Inhibition of the TRPM2 cation channel attenuates morphine tolerance by modulating endoplasmic reticulum stress and apoptosis in rats

Opioid drugs such as morphine are frequently preferred drugs for severe pain in cancer and chronic diseases, but long-term use causes opioid tolerance. The mechanism of tolerance to opioids is quite complex and not fully understood. Our aim in this study was to investigate the effects of TRPM2 cation channel antagonists N-(pamylcinnamoyl) anthranilic acid (ACA) and 2-aminoethoxydiphenyl borate (2-APB) on morphine analgesia and tolerance in rats. Forty-eight Wistar Albino male rats were included in the study and the rats were randomly divided into drug and control (saline) groups. To induce morphine tolerance, the rats were injected with 10 mg/ kg morphine intraperitoneally for 7 days. After thermal analgesia tests, dorsal root ganglion (DRG) and cortex tissues were isolated. Proapoptotic mediators caspase-3 and 9, total oxidant status (TOS) and total antioxidant status (TAS) and ER stress proteins GRP78/BiP, ATF-6, p-IRE1 and pERK levels were measured by biochemical analysis of tissue homogenates. The findings showed that there was a significant decrease in morphine tolerance in rats administered ACA and 2-APB (p<0.05). In addition, biochemical tests revealed a significant decrease in ER stress proteins, proapoptotic biomarkers and TOS levels and a significant increase in TAS levels in DRG, thalamus and sensory cortex tissues (p<0.05). In conclusion, inhibition of TRPM2 cation channel by ACA and 2APB reduces morphine tolerance by preventing ER stress and apoptosis. It may be possible to increase the analgesic potential of morphine by combined application with ACA and 2-APB in the clinic, but further experimental and molecular studies are needed.