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.
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 https://doi.org/10.5281/zenodo.18983374 and is available for download. Source data are provided with this paper.
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Acknowledgements
The authors thank the Center for Microscopy and Image Analysis at the University of Zurich for assistance with the tissue clearing and light-sheet microscopy experiments, and Louis Scheurer and Eva Roth for technical assistance. The work was supported by grants from the Swiss National Science Foundation (grant number: 310030_197888 to H.U.Z.), a grant from the European Union’s Horizon 2020 research and innovation actions (agreement no. 101016787 to H.U.Z.), the Clinical Research Priority Program ‘Pain—from phenotypes to mechanism’ of the Faculty of Medicine, University of Zurich, to H.U.Z., and was supported by the intramural research program of the National Institute of Dental and Craniofacial Research, National Institutes of Health, project ZIADE000721-19 (M.A.H.).
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R.P.G., M.S. H.W. and H.U.Z. conceived and designed the study. R.P.G., M.S., C.B. and F.P. performed behavioral assays, R.P.G., M.S., K.W., S.d’A. and T.A. performed anatomical tracing and histology experiments. R.P.G. and M.R. performed whole-cell electrophysiology experiments, G.J. and V.N. designed and performed in vivo electrophysiological recordings. M.H., P.S. and M.A.H. provided input on the interpretation of the data and discussion of the results. R.P.G., M.S., H.W. and H.U.Z. wrote the manuscript with inputs from all authors.
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Ganley, R.P., Sousa, M., Ji, G. et al. Descending inhibitory rostral ventromedial medulla neurons cause widespread antinociception and contribute to the pain-inhibits-pain phenomenon. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71289-z
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DOI: https://doi.org/10.1038/s41467-026-71289-z
