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The novel inhibitor of the heterotrimeric G-protein complex, BIM-46187, elicits anti-hyperalgesic properties and synergizes with morphine.
Eur J Pharmacol. 2008 Oct 10; 594(1-3):70-6.EJ

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+Show Affiliations

Ipsen-Institut Henri Beaufour, 5 avenue du Canada, 91966 Les Ulis Cedex, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18664366

Citation

Favre-Guilmard, Christine, et al. "The Novel Inhibitor of the Heterotrimeric G-protein Complex, BIM-46187, Elicits Anti-hyperalgesic Properties and Synergizes With Morphine." European Journal of Pharmacology, vol. 594, no. 1-3, 2008, pp. 70-6.
Favre-Guilmard C, Zeroual-Hider H, Soulard C, et al. The novel inhibitor of the heterotrimeric G-protein complex, BIM-46187, elicits anti-hyperalgesic properties and synergizes with morphine. Eur J Pharmacol. 2008;594(1-3):70-6.
Favre-Guilmard, C., Zeroual-Hider, H., Soulard, C., Touvay, C., Chabrier, P. E., Prevost, G., & Auguet, M. (2008). The novel inhibitor of the heterotrimeric G-protein complex, BIM-46187, elicits anti-hyperalgesic properties and synergizes with morphine. European Journal of Pharmacology, 594(1-3), 70-6. https://doi.org/10.1016/j.ejphar.2008.07.016
Favre-Guilmard C, et al. The Novel Inhibitor of the Heterotrimeric G-protein Complex, BIM-46187, Elicits Anti-hyperalgesic Properties and Synergizes With Morphine. Eur J Pharmacol. 2008 Oct 10;594(1-3):70-6. PubMed PMID: 18664366.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The novel inhibitor of the heterotrimeric G-protein complex, BIM-46187, elicits anti-hyperalgesic properties and synergizes with morphine. AU - Favre-Guilmard,Christine, AU - Zeroual-Hider,Hamida, AU - Soulard,Chantal, AU - Touvay,Caroline, AU - Chabrier,Pierre-Etienne, AU - Prevost,Grégoire, AU - Auguet,Michel, Y1 - 2008/07/15/ PY - 2008/04/14/received PY - 2008/07/10/accepted PY - 2008/7/31/pubmed PY - 2008/12/17/medline PY - 2008/7/31/entrez SP - 70 EP - 6 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 594 IS - 1-3 N2 - 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/18664366/The_novel_inhibitor_of_the_heterotrimeric_G_protein_complex_BIM_46187_elicits_anti_hyperalgesic_properties_and_synergizes_with_morphine_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(08)00743-7 DB - PRIME DP - Unbound Medicine ER -