Korean J Physiol Pharmacol.  2023 Jan;27(1):39-48. 10.4196/kjpp.2023.27.1.39.

SKF96365 impedes spinal glutamatergic transmission-mediated neuropathic allodynia

• Wang Q
• Zhang Y
• Du Q
• Zhao X
• Wang W
• Zhai Q
• Xiang M

• KMID: 2537502
• DOI: http://doi.org/10.4196/kjpp.2023.27.1.39

Abstract

Spinal nerve injury causes mechanical allodynia and structural imbalance of neurotransmission, which were typically associated with calcium overload. Storeoperated calcium entry (SOCE) is considered crucial elements-mediating intracellular calcium homeostasis, ion channel activity, and synaptic plasticity. However, the underlying mechanism of SOCE in mediating neuronal transmitter release and synaptic transmission remains ambiguous in neuropathic pain. Neuropathic rats were operated by spinal nerve ligations. Neurotransmissions were assessed by whole-cell recording in substantia gelatinosa. Immunofluorescence staining of STIM1 with neuronal and glial biomarkers in the spinal dorsal horn. The endoplasmic reticulum stress level was estimated from qRT-PCR. Intrathecal injection of SOCE antagonist SKF96365 dose-dependently alleviated mechanical allodynia in ipsilateral hind paws of neuropathic rats with ED ₅₀ of 18 μg. Immunofluorescence staining demonstrated that STIM1 was specifically and significantly expressed in neurons but not astrocytes and microglia in the spinal dorsal horn. Bath application of SKF96365 inhibited enhanced miniature excitatory postsynaptic currents in a dosage-dependent manner without affecting miniature inhibitory postsynaptic currents. Mal-adaption of SOCE was commonly related to endoplasmic reticulum (ER) stress in the central nervous system. SKF96365 markedly suppressed ER stress levels by alleviating mRNA expression of C/ EBP homologous protein and heat shock protein 70 in neuropathic rats. Our findings suggested that nerve injury might promote SOCE-mediated calcium levels, resulting in long-term imbalance of spinal synaptic transmission and behavioral sensitization, SKF96365 produces antinociception by alleviating glutamatergic transmission and ER stress. This work demonstrated the involvement of SOCE in neuropathic pain, implying that SOCE might be a potential target for pain management.

Keyword

Glutamatergic transmission; Neuralgia; SKF96365; STIM1

Figure

• 

  Fig. 1 Intrathecal delivery of SKF96365 exhibited mechanically antiallodynic effects (A, B) in neuropathic rats induced by spinal nerve ligations. Data are presented as means ± SEM (n = 5–6 per group). *p < 0.05, by two-tailed Student t-test or repeated-measures two-way ANOVA followed by Sidak’s post-tests.

• 

  Fig. 2 Dual fluorescence labeling of stromal-interacting molecule-1 (STIM1) with the mature neuronal marker neuronal nuclei (NeuN, A), astrocytic marker GFAP (B), and microglial marker Iba1 (C) in the spinal cord of superficial dorsal horns (laminae I–III), respectively (n = 3 animals). Scale bar: 100 μm (×10) , 50 μm is (×20).

• 

  Fig. 3 Store-operated calcium entry (SOCE) antagonist SKF96365 attenuated the spinal nerve ligation (SNL)-induced increased glutamatergic transmission in the spinal dorsal horn of the ipsilateral hind paws. Sample traces (A), cumulative distribution (B), and statistical analysis (C) of miniature excitatory postsynaptic currents (mEPSCs); Sample traces (D), cumulative distribution (E), and statistical analysis (F) of miniature inhibitory postsynaptic currents (mIPSCs). Data are presented as the means ± SEM (n = 5–6 animals). n.s., not significant. *p < 0.05, by one‐way or repeated‐measures two‐way ANOVA followed by Sidak’s post‐tests).

• 

  Fig. 4 SKF96365 alleviated endoplasmic reticulum stress in neuropathic rats. Relative mRNA expression of C/EBP homologous protein (CHOP) (A) and heat shock protein 70 (HSP70) (B) in spinal dorsal horn. Data are presented as means ± SEM (n = 8 per group). *p < 0.05, by repeated-measures two-way ANOVA followed by Sidak’s post-tests.

• 

  Fig. 5 Schematic diagram showing the role of SKF96365 exerted potential blocking effects via inhibition of STIM1 and Orai1 mediated calcium influx in membrane and downregulation of neuronal calcium homeostasis, subsequently, SKF96365 induced inhibition of spinal excitatory synaptic transmission and pain hypersensitivity in neuropathic pain. STIM1, stromal-interacting molecule-1; CHOP, C/EBP homologous protein; HSP70, heat shock protein 70; NMDAR, N-methyl-D-aspartic acid receptor.

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