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 Ca2+-dependent procedures and involved in the development of central sensitization and pain. Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII alpha), regulated by Ca2+/calmodulin complex, has been shown to have a crucial role in RIPH. This study aims to determine whether SOCCs contribute to RIPH via activating CaMKII alpha. Materials and Methods: Intra-operative infusion of remifentanil (1.0 mu g 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, CaMKII alpha, and p-CaMKII alpha 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 hyper-algesia according to the behavioral tests. In addition, YM-58483 suppressed the phosphorylation of CaMKII alpha 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 CaMKII alpha. Blockade of SOCCs may provide an effective therapeutic approach for RIPH.