Molecular Medicine Partnership Unit

The MMPU is a joint venture between the Medical Faculty of the University of Heidelberg and the European Molecular Biology Laboratory (EMBL).

Chronic Pain and Homeostasis

Robert Prevedel, Theodore Alexandrov, Rohini Kuner and Jan Siemens

Our research interest

Homeostatic dysregulation is a cornerstone for diverse neural disorders, particularly for chronic pain, which is a major health problem worldwide. Our unit addresses key biological challenges in chronic pain and homeostasis, such as understanding metabolic mechanisms of chronic pain and homeostasis, and elucidating cellular circuits in the brain that are involved in these adaptive and maladaptive processes.

Our collaborative activities bridge the expertise in neurobiology (Siemens, Kuner) and cutting-edge molecular imaging and -omics techniques (Alexandrov, Prevedel).


Homeostatic mechanisms are key to fundamental body functions. The brain is not only a mastermind of homeostatic control, but also critically subject to homeostatic regulation. How key homeostatic functions, such as thermoregulation and basic metabolic pathways, are governed by the nervous system remains unclear.

Chronic pain remains a major health problem worldwide, which severely impacts on quality of life. Several forms of chronic pain involve structural and/or functional plasticity or maladaptation processes, which are related, at least in part, to homeostatic dysregulation. Understanding the molecular and circuit basis of maladaptive plasticity leading to chronic pain is critical for designing new therapeutic approaches.


Within our unit, we aim to combine our expertise on the analysis of experimental models (Siemens, Kuner) and molecular and cellular imaging technologies (Alexandrov, Prevedel) to address a number of key questions in chronic pain and homeostasis, while simultaneously further driving innovation and developments of advanced imaging techniques. We plan to study primarily transgenic mouse models, and wherever applicable to employ humanised systems, such as stem cell-derived peripheral and central human neurons or patient material. Cutting-edge technologies represented by the EMBL partners with respect to metabolomics and deep in vivo imaging of cellular circuits will enable us to derive biological insights on chronic pain and homeostatic dysregulation.

Specifically, our current and future work will focus on two themes:

  • Metabolic plasticity in chronic pain and homeostatic compensation and decompensation.
  • Imaging functional organisation and plasticity of brain circuits mediating chronic pain and thermoregulation.

Key project-related publications from the last years

Kuner Group

Neuron–astrocyte metabolic coupling facilitates spinal plasticity and maintenance of inflammatory pain
Sebastián Marty-Lombardi, Shiying Lu, Wojciech Ambroziak, Katrin Schrenk-Siemens, Jialin Wang, Anna A. DePaoli-Roach, Anna M. Hagenston, Hagen Wende, Anke Tappe-Theodor, Manuela Simonetti, Hilmar Bading, Jürgen G. Okun, Rohini Kuner, Thomas Fleming & Jan Siemens
Nature Metabolism 2024 March 5, doi:10.1038/s42255-024-01001-2

Prefrontal engrams of long-term fear memory perpetuate pain perception.
Stegemann A, Liu S, Retana Romero OA, Oswald MJ, Han Y, Beretta CA, Gan Z, Tan LL, Wisden W, Gräff J, Kuner R.
Nat Neurosci. 2023 May;26(5):820-829. doi: 10.1038/s41593-023-01291-x. Epub 2023 Apr 6. PMID: 37024573

Layer-specific pain relief pathways originating from primary motor cortex.
Gan Z, Gangadharan V, Liu S, Körber C, Tan LL, Li H, Oswald MJ, Kang J, Martin-Cortecero J, Männich D, Groh A, Kuner T, Wieland S, Kuner R.
Science. 2022 Dec 23;378(6626):1336-1343. doi: 10.1126/science.add4391. Epub 2022 Dec 22. PMID: 36548429

Cholinergic basal forebrain nucleus of Meynert regulates chronic pain-like behavior via modulation of the prelimbic cortex.
Oswald MJ, Han Y, Li H, Marashli S, Oglo DN, Ojha B, Naser PV, Gan Z, Kuner R.
Nat Commun. 2022 Aug 25;13(1):5014. doi: 10.1038/s41467-022-32558-9. PMID: 36008394

