TY - JOUR T1 - Modification of Nociception and Morphine Tolerance by the Selective Opiate Receptor-Like Orphan Receptor Antagonist (–)-<em>cis</em>-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5<em>H</em>-benzocyclohepten-5-ol (SB-612111) JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 454 LP - 461 DO - 10.1124/jpet.103.055848 VL - 308 IS - 2 AU - Paola F. Zaratin AU - Giuseppe Petrone AU - Massimo Sbacchi AU - Martine Garnier AU - Claudia Fossati AU - Paola Petrillo AU - Silvio Ronzoni AU - Giuseppe A. M. Giardina AU - Mark A. Scheideler Y1 - 2004/02/01 UR - http://jpet.aspetjournals.org/content/308/2/454.abstract N2 - (–)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) is a novel human opiate receptor-like orphan receptor (ORL-1) antagonist that has high affinity for the clonal human ORL-1 receptor (hORL-1 Ki = 0.33 nM), selectivity versus μ-(174-fold), δ-(6391-fold), and κ (486-fold)-opioid receptors and is able to inhibit nociceptin signaling via hORL-1 in a whole cell gene reporter assay. SB-612111 has no measurable antinociceptive effects in vivo in the mouse hot-plate test after intravenous administration but is able to antagonize the antimorphine action of nociceptin [ED50 = 0.69 mg/kg, 95% confidence limit (CL) = 0.34–1.21]. SB-62111 administration can also reverse tolerance to morphine in this model, established via repeated morphine administration. In addition, intravenous SB-612111 can antagonize nociceptin-induced thermal hyperalgesia in a dose-dependent manner (ED50 = 0.62 mg/kg i.v., 95% CL = 0.22–1.89) and is effective per se at reversing thermal hyperalgesia in the rat carrageenan inflammatory pain model. These data show that an ORL-1 receptor antagonist may be a useful adjunct to chronic pain therapy with opioids and can be used to treat conditions in which thermal hyperalgesia is a significant component of the pain response. The American Society for Pharmacology and Experimental Therapeutics ER -