Az orvos-, egészségtudományi- és gyógyszerészképzés tudományos műhelyeinek fejlesztése(EFOP-3.6.3-VEKOP-16-2017-00009)
Támogató: EFOP-VEKOP
The development of opioid tolerance in patients on long-term opioid analgesic treatment
is an unsolved matter in clinical practice thus far. Dose escalation is required to
restore analgesic efficacy, but at the price of side effects. Intensive research is
ongoing to elucidate the underlying mechanisms of opioid analgesic tolerance in the
hope of maintaining opioid analgesic efficacy. N-Methyl-D-aspartate receptor (NMDAR)
antagonists have shown promising effects regarding opioid analgesic tolerance; however,
their use is limited by side effects (memory dysfunction). Nevertheless, the GluN2B
receptor remains a future target for the discovery of drugs to restore opioid efficacy.
Mechanistically, the long-term activation of µ-opioid receptors (MORs) initiates receptor
phosphorylation, which triggers β-arrestin-MAPKs and NOS-GC-PKG pathway activation,
which ultimately ends with GluN2B receptor overactivation and glutamate release. The
presence of glutamate and glycine as co-agonists is a prerequisite for GluN2B receptor
activation. The extrasynaptic localization of the GluN2B receptor means it is influenced
by the glycine level, which is regulated by astrocytic glycine transporter 1 (GlyT1).
Enhanced astrocytic glycine release by reverse transporter mechanisms as a consequence
of high glutamate levels or unconventional MOR activation on astrocytes could further
activate the GluN2B receptor. GlyT1 inhibitors might inhibit this condition, thereby
reducing opioid tolerance.