Genetic Mouse Models to Study Pancreatic Cancer-Induced Pain and Reduction in Well-Being.
Hirth M, Xie Y, Höper C, Prats A, Hackert T, Ebert MP, Kuner R.
Cells. 2022 Aug 24;11(17):2634. doi: 10.3390/cells11172634. PMID: 36078040

Newsroom UKHD May 25, 2022
Mit der Nervenregeneration kommt der chronische Schmerz

Neuropathic pain caused by miswiring and abnormal end organ targeting.
Gangadharan V, Zheng H, Taberner FJ, Landry J, Nees TA, Pistolic J, Agarwal N, Männich D, Benes V, Helmstaedter M, Ommer B, Lechner SG, Kuner T, Kuner R.
Nature. 2022 Jun;606(7912):137-145. doi: 10.1038/s41586-022-04777-z. Epub 2022 May 25. PMID: 35614217

SUMOylation of Enzymes and Ion Channels in Sensory Neurons Protects against Metabolic Dysfunction, Neuropathy, and Sensory Loss in Diabetes.
Agarwal N, Taberner FJ, Rangel Rojas D, Moroni M, Omberbasic D, Njoo C, Andrieux A, Gupta P, Bali KK, Herpel E, Faghihi F, Fleming T, Dejean A, Lechner SG, Nawroth PP, Lewin GR, Kuner R.
Neuron. 2020 Sep 23;107(6):1141-1159.e7. doi: 10.1016/j.neuron.2020.06.037. Epub 2020 Jul 30. PMID: 32735781

CXCL10 and CCL21 Promote Migration of Pancreatic Cancer Cells Toward Sensory Neurons and Neural Remodeling in Tumors in Mice, Associated With Pain in Patients.
Hirth M, Gandla J, Höper C, Gaida MM, Agarwal N, Simonetti M, Demir A, Xie Y, Weiss C, Michalski CW, Hackert T, Ebert MP, Kuner R. Gastroenterology. 2020 Aug;159(2):665-681.e13. doi: 10.1053/j.gastro.2020.04.037. Epub 2020 Apr 21. PMID: 32330476

Gamma oscillations in somatosensory cortex recruit prefrontal and descending serotonergic pathways in aversion and nociception.
Tan LL, Oswald MJ, Heinl C, Retana Romero OA, Kaushalya SK, Monyer H, Kuner R.
Nat Commun. 2019 Feb 28;10(1):983. doi: 10.1038/s41467-019-08873-z. PMID:30816113

A pathway from midcingulate cortex to posterior insula gates nociceptive hypersensitivity.
Tan LL, Pelzer P, Heinl C, Tang W, Gangadharan V, Flor H, Sprengel R, Kuner T, Kuner R.
Nat Neurosci. 2017 Nov;20(11):1591-1601. doi: 10.1038/nn.4645. Epub 2017 Sep 18. PMID:28920932

Semaphorin 4C Plexin-B2 signaling in peripheral sensory neurons is pronociceptive in a model of inflammatory pain.
Paldy E, Simonetti M, Worzfeld T, Bali KK, Vicuña L, Offermanns S, Kuner R.
Nat Commun. 2017 Aug 2;8(1):176. doi: 10.1038/s41467-017-00341-w. PMID: 28765520

The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase.
Vicuña L, Strochlic DE, Latremoliere A, Bali KK, Simonetti M, Husainie D, Prokosch S, Riva P, Griffin RS, Njoo C, Gehrig S, Mall MA, Arnold B, Devor M, Woolf CJ, Liberles SD, Costigan M, Kuner R.
Nat Med. 2015 May;21(5):518-23. doi: 10.1038/nm.3852. Epub 2015 Apr 27. PMID: 25915831

A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain.
Selvaraj D, Gangadharan V, Michalski CW, Kurejova M, Stösser S, Srivastava K, Schweizerhof M, Waltenberger J, Ferrara N, Heppenstall P, Shibuya M, Augustin HG, Kuner R.
Cancer Cell. 2015 Jun 8;27(6):780-96. doi: 10.1016/j.ccell.2015.04.017. Erratum in: Cancer Cell. 2015 Aug 10;28(2):270. PMID:26058077

