Activation of the spinal sigma‐1 receptor enhances NMDA‐induced pain via PKC‐ and PKA‐dependent phosphorylation of the NR1 subunit in mice

Background and purpose: Previously we demonstrated that the spinal sigma‐1 receptor (Sig‐1 R) plays an important role in pain transmission, although the exact mechanism is still unclear. It has been suggested that Sig‐1 R agonists increase glutamate‐induced calcium influx through N‐methyl‐D‐aspartate (NMDA) receptors. Despite data suggesting a link between Sig‐1 Rs and NMDA receptors, there are no studies addressing whether Sig‐1 R activation directly affects NMDA receptor sensitivity. Experimental approach: We studied the effect of intrathecal (i.t.) administration of Sig‐1 R agonists on protein kinase C (PKC) and protein kinase A (PKA) dependent phosphorylation of the NMDA receptor subunit NR1 (pNR1) as a marker of NMDA receptor sensitization. In addition, we examined whether this Sig‐1 R mediated phosphorylation of NR1 plays an important role in sensory function using a model of NMDA‐induced pain. Key results: Both Western blot assays and image analysis of pNR1 immunohistochemical staining in the spinal cord indicated that i.t. injection of the Sig‐1 R agonists, PRE‐084 or carbetapentane dose dependently enhanced pNR1 expression in the murine dorsal horn. This increased pNR1 expression was significantly reduced by pretreatment with the specific Sig‐1 R antagonist, BD‐1047. In another set of experiments Sig‐1 R agonists further potentiated NMDA‐induced pain behaviour and pNR1 immunoreactivity and this was also reversed with BD‐1047. Conclusions and implications: The results of this study suggest that the activation of spinal Sig‐1 R enhances NMDA‐induced pain via PKC‐ and PKA‐dependent phosphorylation of the NMDA receptor NR 1 subunit. British Journal of Pharmacology (2008) 154, 1125–1134; doi:10.1038/bjp.2008.159; published online 19 May 2008