An increase in synaptic NMDA receptors in the insular cortex contributes to neuropathic pain.

Abstract

Neurons in the insular cortex are activated by acute and chronic pain, and inhibition of neuronal activity in the insular cortex has analgesic effects. We found that in a mouse model in which peripheral nerve injury leads to the development of neuropathic pain, the insular cortex showed changes in synaptic plasticity, which were associated with a long-term increase in the amount of synaptic N-methyl-d-aspartate receptors (NMDARs), but not that of extrasynaptic NMDARs. Activation of cyclic adenosine monophosphate (cAMP)-dependent signaling enhanced the amount of synaptic NMDARs in acutely isolated insular cortical slices and increased the surface localization of NMDARs in cultured cortical neurons. We found that the increase in the amount of NMDARs required phosphorylation of the NMDAR subunit GluN2B at Tyr(1472) by a pathway involving adenylyl cyclase subtype 1 (AC1), protein kinase A (PKA), and Src family kinases. Finally, injecting NMDAR or GluN2B-specific antagonists into the insular cortex reduced behavioral responses to normally nonnoxious stimuli in the mouse model of neuropathic pain. Our results suggest that activity-dependent plasticity takes place in the insular cortex after nerve injury and that inhibiting the increase in NMDAR function may help to prevent or treat neuropathic pain.

• Authors: Shuang Qiu, Tao Chen, Kohei Koga, Yan-yan Guo, Hui Xu, Qian Song, Jie-jie Wang, Giannina Descalzi, Bong-Kiun Kaang, Jian-hong Luo, Min Zhuo, Ming-gao Zhao
• Journal: Science signaling (Sci Signal) Vol. 6 Issue 275 Pg. ra34 (May 14 2013) ISSN: 1937-9145 [Electronic] United States
• PMID: 23674822 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NR2B NMDA receptor
• Receptors, N-Methyl-D-Aspartate
• Cyclic AMP
• src-Family Kinases
• Cyclic AMP-Dependent Protein Kinases
• Adenylyl Cyclases
• adenylyl cyclase 1

Topics

• Adenylyl Cyclases (genetics, metabolism)
• Animals
• Cerebral Cortex (metabolism, pathology)
• Cyclic AMP (genetics, metabolism)
• Cyclic AMP-Dependent Protein Kinases (genetics, metabolism)
• Disease Models, Animal
• Male
• Mice
• Mice, Mutant Strains
• Neuralgia (genetics, metabolism, pathology)
• Phosphorylation (genetics)
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors, genetics, metabolism)
• Second Messenger Systems
• Synapses (genetics, metabolism, pathology)
• src-Family Kinases (genetics, metabolism)