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

Abstract

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.

from Wiley: European Journal of Pain: Table of Contents https://ift.tt/2CmJnZj
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