N-methyl D-aspartate receptor subtype 2B antagonist, Ro 25-6981, attenuates neuropathic pain by inhibiting postsynaptic density 95 expression

  • Sci Rep. 2018 May 18;8(1):7848. doi: 10.1038/s41598-018-26209-7.
Ling-Er Huang  1 ,  Shao-Hui Guo  1 ,  Lalita Thitiseranee  2 ,  Yan Yang  3 ,  Yan-Feng Zhou  1 ,  Yong-Xing Yao  4
Affiliations
  • 1. First Affiliated Hospital, Zhejiang University School of Medicine, Department of Anesthesia, Hangzhou, 310003, P.R. China.
  • 2. Zhejiang University School of Medicine, Hangzhou, 310016, P.R. China.
  • 3. Zhejiang University School of Medicine, Centre for Neuroscience, Hangzhou, 310016, P.R. China.
  • 4. First Affiliated Hospital, Zhejiang University School of Medicine, Department of Anesthesia, Hangzhou, 310003, P.R. China. [email protected].
PMID: 29777135 DOI: 10.1038/s41598-018-26209-7
Abstract

Postsynaptic density-95 (PSD-95) is a synaptic scaffolding protein that plays a crucial role in the development of neuropathic pain. However, the underlying mechanism remains unclear. To address the role of PSD-95 in N-methyl-D-aspartate receptor subtype 2B (NR2B) -mediated chronic pain, we investigated the relationship between PSD-95 activation and NR2B function in the spinal cord, by using a rat model of sciatic nerve chronic constriction injury (CCI). We demonstrate that the expression levels of total PSD-95 and cAMP response element binding protein (CREB), as well as phosphorylated NR2B, PSD-95, and CREB, in the spinal dorsal horn, and the interaction of NR2B with PSD-95 were increased in the CCI Animals. Intrathecal injection of the selective NR2B antagonist Ro 25-6981 increased paw withdrawal latency, in a thermal pain assessment test. Moreover, repeated treatment with Ro 25-6981 markedly attenuated the thermal hypersensitivity, and inhibited the CCI-induced upregulation of PSD-95 in the spinal dorsal horn. Furthermore, intrathecal injection of the PSD-95 inhibitor strikingly reversed the thermal and mechanical hyperalgesia. Our results suggest that blocking of NR2B signaling in the spinal cord could be used as a therapeutic candidate for treating neuropathic pain.

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