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).
(-)-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.
GlaxoSmithKline Pharmaceuticals, Department of Neurobiology Research, Milan, Italy.
Paola F
PF
Zaratin
Giuseppe
G
Petrone
Massimo
M
Sbacchi
Martine
M
Garnier
Claudia
C
Fossati
Paola
P
Petrillo
Silvio
S
Ronzoni
Giuseppe A M
GA
Giardina
Mark A
MA
Scheideler
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003508:Cycloheptanes / Q000494:pharmacology* / Q000627:therapeutic use; D004361:Drug Tolerance / Q000502:physiology*; D006801:Humans; D009020:Morphine / Q000009:adverse effects* / Q000627:therapeutic use; D009292:Narcotic Antagonists; D010146:Pain / Q000188:drug therapy; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor
D003508:Cycloheptanes; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; C482404:cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol; D009020:Morphine; D000094942:Nociceptin Receptor