A genetically defined injured C-fibre nociceptor associated with neuromas drives chronic spontaneous neuropathic pain
Year: 2025
Type: preprint
Abstract: Spontaneous pain is a common but poorly understood consequence of peripheral nerve injury 1–3 , including injuries that lead to the formation of neuromas 4,5 . We developed a chronic neuroma model for measuring spontaneous pain-related behaviours in mice, which revealed that limb flicks - emerging predominantly 2 months post-injury - reflect spontaneous paroxysmal pain. Ectopic activity of injured dorsal root ganglia (DRG) sensory neurons whose axonal endings terminate within the neuroma drives this spontaneous pain. In vivo imaging showed that a subset of small-diameter DRG sensory neurons are the source of spontaneous neural signals emanating from the neuroma, and these spontaneously active neurons are distinct from the intact larger diameter sensory neurons that mediate stimulus-evoked mechanical allodynia from spared nerves. Cell-type–specific gain- and loss-of-function studies identified a genetically- and functionally-defined subtype of small-diameter C-fibre nociceptors whose injured axons in neuromas drive spontaneous limb flicks/neuropathic pain. These findings establish the neurobiological basis of spontaneous pain enabling targeted pain management strategies and define a cellular and mechanistic separation between spontaneous and evoked neuropathic pain.
Authors: Xiangsunze Zeng, Rosa I. Martinez-Garcia, Shamsuddin A. Bhuiyan, Keunjung Heo, Natalie MacKinnon-Booth, Elke Bentley, Emily Shea, Kangling Wu, Omer Barkai, Bruna Lenfers Turnes, Selwyn S. Jayakar, Barbara Gomez-Eslava, Mustafa Q. Hameed, Celine Santiago, Karina Lezgiyeva, Emmanuella Osei-Asante, Ivan Furfaro, Alexander Rotenberg, Benjamin R. Johnston, Brian J. Wainger, William Renthal, Stéphanie P. Lacour, David D. Ginty, Clifford J. Woolf
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Howard Hughes Medical Institute, Human Frontier Science Program, National Institutes of Health, Intellectual and Developmental Disabilities Research Center, National Center for Complementary and Integrative Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W4414715855