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Intrathecal Injection of the Peptide Myr-NR2B9c Attenuates Bone Cancer Pain Via Perturbing N-Methyl-D-Aspartate Receptor-PSD-95 Protein Interactions in Mice

Liu, Yue MD; Cui, Xinlong MD; Sun, Yu-E MD; Yang, Xuli MD; Ni, Kun MD; Zhou, Yu MD; Ma, Zhengliang MD, PhD; Gu, Xiaoping MD, PhD

doi: 10.1213/ANE.0000000000000202
Pain and Analgesic Mechanisms: Research Report

BACKGROUND: N-methyl-D-aspartate receptor (NMDARs)-dependent central sensitization plays an important role in cancer pain. Binding of NMDAR subunit 2B (NR2B) by postsynaptic density protein-95 (PSD-95) can couple NMDAR activity to intracellular enzymes, such as neuronal nitric oxide synthase (nNOS), facilitate downstream signaling pathways, and modulate NMDAR stability, contributing to synaptic plasticity. In this study, we investigated whether perturbing the specific interaction between spinal NR2B-containing NMDAR and PSD-95, using a peptide-mimetic strategy, could attenuate bone cancer-related pain behaviors.

METHODS: Osteosarcoma cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce progressive bone cancer-related pain behaviors. Western blotting was applied to examine the expression of spinal phospho-Tyr1472 NR2B, nNOS, and PSD-95. We further investigated the effects of intrathecal injection of the mimetic peptide Myr-NR2B9c, which competitively disrupts the interaction between PSD-95 and NR2B, on nociceptive behaviors and on the upregulation of phospho-Tyr1472 NR2B, nNOS, and PSD-95 associated with bone cancer pain in the spinal cord.

RESULTS: Inoculation of osteosarcoma cells induced progressive bone cancer pain and resulted in a significant upregulation of phospho-Tyr1472 NR2B, nNOS, and PSD-95. Intrathecal administration of Myr-NR2B9c attenuated bone cancer-evoked mechanical allodynia, thermal hyperalgesia, and reduced spinal phospho-Tyr1472 NR2B, nNOS, and PSD-95 expression.

CONCLUSIONS: Intrathecal administration of Myr-NR2B9c reduced bone cancer pain. Internalization of spinal NR2B and dissociation NR2B-containing NMDARs activation from downstream nNOS signaling may contribute to the analgesic effects of Myr-NR2B9c. This approach may circumvent the negative consequences associated with blocking NMDARs, and may be a novel strategy for the treatment of bone cancer pain.

From the Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China.

Accepted for publication December 7, 2013.

Funding: This research was supported by National Natural Science Foundation of China (81171047, 81171048, 81070892, 81371207, 81300950, 81300951), Natural Science Foundation of Jiangsu Province (BK2010105), and the Grant from the Department of Health of Jiangsu Province of China (XK201140, RC2011006).

The authors declare no conflicts of interest.

Drs. Yue Liu and Xinlong Cui are cofirst authors.

Reprints will not be available from the authors.

Address correspondence to Zhengliang Ma, MD, PhD, and Xiaoping Gu, MD, PhD, 321 Zhongshan Rd., Nanjing, China. Address e-mail to;

© 2014 International Anesthesia Research Society