1. Introduction
Opioids remain the first choice for the treatment of moderate-to-severe pain in the clinic. Among them, fentanyl compounds have good analgesic activity, various dosage forms, and a rapid onset of action. They have become the most widely used intraoperative analgesic drugs globally. Fentanyl-like compounds can also be used as anesthetic auxiliary drugs in combination with anesthetics. However, because of their side effects on the central nervous system, such as addiction, tolerance, and respiratory depression, the clinical application of such compounds has been greatly restricted, and these effects are the primary causes of treatment discontinuation by patients. Although the clinical use of opioid receptor antagonists such as naloxone can reverse opioid-induced respiratory depression, these drugs can also significantly reduce the analgesic effect of fentanyl-like drugs. Therefore, by studying the biological mechanism of fentanyl-induced respiratory depression, the development of new analgesic drugs with similar analgesic effects and low risks of respiratory depression has become an important research focus.
Fentanyl exerts biological effects by stimulating opioid receptors in the body. Opioid receptors primarily transduce signals into cells after receptor activation on the surface of the cell membrane via binding by extracellular specific ligands such as fentanyl. On the one hand, the G protein-coupled receptor signaling system exerts a biological effect. Specifically, after the ligand binds to the receptor, the conformational change of the G protein-coupled receptor directly leads to separation of the Gα and Gβγ subunits and subsequently results in various effects (Al-Hasani & Bruchas, 2011). On the other hand, opioid receptors can also generate signals through non-G protein signaling pathways, such as the β-arrestin pathway. β-arrestin is a negative feedback regulatory protein of G protein signaling that is involved in receptor desensitization, internalization, and recycling as well as the termination of G protein signal transduction (Herlitze, Garcia, Mackie, Hille, Scheuer & Catterall, 1996).
Studies have confirmed that β-arrestin2 knockout (βarr2−/−) mice exhibit enhanced morphine analgesia, no significant tolerance to chronic morphine treatment, and a significant reduction in respiratory depression, suggesting that β-arrestin2 regulates morphine-induced respiratory respiration (Raehal, Walker & Bohn, 2005). Whether fentanyl-like compound-induced respiratory depression is related to β-arrestin2 is unclear. In this study, we aimed to verify whether β-arrestin2 participates in fentanyl-induced respiratory depression by regulating the β-arrestin2 signaling pathway using βarr2-KO mice and morphine as a comparator.