Propofol produces preventive analgesia via GluN2B-containing NMDA receptor/ERK1/2 signaling pathway in a rat model of inflammatory pain

Abstract

Propofol, an intravenous anesthetic, has been shown to offer superior analgesic effect clinically. Whether propofol has preventive analgesic property remains unexplored. The present study investigated the antinociceptive effect of propofol and underlying molecular and cellular mechanisms via pre-emptive administration in a formalin-induced inflammatory pain model in rats. Male adult Sprague–Dawley rats were randomly allocated into four groups: naïve (Group Naïve), formalin injection only (Group Formalin), and formalin injection at 30 min (Group P-30 min) or 2 h (Group P-2 h) after intravenous infusion of propofol (0.6 mg kg−1 min−1) for 1 h. Nociceptive responses and protein expression of phosphorylated- or pan-GluN2B, ERK1/2, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase in the spinal dorsal horn were evaluated. Alteration of intracellular Ca2+ concentration induced by N-methyl-D-aspartate (NMDA) receptor agonists with or without pre-treatment of propofol was measured using fluorometry in SH-SY5Y cells while neuronal activation in the spinal dorsal horn by immunofluorescence. Pre-emptive propofol reduced pain with a delayed response to formalin and a reduction in hypersensitivity that lasted at least for 2 h. The formalin-induced activation of spinal GluN2B and ERK1/2 but not p38 or c-Jun N-terminal kinase was also diminished by propofol treatment. Preconditioning treatment with 3 µM and 10 µM of propofol inhibited Ca2+ influx mediated through NMDA receptors in SH-SY5Y cells. Propofol also reduced the neuronal expression of c-Fos and p-ERK induced by formalin. This study shows that pre-emptive administration of propofol produces preventive analgesic effects on inflammatory pain through regulating neuronal GluN2B-containing NMDA receptor and ERK1/2 pathway in the spinal dorsal horn.

Icaritin Alleviates Glutamate-Induced Neuronal Damage by Inactivating GluN2B-Containing NMDARs Through the ERK/DAPK1 Pathway

“…In this study, icaritin eventually played a neuroprotective role by regulating the expression and/or activation of DAPK1, GluN2B and GluN2A. Some studies indicated that GluN2B/CaMKII could regulate the activation of ERK in the upstream of ERK ( Cao et al, 2012 ; El Gaamouch et al, 2012 ; Melgarejo et al, 2016 ; Qiu et al, 2017 ; Buonarati et al, 2020 ). DAPK1 could bind to GluN2B regions, which required allosteric regulation of CaMKII ( Cao et al, 2012 ; Goodell et al, 2017 ; Tu et al, 2018 ; Buonarati et al, 2020 ).…”

Propofol attenuates TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells by inhibiting Ca2+/CAMK II/ERK/NF-κB signaling pathway

“…In another study, it was reported that propofol protected against LPS-mediated inflammation in primary microglial cells, and the protective effect was mediated by inhibition of NMDA receptors and the Ca 2+ /CaMKII pathway [48]. An animal study also showed that propofol inhibited the NMDA receptor/ERK signaling pathway, exerting preventive analgesia in a rat model of inflammatory pain [49]. In combining these data with our current findings, although we did not examine which receptor is responsible for the effect of propofol in this study, we believe that it is mediated by inhibition of NMDA receptors.…”

Pharmacologic Modulation of Noxious Stimulus-evoked Brain Activation in Cynomolgus Macaques Observed with Functional Neuroimaging

“…4,26,27,34,64 Data from rodent studies suggest that sedative doses of propofol, both 36 and 90 mg/kg/hr., are antinociceptive. 74,94 It is possible that propofol's analgesic effect in NHP could be observed at doses that are higher than that needed for stable sedation, which would be, in macaques, between 12 to 36 mg/ kg/hr. 34 The current study tested the effects of 20 and 30 mg/ kg/hr propofol on noxious stimulus-evoked brain activation.…”