Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Genetic enhancement of inflammatory pain by forebrain NR2B overexpression


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

    Collingridge, G. L. & Bliss, T. V. Memories of NMDA receptors and LTP. Trends Neurosci. 18, 54–56 (1995).

    CAS  Article  Google Scholar 

  2. 2

    Choi, D. W. & Rothman, S. M. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu. Rev. Neurosci. 13, 171–182 (1990).

    CAS  Article  Google Scholar 

  3. 3

    Haley, J. E., Sullivan, A. F. & Dickenson, A. H. Evidence for spinal N-methyl-d-aspartate receptor involvement in prolonged chemical nociception in the rat. Brain Res. 518, 218–226 (1990).

    CAS  Article  Google Scholar 

  4. 4

    Coderre, T. J., Katz, J., Vaccarino, A. L. & Melzack, R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 52, 259–285 (1993).

    CAS  Article  Google Scholar 

  5. 5

    Yaksh, T. L. The spinal pharmacology of facilitation of afferent processing evoked by high-threshold afferent input of the postinjury pain state. Curr. Opin. Neurol. Neurosurg. 6, 250–256 (1993).

    CAS  PubMed  Google Scholar 

  6. 6

    Woolf, C. J. & Costigan, M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc. Natl. Acad. Sci. USA 96, 7723–7730 (1999).

    CAS  Article  Google Scholar 

  7. 7

    Nakanishi, S. Molecular diversity of glutamate receptors and implications for brain function. Science 258, 597–603 (1992).

    CAS  Article  Google Scholar 

  8. 8

    Hollmann, M. & Heinemann, S. Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108 (1994).

    CAS  Article  Google Scholar 

  9. 9

    Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B. & Seeburg, P. H. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12, 529–540 (1994).

    CAS  Article  Google Scholar 

  10. 10

    Sheng, M., Cummings, J., Roldan, L. A., Jan, Y. N. & Jan, L. Y. Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature 368, 144–147 (1994).

    CAS  Article  Google Scholar 

  11. 11

    Kato, N., Artola, A. & Singer, W. Developmental changes in the susceptibility to long-term potentiation of neurones in rat visual cortex slices. Brain Res. Dev. Brain Res. 60, 43–50 (1991).

    CAS  Article  Google Scholar 

  12. 12

    Carmignoto, G. & Vicini, S. Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. Science 258, 1007–1011 (1992).

    CAS  Article  Google Scholar 

  13. 13

    Hestrin, S. Developmental regulation of NMDA receptor-mediated synaptic currents at a central synapse. Nature 357, 686–689 (1992).

    CAS  Article  Google Scholar 

  14. 14

    Teng, C. J. & Abbott, F. V. The formalin test: a dose-response analysis at three developmental stages. Pain 76, 337–347 (1998).

    CAS  Article  Google Scholar 

  15. 15

    Tang, Y. P. et al. Genetic enhancement of learning and memory in mice. Nature 401, 63–69 (1999).

    CAS  Article  Google Scholar 

  16. 16

    Wei, F., Li, P. & Zhuo, M. Loss of synaptic depression in mammalian anterior cingulate cortex after amputation. J. Neurosci. 19, 9346–9354 (1999).

    CAS  Article  Google Scholar 

  17. 17

    Sah, P. & Nicoll, R. A. Mechanisms underlying potentiation of synaptic transmission in rat anterior cingulate cortex in vitro. J. Physiol. (Lond.) 433, 615–630 (1991).

    CAS  Article  Google Scholar 

  18. 18

    Dubuisson, D. & Dennis, S. G. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4, 161–174 (1977).

    CAS  Article  Google Scholar 

  19. 19

    Tjolsen, A., Berge, O. G., Hunskaar, S., Rosland, J. H. & Hole, K. The formalin test: an evaluation of the method. Pain 51, 5–17 (1992).

    CAS  Article  Google Scholar 

  20. 20

    Morgan, J. I. & Curran, T. Stimulus–transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Annu. Rev. Neurosci. 14, 421–451 (1991).

    CAS  Article  Google Scholar 

  21. 21

    Herrera, D. G. & Robertson, H. A. Activation of c-fos in the brain. Prog. Neurobiol. 50, 83–107 (1996).

    CAS  Article  Google Scholar 

  22. 22

    Munglani, R. & Hunt, S. P. Proto-oncogenes: basic concepts and stimulation induced changes in the spinal cord. Brain Res. Prog. Brain Res. 104, 283–298 (1995).

    CAS  Article  Google Scholar 

  23. 23

    Casey, K. L. Forebrain mechanisms of nociception and pain: analysis through imaging. Proc. Natl. Acad. Sci. USA 96, 7668–7674 (1999).

    CAS  Article  Google Scholar 

  24. 24

    Treede, R. D., Kenshalo, D. R., Gracely, R. H. & Jones, A. K. The cortical representation of pain. Pain 79, 105–111 (1999).

    CAS  Article  Google Scholar 

  25. 25

    Kim, S. J., Calejesan, A. A., Li, P., Wei, F. & Zhuo, M. Sex differences in late behavioral response to subcutaneous formalin injection in mice. Brain Res. 829, 185–189 (1999).

    CAS  Article  Google Scholar 

  26. 26

    Taylor, B. K., Peterson, M. A. & Basbaum, A. I. Persistent cardiovascular and behavioral nociceptive responses to subcutaneous formalin require peripheral nerve input. J. Neurosci. 15, 7575–7584 (1995).

    CAS  Article  Google Scholar 

  27. 27

    Birren, S. J., Lo, L. C. & Anderson, D. J. Sympathetic neurons undergo a developmental switch in trophic dependence. Development 119, 597–610 (1993).

    CAS  PubMed  Google Scholar 

  28. 28

    Franklin, K. B. J. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates (Academic, New York, 1997).

    Google Scholar 

  29. 29

    Calejesan, A. A., Kim, S. J. & Zhuo, M. Descending facilitatory modulation of a behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex. Eur. J. Pain 4, 83–96 (2000).

    CAS  Article  Google Scholar 

  30. 30

    Lee, D. E., Kim, S. J. & Zhuo, M. Comparison of behavioral responses to noxious cold and heat in mice. Brain Res. 845, 117–121 (1999).

    CAS  Article  Google Scholar 

  31. 31

    Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M. & Yaksh, T. L. Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53, 55–63 (1994).

    CAS  Article  Google Scholar 

Download references


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.

Author information



Corresponding author

Correspondence to Min Zhuo.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing