Isobolographic analysis of interaction between intrathecal morphine and clonidine in the formalin test in rats.

The formalin test, an experimental model of injury-induced central sensitisation, was used. The antinociceptive interaction between intrathecal morphine and clonidine was evaluated based on the inhibition of the phase 1 and 2 of the formalin response, induced by both drugs, given alone or in combinations with fixed dose ratios. Morphine and clonidine, at doses not affecting motor performance, produced dose-dependent inhibition in the formalin test, with similar ID50 values in phase 1 and 2; 0.66 and 0.45 nmol and 4.1 and 3.5 nmol, respectively. Isobolographic analysis revealed a significant synergy. The combination ID50 was found to be significantly lower than the respective theoretical additive ID50 for both fixed dose ratios (1:3 and 1:10) in both phases of the formalin test. The similar total dose fraction of the additive ID50 in phase 1 and 2 indicates the same magnitude of synergy and may suggest that the mechanisms of the spinal clonidine-morphine synergy do not differ significantly between both phases of the formalin test.