Spinal sigma-1 receptor activation increases the production of D-serine in astrocytes which contributes to the development of mechanical allodynia in a mouse model of neuropathic pain

We have previously demonstrated that activation of the spinal sigma-1 receptor (Sig-1R) plays an important role in the development of mechanical allodynia (MA) via secondary activation of the N-methyl-D-aspartate (NMDA) receptor. Sig-1 Rs have been shown to localize to astrocytes, and blockade of Sig-1Rs inhibits the pathologic activation of astrocytes in neuropathic mice. However, the mechanism by which Sig-1R activation in astrocytes modulates NMDA receptors in neurons is currently unknown. D-serine, synthesized from L-serine by serine racemase (Srr) in astrocytes, is an endogenous co-agonist for the NMDA receptor glycine site and can control NMDA receptor activity. Here, we investigated the role of D-serine in the development of MA induced by spinal Sig-1R activation in chronic constriction injury (CCI) mice. The production of D-serine and Srr expression were both significantly increased in the spinal cord dorsal horn post-CCI surgery. Srr and D-serine were only localized to astrocytes in the superficial dorsal horn, while D-serine was also localized to neurons in the deep dorsal horn. Moreover, we found that Srr exists in astrocytes that express Sig-1 Rs. The CCI-induced increase in the levels of D-serine and Srr was attenuated by sustained intrathecal treatment with the Sig-1R antagonist, BD-1047 during the induction phase of neuropathic pain. In behavioral experiments, degradation of endogenous D-serine with DAAO, or selective blockade of Srr by LSOS, effectively reduced the development of MA, but not thermal hyperalgesia in CCI mice. Finally, BD-1047 administration inhibited the development of MA and this inhibition was reversed by intrathecal treatment with exogenous D-serine. These findings demonstrate for the first time that the activation of Sig-1 Rs increases the expression of Srr and D-serine in astrocytes. The increased production of D-serine induced by CCI ultimately affects dorsal horn neurons that are involved in the development of MA in neuropathic mice. (C) 2015 Elsevier Ltd. All rights reserved.