Aspirin attenuates morphine antinociceptive tolerance in rats with diabetic neuropathy by inhibiting apoptosis in the dorsal root ganglia

Abstract

Morphine is a drug used in chronic pain such as diabetic neuropathy, but the development of tolerance to its antinociceptive effect is an important clinical problem. Recently, it has been stated that morphineinduced neuronal apoptosis can stimulate morphine tolerance. Our aim in this study was to investigate the effects of aspirin on morphine-induced neuronal apoptosis and analgesic tolerance in rats with diabetic neuropathy. After morphine tolerance induction, the antinociceptive effects of aspirin (50 mg/kg) and morphine (5 mg/kg) were evaluated by thermal pain tests at 15 or 30 minute intervals.Streptozotocin (STZ, 65 mg/kg) was injected intraperitoneally to induce diabetic neuropathy. To evaluate apoptosis in dorsal root ganglion (DRG) tissue, ELISA kits were used to measure caspase-3, Bax and Bcl-2 levels. Apoptotic cells were detected histologically by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) method. Study results indicate that prior administration of aspirin to diabetic rats signi cantly increased the antinociceptive e cacy of morphine compared to morphine alone. Thermal pain tests showed that aspirin signi cantly reduced morphine tolerance in rats with diabetic neuropathy. Biochemical analysis revealed that aspirin signi cantly decreased the levels of proapoptotic proteins, caspase-3 and Bax, while increasing the anti-apoptotic Bcl-2 in DRG neurons. Semiquantitative scoring demonstrated that aspirin provided a signi cant reduction in apoptotic cell counts in diabetic rats. In conclusion, these data suggested that aspirin attenuated morphine antinociceptive tolerance through anti-apoptotic activity in diabetic rat DRG neurons. Further studies are needed to elucidate these effects of aspirin on morphine tolerance.