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.