Abstract
We identified a novel nociceptin/orphanin FQ (NOP)/μ-opioid receptor agonist, SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], with high binding affinity and partial agonist activity at both receptors. It was hypothesized that SR 16435 would produce antinociception and yet, unlike morphine, would have diminished rewarding properties and tolerance development. Antinociception was assessed in mice using the tail-flick assay, whereas behavioral and rewarding effects were assessed using the place conditioning (PC) paradigm. PC was established by pairing drug injections with a distinct compartment. Behavioral effects were measured after acute and repeated drug administration, and the test for PC was carried out 24 h after four drug- and vehicle-pairing sessions. SR 16435 produced an increase in tail-flick latency, but SR 16435-induced antinociception was lower than that observed with morphine. Given that naloxone blocked SR 16435-induced antinociception, it is highly likely that this effect was mediated by μ-opioid receptors. Compared with morphine, chronic SR 16435 treatment resulted in reduced development of tolerance to its antinociceptive effects. SR 16435-induced conditioned place preference (CPP) was evident, an effect that was probably mediated via μ-opioid receptors, as it was reversed by coadministration of naloxone. NOP agonist activity was also present, given that SR 16435 decreased global activity, and this effect was partially reversed with the selective NOP antagonist, SR 16430 [1-(cyclooctylmethyl)-4-(3-(trifluoromethyl)phenyl)piperidin-4-ol]. Naloxone, however, also reversed the SR 16435-induced decrease in activity, indicating that both opioid and NOP receptors mediate this behavior. In summary, the mixed NOP/μ-opioid partial agonist SR 16435 exhibited both NOP and μ-opioid receptor-mediated behaviors.
Footnotes
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This research was supported by National Institute on Drug Abuse Grant DA14026 (to N.T.Z.).
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Preliminary reports of these data were presented at the following annual meetings: Khroyan TV, Zaveri NT, Polgar WE, Orduna J, Olsen C, Jiang F, and Toll L (2006) Differential effects of mixed NOP/mu receptor ligands in antinociception and reward in mice, in College on Problems of Drug Dependence Abst.; 2006 June 17–22; Phoenix, AZ. College on Problems of Drug Dependence, Philadelphia; Khroyan TV, Zaveri N, Polgar WE, Orduna J, and Toll L (2004). Rewarding and analgesic effects of a novel mu-opioid, ORL1 agonist, in College on Problems of Drug Dependence Conference; 2004 June 12–17; San Juan, Puerto Rico. College on Problems of Drug Dependence, Philadelphia; and Khroyan TV, Zaveri N, Polgar WE, Orduna J, and Toll L (2004) Examining the analgesic and rewarding effects of SR16435, a novel mu-opioid/NOP agonist, in Society for Neuroscience Abst; 2004 Oct 23–27; San Diego, CA. Society for Neuroscience, Washington, DC.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.111997.
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ABBREVIATIONS: NOP receptor, nociceptin/orphanin FQ receptor, opioid receptor-like receptor (ORL1); N/OFQ, nociceptin/orphanin FQ; i.c.v., intracerebroventricular; i.t., intrathecal; UFP-101, [Nphe1,Arg14,Lys15]N/OFQ-NH2; PC, place conditioning; J-113397, (1-[3R,4R)-1-cyclooctymethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3,-dihydro-2H-benzimidazol-2-one; SB-612611, (–)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol; JTC-801, N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride; Ro 64-6198, 1S,3aS-8–2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one; PC, place conditioning; CPP, conditioned place preference, CPA, conditioned place aversion; GTPγS, guanosine 5′-O-(3-thio)triphosphate; SR 16435, 1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one; SR 16430, 1-(cyclooctylmethyl)-4-(3-(trifluoromethyl)phenyl)piperidin-4-ol; %MPE, % maximal potential effect; ANOVA, analysis of variance; SR 14150 1-(1-cyclooctyl-piperidin-4-yl)1,3-dihydro-indol-2-one.
- Received August 3, 2006.
- Accepted November 21, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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SR 16435 [1-(1-(Bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], a Novel Mixed Nociceptin/Orphanin FQ/μ-Opioid Receptor Partial Agonist: Analgesic and Rewarding Properties in Mice
