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The Journal of Neuroscience, June 15, 2003, 23(12):5031-5040

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A Conditional Deletion of the NR1 Subunit of the NMDA Receptor in Adult Spinal Cord Dorsal Horn Reduces NMDA Currents and Injury-Induced Pain

Samantha M. South,¹ Tatsuro Kohno,² Brian K. Kaspar,³ Deborah Hegarty,¹ Bryce Vissel,³ Carrie T. Drake,¹ Megumi Ohata,¹ Shirzad Jenab,¹ Andreas W. Sailer,³ Shelle Malkmus,⁴ Takashi Masuyama,⁴ Philip Horner,³ Johanna Bogulavsky,¹ Fred H. Gage,³ Tony L. Yaksh,⁴ Clifford J. Woolf,² Stephen F. Heinemann,³ and Charles E. Inturrisi¹

¹Departments of Pharmacology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, ²Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, ³Laboratory of Genetics and of Molecular Neurobiology, The Salk Institute for Biological Studies, La Jolla, California 92037, and ⁴Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093

To determine the importance of the NMDA receptor (NMDAR) in pain hypersensitivity after injury, the NMDAR1 (NR1) subunit was selectively deleted in the lumbar spinal cord of adult mice by the localized injection of an adenoassociated virus expressing Cre recombinase into floxed NR1 mice. NR1 subunit mRNA and dendritic protein are reduced by 80% in the area of the virus injection, and NMDA currents, but not AMPA currents, are reduced 86–88% in lamina II neurons. The spatial NR1 knock-out does not alter heat or cold paw-withdrawal latencies, mechanical threshold, or motor function. However, injury-induced pain produced by intraplantar formalin is reduced by 70%. Our results demonstrate conclusively that the postsynaptic NR1 receptor subunit in the lumbar dorsal horn of the spinal cord is required for central sensitization, the central facilitation of pain transmission produced by peripheral injury.

Key words: NMDA receptor; conditional knock-out; Cre–loxP; formalin pain; spinal cord dorsal horn; synaptic transmission; central sensitization

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Received Jan. 17, 2003; revised Mar. 27, 2003; accepted Mar. 28, 2003.

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