Hydrogen-rich saline prevents remifentanil-induced hyperalgesia and inhibits MnSOD nitration via regulation of NR2B-containing NMDA receptor in rats

Abstract:

Remifentanil administration may subsequently cause paradoxical hyperalgesia in animals and humans, but mechanisms remain unclear. MnSOD nitration and inactivation caused by generation of reactive oxygen species and activation of NMDA receptors are involved in the induction and maintenance of central neuropathic pain. Hydrogen which selectively removes superoxide has gained much attention in recent years. In this study, we investigated antinociceptive effects of hydrogen-rich saline (HRS) on remifentanil-induced postsurgical hyperalgesia in a rat model of incisional pain. HRS was injected intraperitoneally 10min before remifentanil infusion (1μg·kg(-1)·min(-1)for 60min). A selective NR2B antagonist Ro25-6981 was used to investigate whether antihypernociception of HRS is associated with NMDAR. Nociception was evaluated by the paw withdrawal mechanical threshold and thermal latency respectively. Then we assessed MnSOD, NR2A and NR2B in spinal cord dorsal horn via Western blot and immunohistochemistry after nociceptive tests. Here, we found that the analgesic effect of remifentanil was followed by long-term hyperalgesia lasting at least postoperative 7 days, which was accompanied with increase in NR2B expression and trafficking from cytoplasm to surface and MnSOD nitration in dorsal horn. Pretreatment with HRS (10ml/kg) significantly attenuated mechanical and thermal hyperalgesia, blocked NR2B trafficking and MnSOD nitration in dorsal horn after remifentanil infusion. Ro25-6981 not 5 μg but 10 and 50 μg dosage-dependently attenuated hyperalgesia, and inhibited MnSOD nitration. Hyperalgesia and MnSOD nitration were attenuated after the combination of HRS (2.5ml/kg) and Ro25-6981(5μg). In conclusion, hydrogen-rich saline (10ml/kg) might reverse remifentanil-induced hyperalgesia, through regulating NR2B-containing NMDAR trafficking to control MnSOD nitration and enhance MnSOD activity.