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Genetic enhancement of inflammatory pain by forebrain NR2B overexpression

Abstract

N-methyl-D-aspartate (NMDA) receptors contribute to many brain functions. We studied the effect of forebrain-targeted overexpression of the NMDA receptor subunit NR2B on the response of mice to tissue injury and inflammation. Transgenic mice exhibited prominent NR2B expression and enhanced NMDA receptor-mediated synaptic responses in two pain-related forebrain areas, the anterior cingulate cortex and insular cortex, but not in the spinal cord. Although transgenic and wild type mice were indistinguishable in tests of acute pain, transgenic mice exhibited enhanced responsiveness to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant. Genetic modification of forebrain NMDA receptors can therefore influence pain perception, which suggests that forebrain-selective NMDA receptor antagonists, including NR2B-selective agents, may be useful analgesics for persistent pain.

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Figure 1: Forebrain-targeted NR2B overexpression enhanced NMDA receptor-mediated synaptic responses in the ACC and insular cortex.
Figure 2: NMDA receptor-mediated synaptic responses in the spinal cord were not affected by forebrain-targeted NR2B overexpression.
Figure 3: Enhanced NR2B expression in the ACC and insular cortex but not the spinal dorsal horn in NR2B transgenic mice.
Figure 4: Enhanced forebrain c-Fos expression following formalin injection in NR2B transgenic mice.
Figure 5: Enhanced forebrain c-Fos expression following formalin injection in NR2B transgenic mice.
Figure 6: Enhanced behavioral responses to formalin or CFA injection in NR2B transgenic mice.

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Acknowledgements

We thank J.Z. Tsien (Princeton University) for his supply of mice, and G. Liu (M.I.T.) and other members of Zhuo lab for their comments and advice on the manuscript.

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Correspondence to Min Zhuo.

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Wei, F., Wang, GD., Kerchner, G. et al. Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nat Neurosci 4, 164–169 (2001). https://doi.org/10.1038/83993

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