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Modification of nociception and morphine tolerance by the selective opiate receptor-like orphan 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).
Zaratin, Paola F; Petrone, Giuseppe; Sbacchi, Massimo; Garnier, Martine; Fossati, Claudia; Petrillo, Paola; Ronzoni, Silvio; Giardina, Giuseppe A M; Scheideler, Mark A.
Afiliação
  • Zaratin PF; GlaxoSmithKline Pharmaceuticals, Department of Neurobiology Research, Milan, Italy.
J Pharmacol Exp Ther ; 308(2): 454-61, 2004 Feb.
Article em En | MEDLINE | ID: mdl-14593080
(-)-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 K(i) = 0.33 nM), selectivity versus mu-(174-fold), delta-(6391-fold), and kappa (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 [ED(50) = 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 (ED(50) = 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.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperidinas / Cicloeptanos / Tolerância a Medicamentos / Morfina / Antagonistas de Entorpecentes Limite: Animals / Humans Idioma: En Revista: J Pharmacol Exp Ther Ano de publicação: 2004 Tipo de documento: Article País de afiliação: Itália País de publicação: Estados Unidos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperidinas / Cicloeptanos / Tolerância a Medicamentos / Morfina / Antagonistas de Entorpecentes Limite: Animals / Humans Idioma: En Revista: J Pharmacol Exp Ther Ano de publicação: 2004 Tipo de documento: Article País de afiliação: Itália País de publicação: Estados Unidos