NMDA Receptor Activation Underlies the Loss of Spinal Dorsal Horn Neurons and the Transition to Persistent Pain after Peripheral Nerve Injury
Perrine Inquimbert,
Martin Moll,
Alban Latremoliere,
Chi-Kun Tong,
John Whang,
Gregory F. Sheehan,
Brendan M. Smith,
Erica Korb,
Maria C.P. Athié,
Olusegun Babaniyi,
Nader Ghasemlou,
Yuchio Yanagawa,
C. David Allis,
Patrick R. Hof,
Joachim Scholz
Affiliations
Perrine Inquimbert
Centre National de la Recherche Scientifique, UPR 3212, Institut des Neurosciences Cellulaires et Intégratives and Université de Strasbourg, 67084 Strasbourg, France
Martin Moll
Departments of Anesthesiology and Pharmacology, Columbia University Medical Center, New York, NY 10032, USA
Alban Latremoliere
F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Chi-Kun Tong
Departments of Anesthesiology and Pharmacology, Columbia University Medical Center, New York, NY 10032, USA
John Whang
Departments of Anesthesiology and Pharmacology, Columbia University Medical Center, New York, NY 10032, USA
Gregory F. Sheehan
Departments of Anesthesiology and Pharmacology, Columbia University Medical Center, New York, NY 10032, USA
Brendan M. Smith
Departments of Anesthesiology and Pharmacology, Columbia University Medical Center, New York, NY 10032, USA
Erica Korb
Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, NY 10065, USA
Maria C.P. Athié
Department of Structural and Functional Biology, State University of Campinas, Campinas, SP 13083-865, Brazil
Olusegun Babaniyi
F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Nader Ghasemlou
F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Yuchio Yanagawa
Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
C. David Allis
Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, NY 10065, USA
Patrick R. Hof
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Joachim Scholz
Departments of Anesthesiology and Pharmacology, Columbia University Medical Center, New York, NY 10032, USA
Peripheral nerve lesions provoke apoptosis in the dorsal horn of the spinal cord. The cause of cell death, the involvement of neurons, and the relevance for the processing of somatosensory information are controversial. Here, we demonstrate in a mouse model of sciatic nerve injury that glutamate-induced neurodegeneration and loss of γ-aminobutyric acid (GABA)ergic interneurons in the superficial dorsal horn promote the transition from acute to chronic neuropathic pain. Conditional deletion of Grin1, the essential subunit of N-methyl-d-aspartate-type glutamate receptors (NMDARs), protects dorsal horn neurons from excitotoxicity and preserves GABAergic inhibition. Mice deficient in functional NMDARs exhibit normal nociceptive responses and acute pain after nerve injury, but this initial increase in pain sensitivity is reversible. Eliminating NMDARs fully prevents persistent pain-like behavior. Reduced pain in mice lacking proapoptotic Bax confirmed the significance of neurodegeneration. We conclude that NMDAR-mediated neuron death contributes to the development of chronic neuropathic pain.
