Blocking SphK/S1P/S1PR1 axis signaling pathway alleviates remifentanil-induced hyperalgesia in rats

by Selleckchem | Jan 19 2024

Recent research shows a correlation between altered sphingolipid metabolism and nociceptive processing. Activation of the sphingosine-1-phosphate receptor 1 subtype (S1PR1) by its ligand, sphingosine-1-phosphate (S1P), causes neuropathic pain. However, its role in remifentanil-induced hyperalgesia (RIH) has not been investigated. The purpose of this research was to establish if the SphK/S1P/S1PR1 axis mediated remifentanil-induced hyperalgesia and identify its potential targets. This study examined the protein expression of ceramide, sphingosine kinases (SphK), S1P, and S1PR1 in the spinal cord of rats treated with remifentanil (1.0 μg/kg/min for 60 min). Prior to receiving remifentanil, rats were injected with SK-1 (a SphK inhibitor); LT1002 (a S1P monoclonal antibody); CYM-5442, FTY720, and TASP0277308（the S1PR1 antagonists); CYM-5478 (a S1PR2 agonist); CAY10444 (a S1PR3 antagonist); Ac-YVAD-CMK (a caspase-1 antagonist); MCC950 (the NOD-like receptor protein 3 (NLRP3) inflammasome antagonist); and N-tert-Butyl-α-phenylnitrone (PBN, a reactive oxygen species (ROS) scavenger). Mechanical and thermal hyperalgesia were evaluated at baseline (24 h prior to remifentanil infusion) and 2, 6, 12, and 24 h following remifentanil administration. The expression of the NLRP3-related protein (NLRP3, caspase-1), pro-inflammatory cytokines (interleukin-1β(IL-1β), IL-18), and ROS was found in the spinal dorsal horns. In the meantime, immunofluorescence was used to ascertain if S1PR1 co-localizes with astrocytes. Remifentanil infusion induced considerable hyperalgesia in addition to increased ceramide, SphK, S1P, and S1PR1, NLRP3-related protein (NLRP3, Caspase-1, IL-1β, IL-18) and ROS expression, and S1PR1 localized astrocytes. By blocking the SphK/S1P/S1PR1 axis, remifentanil-induced hyperalgesia was reduced, as was the expression of NLRP3, caspase-1, pro-inflammatory cytokines (IL-1β, IL-18) and ROS in the spinal cord. In addition, we observed that suppressing NLRP3 or ROS signal attenuated the mechanical and thermal hyperalgesia induced by remifentanil. Our findings indicate that the SphK/SIP/S1PR1 axis regulates the expression of NLRP3, Caspase-1, IL-1β, IL-18 and ROS in the spinal dorsal horn to mediate remifentanil-induced hyperalgesia. These findings may contribute to pain and SphK/S1P/S1PR1 axis research positively, and inform the future study of this commonly used analgesic.

Comments:

That's a complex study! It seems to explore the role of the SphK/S1P/S1PR1 axis in mediating remifentanil-induced hyperalgesia and potential targets to mitigate this effect. It's fascinating to see how sphingolipid metabolism, particularly involving S1P and its receptors, could impact nociceptive processing.

From your description, the study examined the effects of various inhibitors and antagonists targeting different points within this pathway. The findings suggest that blocking the SphK/S1P/S1PR1 axis reduced remifentanil-induced hyperalgesia, along with decreasing the expression of NLRP3, caspase-1, pro-inflammatory cytokines (IL-1β, IL-18), and ROS in the spinal cord.

The co-localization of S1PR1 with astrocytes in the spinal cord might indicate a specific cell type involved in this pathway's modulation. Additionally, suppressing NLRP3 or ROS signals seemed to attenuate the hyperalgesic effects induced by remifentanil, further supporting their involvement in this process.

Overall, these findings shed light on a potential mechanism underlying opioid-induced hyperalgesia, providing insights into pathways and molecules that could be targeted to mitigate this effect. Understanding these mechanisms could indeed contribute positively to pain management strategies and potentially influence future research and development of analgesics.

Did this study prompt any specific thoughts or questions for you?