Background and purpose
Neuropathic pain is a widespread health problem with limited curative treatment. Decreased sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA) expression has been reported in dorsal root ganglion (DRG) of animals suffering from neuropathic pain. We aimed to establish the relationship between SERCA expression and the pain responses and to elucidate the underlying molecular mechanism. Experimental approach: Neuropathic pain was modelled using rat chronic constriction injury (CCI). Ca2+ imaging and current clamp patch-clamp were used to determine cytosolic Ca2+ levels and action potential firing, respectively. Western blots, immunofluorescence staining and qRT-PCR were used to quantitatively assess protein and mRNA expression, respectively. H&E staining and coupled enzyme assays were used to evaluate the nerve injury and SERCA2b activity, respectively. Key
Purpose
Neuropathic pain is a widespread health problem with limited curative treatment. Decreased sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA) expression has been reported in dorsal root ganglion (DRG) of animals suffering from neuropathic pain. We aimed to establish the relationship between SERCA expression and the pain responses and to elucidate the underlying molecular mechanism. Experimental approach: Neuropathic pain was modelled using rat chronic constriction injury (CCI). Ca2+ imaging and current clamp patch-clamp were used to determine cytosolic Ca2+ levels and action potential firing, respectively. Western blots, immunofluorescence staining and qRT-PCR were used to quantitatively assess protein and mRNA expression, respectively. H&E staining and coupled enzyme assays were used to evaluate the nerve injury and SERCA2b activity, respectively. Key
Results
SERCA2b is the predominant SERCA isoform in rat DRG and its expression is decreased after CCI at mRNA, protein and activity levels. Whereas inhibiting SERCA with thapsigargin causes neuronal hyperexcitation, nerve injury, endoplasmic reticulum (ER) stress, satellite glial cell activation and mechanical allodynia, activating SERCA by CDN1163 or overexpressing SERCA2b in DRG after CCI produces long-term relief of mechanical and thermal allodynia accompanied by morphological and functional restoration through alleviation of ER stress. Furthermore, the down-regulation of DRG SERCA2b in CCI rats is caused by increased production of ROS through Sp1-dependent transcriptional inhibition.