The dorsal column nuclei scale mechanical sensitivity in naive and neuropathic pain states
During pathological conditions, tactile stimuli can aberrantly engage nociceptive pathways leading to the perception of touch as pain, known as mechanical allodynia. The brain stem dorsal column nuclei integrate tactile inputs, yet their role in mediating tactile sensitivity and allodynia remains understudied. We found that gracile nucleus (Gr) inhibitory interneurons and thalamus-projecting neurons are differentially innervated by primary afferents and spinal inputs. Functional manipulations of these distinct Gr neuronal populations bidirectionally shifted tactile sensitivity but did not affect noxious mechanical or thermal sensitivity. During neuropathic pain, Gr neurons exhibited increased sensory-evoked activity and asynchronous excitatory drive from primary afferents. Silencing Gr projection neurons or activating Gr inhibitory neurons in neuropathic mice reduced tactile hypersensitivity, and enhancing inhibition ameliorated paw-withdrawal signatures of neuropathic pain and induced conditioned place preference. These results suggest that Gr activity contributes to tactile sensitivity and affective, pain-associated phenotypes of mechanical allodynia.
Authors
- Fumiyasu Imai (ORCID: https://orcid.org/0000-0003-1364-1846)
- Chloe Azadegan (ORCID: https://orcid.org/0000-0002-1266-1637)
- Victoria E. Abraira (ORCID: https://orcid.org/0000-0001-9936-9921)
- Aman Upadhyay (ORCID: https://orcid.org/0000-0001-6447-0368)
- Simon Ogundare (ORCID: https://orcid.org/0000-0002-6243-2779)
- Joshua K. Thackray (ORCID: https://orcid.org/0000-0003-2828-452X)
- Ishmail Abdus-Saboor (ORCID: https://orcid.org/0000-0003-2120-0063)
- Manon Bohic (ORCID: https://orcid.org/0000-0003-4400-8314)
- Thomas J. Vajtay (ORCID: https://orcid.org/0000-0002-7026-2060)
- Mark A. Gradwell (ORCID: https://orcid.org/0000-0003-3308-8005)
- Yutaka Yoshida (ORCID: https://orcid.org/0000-0003-0664-0888)
- Eiman Azim (ORCID: https://orcid.org/0000-0002-1015-1772)
- James Conner (ORCID: https://orcid.org/0000-0002-0731-8746)
- Arnab A. Sanyal
- Komal Patel
Institutions
- Rutgers, The State University of New Jersey (US)
- Salk Institute for Biological Studies (US)
- Cornell University (US)
- MIND Research Institute (US)
- Burke Medical Research Institute (US)
- Columbia University (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115556
- Citations
- 4
- Primary Topic
- Pain Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 4.66
Funders
- Pew Charitable Trusts
- Rita Allen Foundation
- New Jersey Commission on Spinal Cord Research
- National Institute of Neurological Disorders and Stroke