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

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.

• Authors: Ling-Er Huang, Shao-Hui Guo, Lalita Thitiseranee, Yan Yang, Yan-Feng Zhou, Yong-Xing Yao
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 7848 (05 18 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29777135 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Disks Large Homolog 4 Protein
• Dlg4 protein, rat
• NR2B NMDA receptor
• Phenols
• Piperidines
• Receptors, N-Methyl-D-Aspartate
• Ro 25-6981
• CREB-Binding Protein
• Crebbp protein, rat

Topics

• Animals
• Behavior, Animal (drug effects)
• CREB-Binding Protein (metabolism)
• Disease Models, Animal
• Disks Large Homolog 4 Protein (antagonists & inhibitors, metabolism)
• Hyperalgesia (pathology, prevention & control)
• Injections, Spinal
• Male
• Neuralgia (drug therapy, pathology)
• Phenols (pharmacology, therapeutic use)
• Phosphorylation (drug effects)
• Piperidines (pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
• Sciatic Nerve (injuries)
• Signal Transduction (drug effects)
• Spinal Cord Dorsal Horn (metabolism)
• Up-Regulation (drug effects)