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.