Role of mitochondrial Ca2+ uniporter in remifentanil-induced postoperative allodynia

Abstract

Opioid-induced hyperalgesia and allodynia (OIH) is a well-known phenomenon and refers to the pain sensitization in patients after prolonged opioid exposure. OIH limits the use of opioids in pain control, but the underlying mechanisms are not fully clear. The present study investigated the role of mitochondrial Ca²⁺ uniporter (MCU) in remifentanil (a commonly used opioid analgesic)-induced allodynia. Using a rat model of OIH, we found that incision- and remifentanil-induced mechanical allodynia were remarkably attenuated by pretreatment with Ru360, a specific MCU antagonist, suggesting a critical role of MCU in both incision- and opioid-induced allodynia. In addition, imaging studies with Rhod-2 (a mitochondrial Ca²⁺ dye) in spinal tissues demonstrated increased mitochondrial Ca²⁺ level in response to incision and remifentanil infusion, which was attenuated by Ru360. Western blot and immunohistochemistry showed that pNR (phosphorylated N-methyl-D-aspartate (NMDA) receptor) and pERK (phosphorylated extracellular signal-regulated kinase) are increased during both incision- and remifentanil-induced hyperalgesia, and again the increases in pNR and pERK were remarkably attenuated by Ru360. Together, our data demonstrate that MCU plays a critical role in remifentanil-induced postoperative mechanical allodynia, with NMDA receptor and ERK as possible downstream effectors. Our findings provide novel mechanisms for remifentanil-induced mechanical allodynia, and encourage future studies to examine the mitochondrial Ca²⁺ uniporter as a potential therapeutic target for prevention of OIH.

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