The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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SKF96365 impedes spinal glutamatergic transmission-mediated neuropathic allodynia

  • Qiru Wang (Department of Pharmacy, Fudan University Shanghai Cancer Center) ;
  • Yang Zhang (Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center) ;
  • Qiong Du (Department of Pharmacy, Fudan University Shanghai Cancer Center) ;
  • Xinjie Zhao (Department of Pharmacy, Fudan University Shanghai Cancer Center) ;
  • Wei Wang (Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center) ;
  • Qing Zhai (Department of Pharmacy, Fudan University Shanghai Cancer Center) ;
  • Ming Xiang (Department of Pharmacy, Fudan University Shanghai Cancer Center)
  • Received : 2022.06.08
  • Accepted : 2022.09.08
  • Published : 2023.01.01
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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 ED50 of 18 ㎍. 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.

Keywords

Acknowledgement

Thanks to the contribution of Minhang Branch of Fudan University Shanghai Cancer Center and Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center for their support.

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