Store-Operated Calcium Channels Contribute to Remifentanil-Induced Postoperative Hyperalgesia via Phosphorylation of CaMKIIα in Rats

PURPOSE: The mechanisms of remifentanil-induced postoperative hyperalgesia (RIPH) remain unclear. Store-operated calcium channels (SOCCs) are mainly comprised of stromal interaction molecules 1 (STIM1) and pore-forming subunits (Orai1). They were found to take a pivotal part in Ca(2+)-dependent procedures and involved in the development of central sensitization and pain. Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα), regulated by Ca(2+)/calmodulin complex, has been shown to have a crucial role in RIPH. This study aims to determine whether SOCCs contribute to RIPH via activating CaMKIIα. MATERIALS AND METHODS: Intra-operative infusion of remifentanil (1.0 µg kg(−1) min(−1), 60 min) was used to establish a RIPH rat model. The SOCCs blocker (YM-58483) was applied intrathecally to confirm the results. Animal behavioral tests including paw withdrawal thermal latency (PWTL) and paw withdrawal mechanical threshold (PWMT) were performed at −24, 2, 6, 24, 48 h after incision and remifentanil treatments. The protein expression of STIM1, Orai1, CaMKIIα, and p-CaMKIIα was assayed with Western blot, and the number of STIM1 and Orai1 positive cells was shown by immunofluorescence. RESULTS: Remifentanil administration significantly induced postoperative mechanical and thermal hyperalgesia, as well as increased STIM1 and Orai1 protein expression in the spinal dorsal horn. Furthermore, the intrathecal administration of YM-58483 effectively alleviated remifentanil-induced postoperative mechanical and thermal hyperalgesia according to the behavioral tests. In addition, YM-58483 suppressed the phosphorylation of CaMKIIα but had no effect on the expression of STIM1 and Orai1. CONCLUSION: Our study demonstrated that SOCCs are involved in RIPH. The over-expressed STIM1 and Orai1 in the spinal cord contribute to RIPH via mediating the phosphorylation of CaMKIIα. Blockade of SOCCs may provide an effective therapeutic approach for RIPH.