Mechanistic Differences in Neuropathic Pain Modalities Revealed by Correlating Behavior with Global Expression Profiling
Enrique J. Cobos,
Chelsea A. Nickerson,
Fuying Gao,
Vijayendran Chandran,
Inmaculada Bravo-Caparrós,
Rafael González-Cano,
Priscilla Riva,
Nick A. Andrews,
Alban Latremoliere,
Corey R. Seehus,
Gloria Perazzoli,
Francisco R. Nieto,
Nicole Joller,
Michio W. Painter,
Chi Him Eddie Ma,
Takao Omura,
Elissa J. Chesler,
Daniel H. Geschwind,
Giovanni Coppola,
Manu Rangachari,
Clifford J. Woolf,
Michael Costigan
Affiliations
Enrique J. Cobos
Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Pharmacology and Institute of Neuroscience, Faculty of Medicine and Biomedical Research Center, University of Granada, 18071 Granada, Spain; Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain
Chelsea A. Nickerson
Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Fuying Gao
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Vijayendran Chandran
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pediatrics, School of Medicine, University of Florida, Gainesville, FL 32610-0296, USA
Inmaculada Bravo-Caparrós
Department of Pharmacology and Institute of Neuroscience, Faculty of Medicine and Biomedical Research Center, University of Granada, 18071 Granada, Spain
Rafael González-Cano
Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Priscilla Riva
Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Nick A. Andrews
Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Alban Latremoliere
Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Corey R. Seehus
Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Gloria Perazzoli
Department of Pharmacology and Institute of Neuroscience, Faculty of Medicine and Biomedical Research Center, University of Granada, 18071 Granada, Spain; Department of Anatomy and Embryology, School of Medicine, University of Granada, 18071 Granada, Spain
Francisco R. Nieto
Department of Pharmacology and Institute of Neuroscience, Faculty of Medicine and Biomedical Research Center, University of Granada, 18071 Granada, Spain; Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain
Nicole Joller
Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Michio W. Painter
Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Chi Him Eddie Ma
Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Takao Omura
Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Elissa J. Chesler
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
Daniel H. Geschwind
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Giovanni Coppola
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Manu Rangachari
Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurosciences, Centre de recherche du CHU de Québec, Université Laval, Québec, QC, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC G1V 0A6, Canada
Clifford J. Woolf
Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Michael Costigan
Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Anesthesia, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Summary: Chronic neuropathic pain is a major morbidity of neural injury, yet its mechanisms are incompletely understood. Hypersensitivity to previously non-noxious stimuli (allodynia) is a common symptom. Here, we demonstrate that the onset of cold hypersensitivity precedes tactile allodynia in a model of partial nerve injury, and this temporal divergence was associated with major differences in global gene expression in innervating dorsal root ganglia. Transcripts whose expression change correlates with the onset of cold allodynia were nociceptor related, whereas those correlating with tactile hypersensitivity were immune cell centric. Ablation of TrpV1 lineage nociceptors resulted in mice that did not acquire cold allodynia but developed normal tactile hypersensitivity, whereas depletion of macrophages or T cells reduced neuropathic tactile allodynia but not cold hypersensitivity. We conclude that neuropathic pain incorporates reactive processes of sensory neurons and immune cells, each leading to distinct forms of hypersensitivity, potentially allowing drug development targeted to each pain type. : Cobos et al. correlated gene expression with behavior after nerve injury and found that two distinct processes contribute to neuropathic pain: one that occurs in neurons, leading to cold allodynia, and another that includes immune cells and neurons, leading to tactile allodynia. Keywords: neuropathic pain, macrophages, T cells, immune system, TrpV1, tactile allodynia, cold allodynia, gene expression, transcript profiling, WCGNA
