Effects of glial glutamate transporter activator in formalin-induced pain behaviour in mice

Background: Nociceptive pain remains a prevalent clinical problem and often poorly responsive to the currently available analgesics. Previous studies have shown that astroglial glutamate transporter-1 (GLT-1) in the hippocampus and anterior cingulate cortex (ACC) is critically involved in pain processing and modulation. However, the role of astroglial GLT-1 in nociceptive pain involving the hippocampus and ACC remains unknown. We investigated the role of 3-[[(2-Methylphenyl) methyl]thio]-6-(2-pyridinyl)-pyridazine (LDN-212320), a GLT-1 activator, in nociceptive pain model and hippocampal-dependent behavioural tasks in mice.

Methods: We evaluated the effects of LDN-212320 in formalin-induced nociceptive pain model. In addition, formalin-induced impaired hippocampal-dependent behaviours were measured using Y-maze and object recognition test. Furthermore, GLT-1 expression and extracellular signal-regulated kinase phosphorylation (pERK1/2) were measured in the hippocampus and ACC using Western blot analysis and immunohistochemistry.

Results: The LDN-212320 (10 or 20 mg/kg, i.p) significantly attenuated formalin-evoked nociceptive behaviour. The antinociceptive effects of LDN-212320 were reversed by systemic administration of DHK (10 mg/kg, i.p), a GLT-1 antagonist. Moreover, LDN-212320 (10 or 20 mg/kg, i.p) significantly reversed formalin-induced impaired hippocampal-dependent behaviour. In addition, LDN-212320 (10 or 20 mg/kg, i.p) increased GLT-1 expressions in the hippocampus and ACC. On the other hand, LDN-212320 (20 mg/kg, i.p) significantly reduced formalin induced-ERK phosphorylation, a marker of nociception, in the hippocampus and ACC.

Conclusion: These results suggest that the GLT-1 activator LDN-212320 prevents nociceptive pain by upregulating astroglial GLT-1 expression in the hippocampus and ACC. Therefore, GLT-1 activator could be a novel drug candidate for nociceptive pain.

Significance: The present study provides new insights and evaluates the role of GLT-1 activator in the modulation of nociceptive pain involving hippocampus and ACC. Here, we provide evidence that GLT-1 activator could be a potential therapeutic utility for the treatment of nociceptive pain.