Fig. 6. Synergistic analgesic action of L838,417 and CLP257.

a Partial reversal of mechanical allodynia produced by L838,417 and CLP257 co-injected at a fixed dose ratio [1:55] in 14-28 day post-surgery PNI rats. b Normalized dose-response curve of L838,417 (black line), CLP257 (gray line), expected L838,417 + CLP257 (dashed red line) and observed L838,417 + CLP257 (red line) at different proportions of their EC50s (see methods and Fig. 4). c Isobologram of the fits obtained in Fig. 6b. d, e Surface plots of computer simulated analgesic effect of co-administration of L838,417 and CLP257 when they act on a common effector (Fig. 6d and Eq. 10) or when they target two distinct mechanisms (inhibitory conductance and KCC2 activity) (Fig. 6e and Eq. 11). f 3D plot of the pharmacological synergism between L838,417 and CLP257. Copper-colored surface represents the theoretical analgesia calculated from the respective L838,417 and CLP257 dose-response curves using equivalent dose under the common effector assumption. The experimentally obtained maximum possible analgesia (MPA) for each dose combination tested in PNI animals is indicated by red dots. g Over-additive effect of the combined doses of 10 mg kg⁻¹ of L838,417 with 100 mg kg⁻¹ of CLP257 compared to a single dose of L838,417 or CLP257 or to the expected analgesic effect (MPA ≈ 30%) of the two-drug combination presented in Fig. 6f. h Maximum distance on rod of CLP257 at 100 mg kg⁻¹ 2 h after i.p. injection. i Identical MPA over 4 h for a combination of L838,417 (0.53 mg kg⁻¹) with CLP257 (29 mg kg^-1) vs. Gabapentin (10 mg kg^-1). j Rotarod testing Maximum distance run with the same drugs as in i, 2 h after i.p. injection. (*P < 0.05; **P < 0.01). Source data is available as a Source Data file.