N/OFQ blocks the reward induced by opiates and many other drugs of abuse (Murphy et al., 1999; Kotlinska et al., 2003; Ciccocioppo et al., 2004; Sakoori and Murphy, 2004). Despite its moderate to low affinity at NOP receptors, there are reports of agonist or partial agonist activity of buprenorphine at NOP receptors, with EC50 values ranging from 8 to 100 nM, in a variety of in vitro activity assays (Wnendt et al., 1999; Hashimoto et al., 2000; Huang et al., 2001; Lutfy et al., 2003). However, other reports have shown a lack of any intrinsic activity for buprenorphine at NOP receptor (Lester and Traynor, 2006; Spagnolo et al., 2008). Based on the agonist activity of buprenorphine at NOP receptors, Lutfy et al. (2003) hypothesized that the NOP receptor agonist activity of buprenorphine attenuated its own antinociceptive activity, and this was the reason for the partial agonist activity of buprenorphine and the inverted U-shaped dose-response curve in the tail-flick test. Experiments using NOP receptor knockout mice, and a selective NOP receptor antagonist, J113397, demonstrated full agonist activity for buprenorphine, in the tail-flick test, under conditions when NOP receptor agonist activity would be absent, supporting their hypothesis (Lutfy et al., 2003). Certainly, the most straightforward explanation for the high-dose activity of buprenorphine is that it is activating NOP receptors to attenuate its MOP receptor-mediated antinociceptive activity. However, there are reasons to question this hypothesis. First, the affinity of buprenorphine for NOP receptors is far less than its affinity for any of the opioid receptors. Nevertheless, in the tail-flick experiments, its activity was potentiated by the NOP receptor antagonist J113397, even at the lowest doses of buprenorphine (Lutfy et al., 2003). Second, it is a weak partial agonist, at best, at NOP receptor in most in vitro assays. It is conceivable that other properties could explain the behavior discussed above. To further test the hypothesis that buprenorphine acts at NOP receptors to attenuate it own antinociceptive activity, we conducted experiments by use of agonists with varying affinities and efficacies at NOP and MOP receptors, and determined whether their antinociceptive activity could be potentiated by the selective high-affinity NOP receptor antagonist SB-612111 (Zaratin et al., 2004). Materials and Methods