Spontaneous neuropathic pain
- 1F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA, United States
Abstract
Spontaneous pain is a highly prevalent and disabling consequence of neuropathic disorders, yet it remains mechanistically underdefined and therapeutically underserved. Historically, preclinical animal models and clinical trials have been overwhelmingly biased toward stimulus-evoked hypersensitivity, relegating spontaneous pain to a secondary manifestation. Emerging evidence now challenges this view. Converging data from pharmacology, neural recordings, and systems-level causal manipulations indicate that spontaneous and stimulus-evoked pain arise from substantially dissociable molecular, cellular, and circuit substrates. Injured-fiber–derived ectopic activity within specific sensory neuron subtypes serves as a dominant peripheral generator of spontaneous pain, whereas cellularly distinct, intact spared-fiber pathways mediate stimulus-evoked hypersensitivity. At spinal and supraspinal levels, spontaneous pain preferentially engages affective–salience networks during pain chronification and may ultimately become stabilized within higher-order circuitry—while remaining dynamically coupled to afferent input. This mechanistic delineation carries critical translational implications. Current diagnostic and treatment guidelines rarely differentiate symptom domains, and most therapies have been validated primarily using stimulus-evoked or overall pain intensity endpoints—potentially contributing to a mechanism–therapy mismatch and variable efficacy. We argue that spontaneous neuropathic pain should be defined as a separate symptom domain rather than considered as a spontaneous manifestation of evoked pain mechanisms. This recognition demands longitudinal, biomarker-informed phenotyping to capture its persistent and fluctuating nature, and thereby enable robust mechanistic dissection at peripheral, spinal, and cortical nodes. Reframing spontaneous neuropathic pain along these lines will provide a foundation for precision therapeutics that target defined cell types, specific molecular drivers, and maladaptive network states—enabling mechanism-based, symptom-aligned treatments.
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BibTeX
@article{zeng2026spontaneous,
title = {{Spontaneous neuropathic pain}},
author = {Xiangsunze Zeng and Clifford J. Woolf},
journal = {Pain},
year = {2026},
month = oct,
doi = {10.1097/j.pain.0000000000004054},
url = {https://europepmc.org/article/PMC/PMC13714776},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Spontaneous neuropathic pain
AU - Xiangsunze Zeng
AU - Clifford J. Woolf
PY - 2026
DA - 2026/10/31
JO - Pain
DO - 10.1097/j.pain.0000000000004054
UR - https://europepmc.org/article/PMC/PMC13714776
AB - Spontaneous pain is a highly prevalent and disabling consequence of neuropathic disorders, yet it remains mechanistically underdefined and therapeutically underserved. Historically, preclinical animal models and clinical trials have been overwhelmingly biased toward stimulus-evoked hypersensitivity, relegating spontaneous pain to a secondary manifestation. Emerging evidence now challenges this view. Converging data from pharmacology, neural recordings, and systems-level causal manipulations indicate that spontaneous and stimulus-evoked pain arise from substantially dissociable molecular, cellular, and circuit substrates. Injured-fiber–derived ectopic activity within specific sensory neuron subtypes serves as a dominant peripheral generator of spontaneous pain, whereas cellularly distinct, intact spared-fiber pathways mediate stimulus-evoked hypersensitivity. At spinal and supraspinal levels, spontaneous pain preferentially engages affective–salience networks during pain chronification and may ultimately become stabilized within higher-order circuitry—while remaining dynamically coupled to afferent input. This mechanistic delineation carries critical translational implications. Current diagnostic and treatment guidelines rarely differentiate symptom domains, and most therapies have been validated primarily using stimulus-evoked or overall pain intensity endpoints—potentially contributing to a mechanism–therapy mismatch and variable efficacy. We argue that spontaneous neuropathic pain should be defined as a separate symptom domain rather than considered as a spontaneous manifestation of evoked pain mechanisms. This recognition demands longitudinal, biomarker-informed phenotyping to capture its persistent and fluctuating nature, and thereby enable robust mechanistic dissection at peripheral, spinal, and cortical nodes. Reframing spontaneous neuropathic pain along these lines will provide a foundation for precision therapeutics that target defined cell types, specific molecular drivers, and maladaptive network states—enabling mechanism-based, symptom-aligned treatments.
SN - 0304-3959
SN - 1872-6623
ER -