title: The novel inhibitor of the heterotrimeric G-protein complex, BIM-46187, elicits anti-hyperalgesic properties and synergizes with morphine.
abstract: BIM-46187 (7-[2-amino-1-oxo-3-thio-propyl]-8-cyclohexylmethyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine dimer, hydrochloride) is an inhibitor of the heterotrimeric G-protein complex signalling. Since many mediators of pain act through G-protein coupled receptors, the anti-hyperalgesic effects of BIM-46187 were assessed on experimental models of pain. In addition since opioids are widely used in pain management and act through specific G-protein-coupled receptors, the effects of BIM-46187 on the analgesic properties of morphine have also been investigated. BIM-46187 elicited a dose dependent analgesic effect in the models of carrageenan-induced hyperalgesia (0.1-1 mg/kg; i.v.) and chronic constriction injury (0.3-3 mg/kg; i.v.) in rats. BIM-46187, however, up to 10 mg/kg did not modify the paw oedema induced by carrageenan excluding an anti-inflammatory effect. In addition, at these doses, the compound was not sedative as shown by the lack of effect on the motor performance in the rotarod test. The combination of BIM-46187 and morphine (ratio 1/1) resulted in an unexpected synergistic effect in the model of carrageenan-induced hyperalgesia and in the chronic constriction injury model in rats when evaluated by isobolographic analysis. This synergy allowed a reduction of at least 20 fold in the dose of each compound. Conversely, the drug combination did not increase the side effects of morphine as assessed in the rotarod test. In conclusion, BIM-46187 elicits a potent anti-hyperalgesic effect and strongly synergizes with morphine. This work highlights the role of heterotrimeric G-protein complexes in pain and supports further investigations of the use of BIM-46187 alone, or in combination with low doses of morphine, in the management of pain.
authors.affiliation: Ipsen-Institut Henri Beaufour, 5 avenue du Canada, 91966 Les Ulis Cedex, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Favre-Guilmard
authors.forename: Hamida
authors.initials: H
authors.lastname: Zeroual-Hider
authors.forename: Chantal
authors.initials: C
authors.lastname: Soulard
authors.forename: Caroline
authors.initials: C
authors.lastname: Touvay
authors.forename: Pierre-Etienne
authors.initials: PE
authors.lastname: Chabrier
authors.forename: Grégoire
authors.initials: G
authors.lastname: Prevost
authors.forename: Michel
authors.initials: M
authors.lastname: Auguet
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002351:Carrageenan; D003251:Constriction, Pathologic / Q000473:pathology; D003510:Cyclohexanes / Q000494:pharmacology*; D004357:Drug Synergism; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D020962:Heterotrimeric GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000473:pathology / Q000523:psychology; D011597:Psychomotor Performance / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C533004:7-(2-amino-1-oxo-3-thio-propyl)-8-cyclohexylmethyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-(1,2a)-pyrazine dimer, hydrochloride; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003510:Cyclohexanes; D011719:Pyrazines; D009020:Morphine; D002351:Carrageenan; D020962:Heterotrimeric GTP-Binding Proteins