Fig. 3.

CD38 inhibitors with morphine 3-day tolerance. Drugs that block the CD38–cADPR–ryanodine receptor pathway reversed morphine tolerance. Mice were implanted with placebo or 75-mg morphine pellets for 72 h and then administered inhibitor intracerebroventricularly and various morphine doses subcutaneously. Antinociception was measured 30 min later, and %MPE was calculated and used to construct dose–response curves for calculation of ED₅₀ values and potency ratios. All three inhibitors, ryanodine (1.0 nmol/mouse) (A), nicotinamide (200 pmol/mouse) (B), and 8-bromo-cADPR (10 nmol/mouse) (C), were able to fully reverse 72-h morphine tolerance. Each data point represents six mice. ●, placebo pellet with inhibitor; ▴, placebo pellet with vehicle; ♦, morphine pellet with inhibitor; ■, morphine pellet with vehicle.