Propofol produces preventive analgesia via GluN2B-containing NMDA Receptor/ERK1/2 Signaling Pathway in a rat model of Inflammatory Pain

Abstract

Compared to other anesthetics, propofol has showed superior analgesic effect used during surgical procedures on acute post-surgical pain. Whether propofol has preventive analgesic property remain debated. 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 4 groups: naïve (Group Naïve), formalin injection only (Group Formalin), and formalin injection at 30 min (Group P-30min) or 2 h (Group P-2h) after intravenous infusion of propofol (0.6 mg kg-1 min-1) for 1 h. Nociceptive responses were evaluated by composite pain score-weighted scores. Protein expression of phosphorylated- or pan-GluN2B, ERK1/2, p38 MAPK and JNK in the spinal dorsal horn was assessed by Western blot. Alteration of intracellular Ca2+ concentration induced by NMDA receptor agonists with or without pre-treatment of propofol was measured using fluorometry in SH-SY5Y cells. Neuronal activation was assessed 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 JNK were 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. These findings indicate 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.