Descending inhibitory rostral ventromedial medulla neurons cause widespread antinociception and contribute to the pain-inhibits-pain phenomenon.

Overview

Authors: Robert P Ganley^1,2, Marília Sousa^1,3, Guangchen Ji⁴, Matteo Ranucci^1,3, Camilla Beccarini^1,3, Kira Werder¹, Francesca Pietrafesa^1,3, Simon d’Aquin¹, Tugce Akyüz⁵, Michèle Hubli⁶, Petra Schweinhardt⁷, Volker Neugebauer⁴, Mark A Hoon², Hendrik Wildner¹, Hanns Ulrich Zeilhofer^1,3,5

ORCID iDs: Robert P Ganley, Marília Sousa, Guangchen Ji, Matteo Ranucci, Camilla Beccarini, Kira Werder, Francesca Pietrafesa, Petra Schweinhardt, Volker Neugebauer, Mark A Hoon, Hanns Ulrich Zeilhofer

Institutions: National Institutes of Health (United States); University of Zurich (Switzerland); National Institute of Dental and Craniofacial Research (United States); Texas Tech University (United States); Texas Tech University Health Sciences Center (United States); ETH Zurich (Switzerland); Institute of Pharmaceutical Sciences (Switzerland); Universitätsklinik Balgrist (Switzerland)

Journal: Nature communications, volume 17, issue 1, article 4765

Dates: received 29 November 2024; accepted 18 March 2026; published online 2 April 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1038/s41467-026-71289-z · PMID 41927569 · PMCID PMC13216533 · OpenAlex W7148462155

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: mouse (organism), pain (population), systems (subfield)

Methods: Statistics

Keywords: Neural circuits, Sensory processing

MeSH: Medulla Oblongata*, Neurons*, Nociception*, Pain*, Animals, Chronic Pain, Hot Temperature, Hyperalgesia, Male, Mice, Mice, Inbred C57BL, Optogenetics, Spinal Cord (* major topic)

Topic: Pain Mechanisms and Treatments (Physiology, Medicine), according to OpenAlex

Funding: Swiss National Science Foundation (310030_197888, 197888, 310030); NINDS NIH HHS (R01 NS118731, R01 NS038261); EC | Horizon 2020 Framework Programme (101016787); Universität Zürich (University of Zurich) (Clinical Research Priority Program 'Pain - from phenotypes to mechanism', Clinical Research Priority Program ‘Pain – from phenotypes to mechanism’); U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR) (ZIADE000721-19); U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (ZIADE000721-19)

Citations: cited by 2 papers (Europe PMC); 78 references in the paper

Abstract

Acute painful stimuli applied to one body site reduce pain at other sites. The circuit basis of this “pain-inhibits-pain” phenomenon, also known as diffuse noxious inhibitory control (DNIC) in animals or conditioned pain modulation (CPM) in humans, is largely unknown. Using anatomical and optogenetic circuit tracing, we identified a population of descending inhibitory neurons of the rostral ventromedial medulla (RVM) that densely and bilaterally innervate the spinal cord along its rostrocaudal axis. Activating these neurons reduced heat and cold sensitivity widely in healthy mice and caused similarly wide-spread antihyperalgesia in chronic pain models, while their silencing evoked mechanical allodynia and spontaneous pain-like behaviors. Noxious stimuli activated subsets of these neurons in the lateral paragigantocellularis nucleus (LPGi), which inhibited nociception upon chemogenetic reactivation. Spinally projecting inhibitory RVM neurons are hence ideally positioned to function as circuit elements of DNIC and CPM, while their dysfunction may contribute to wide-spread chronic pain syndromes.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

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Data

Datasets cited

zenodo:18983374, at Zenodo; found in “Data availability”

Data availability

All unique materials are available from the authors. All quantitative data generated in this study are provided in the Source Data file. Raw data acquired in these experiments has been uploaded to 10.5281/zenodo.18983374 and is available for download. Source data are provided with this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 2 keywords, 13 MeSH terms, 6 funders, 78 references.

Cite

This paper

Ganley, R. P., Sousa, M., Ji, G., Ranucci, M., Beccarini, C., Werder, K., Pietrafesa, F., d’Aquin, S., Akyüz, T., Hubli, M., Schweinhardt, P., Neugebauer, V., Hoon, M. A., Wildner, H., & Zeilhofer, H. U. (2026). Descending inhibitory rostral ventromedial medulla neurons cause widespread antinociception and contribute to the pain-inhibits-pain phenomenon. Nature communications, 17(1), 4765. https://doi.org/10.1038/s41467-026-71289-z

BibTeX

@article{ganley2026descending, author = {Ganley, Robert P and Sousa, Marília and Ji, Guangchen and Ranucci, Matteo and Beccarini, Camilla and Werder, Kira and Pietrafesa, Francesca and d’Aquin, Simon and Akyüz, Tugce and Hubli, Michèle and Schweinhardt, Petra and Neugebauer, Volker and Hoon, Mark A and Wildner, Hendrik and Zeilhofer, Hanns Ulrich}, title = {{Descending inhibitory rostral ventromedial medulla neurons cause widespread antinociception and contribute to the pain-inhibits-pain phenomenon}}, journal = {Nature communications}, year = {2026}, month = apr, volume = {17}, number = {1}, pages = {4765}, publisher = {Nature Publishing Group}, issn = {2041-1723}, doi = {10.1038/s41467-026-71289-z}, url = {https://doi.org/10.1038/s41467-026-71289-z}, pmid = {41927569}, pmcid = {PMC13216533} }

RIS

TY - JOUR AU - Ganley, Robert P AU - Sousa, Marília AU - Ji, Guangchen AU - Ranucci, Matteo AU - Beccarini, Camilla AU - Werder, Kira AU - Pietrafesa, Francesca AU - d’Aquin, Simon AU - Akyüz, Tugce AU - Hubli, Michèle AU - Schweinhardt, Petra AU - Neugebauer, Volker AU - Hoon, Mark A AU - Wildner, Hendrik AU - Zeilhofer, Hanns Ulrich TI - Descending inhibitory rostral ventromedial medulla neurons cause widespread antinociception and contribute to the pain-inhibits-pain phenomenon T2 - Nature communications J2 - Nat Commun PY - 2026 DA - 2026/04/02 VL - 17 IS - 1 SP - 4765 SN - 2041-1723 PB - Nature Publishing Group DO - 10.1038/s41467-026-71289-z UR - https://doi.org/10.1038/s41467-026-71289-z LA - en ER -

CSL-JSON

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