Prevedel Group

High-resolution line-scan Brillouin microscopy for live imaging of mechanical properties during embryo development.
Bevilacqua C, Gomez JM, Fiuza UM, Chan CJ, Wang L, Hambura S, Eguren M, Ellenberg J, Diz-Muñoz A, Leptin M, Prevedel R.
Nat Methods. 2023 May;20(5):755-760. doi: 10.1038/s41592-023-01822-1. Epub 2023 Mar 30.PMID: 36997817

High-resolution structural and functional deep brain imaging using adaptive optics three-photon microscopy.
Streich L, Boffi JC, Wang L, Alhalaseh K, Barbieri M, Rehm R, Deivasigamani S, Gross CT, Agarwal A, Prevedel R. Nat Methods. 2021 Sep 30. doi: 10.1038/s41592-021-01257-6. Online ahead of print. PMID: 34594033

Deep learning-enhanced light-field imaging with continuous validation.
Wagner N, Beuttenmueller F, Norlin N, Gierten J, Boffi JC, Wittbrodt J, Weigert M, Hufnagel L, Prevedel R, Kreshuk A.
Nat Methods. 2021 May;18(5):557-563. doi: 10.1038/s41592-021-01136-0. Epub 2021 May 7. PMID: 33963344

Instantaneous isotropic volumetric imaging of fast biological processes.
Wagner N, Norlin N, Gierten J, de Medeiros G, Balázs B, Wittbrodt J, Hufnagel L, Prevedel R.
Nat Methods. 2019 Jun;16(6):497-500. doi: 10.1038/s41592-019-0393-z. Epub 2019 Apr 29. PMID: 31036959

Fast volumetric calcium imaging across multiple cortical layers using sculpted light.
Prevedel R, Verhoef AJ, Pernía-Andrade AJ, Weisenburger S, Huang BS, Nöbauer T, Fernández A, Delcour JE, Golshani P, Baltuska A, Vaziri A.
Nat Methods. 2016 Dec;13(12):1021-1028. doi: 10.1038/nmeth.4040. Epub 2016 Oct 31. PMID:27798612

Simultaneous whole-animal 3D imaging of neuronal activity using light-field microscopy.
Prevedel R, Yoon YG, Hoffmann M, Pak N, Wetzstein G, Kato S, Schrödel T, Raskar R, Zimmer M, Boyden ES, Vaziri A.
Nat Methods. 2014 Jul;11(7):727-730. doi: 10.1038/nmeth.2964. Epub 2014 May 18. PMID: 24836920

Brain-wide 3D imaging of neuronal activity in Caenorhabditis elegans with sculpted light.
Schrödel T, Prevedel R, Aumayr K, Zimmer M, Vaziri A.
Nat Methods. 2013 Oct;10(10):1013-20. doi: 10.1038/nmeth.2637. Epub 2013 Sep 8. PMID: 24013820

Alexandrov Team

SpaceM reveals metabolic states of single cells.
Rappez L, Stadler M, Triana S, Gathungu RM, Ovchinnikova K, Phapale P, Heikenwalder M, Alexandrov T.
Nat Methods. 2021 Jul;18(7):799-805. doi: 10.1038/s41592-021-01198-0. Epub 2021 Jul 5. PMID: 34226721

Single-cell transcriptomics reveals immune response of intestinal cell types to viral infection.
Triana S, Stanifer ML, Metz-Zumaran C, Shahraz M, Mukenhirn M, Kee C, Serger C, Koschny R, Ordoñez-Rueda D, Paulsen M, Benes V, Boulant S, Alexandrov T.
Mol Syst Biol. 2021 Jul;17(7):e9833. doi: 10.15252/msb.20209833. PMID: 34309190

Single-cell analyses reveal SARS-CoV-2 interference with intrinsic immune response in the human gut.
Triana S, Metz-Zumaran C, Ramirez C, Kee C, Doldan P, Shahraz M, Schraivogel D, Gschwind AR, Sharma AK, Steinmetz LM, Herrmann C, Alexandrov T, Boulant S, Stanifer ML.
Mol Syst Biol. 2021 Apr;17(4):e10232. doi: 10.15252/msb.202110232. PMID: 33904651

Spatial single-cell profiling of intracellular metabolomes in situ.
Rappez L, Stadler M, Triana S, Phapale P, Heikenwalder M, Alexandrov T.
BioRxiv 510222 (2019)

METASPACE: A community-populated knowledge base of spatial metabolomes in health and disease.
Alexandrov T, Ovchinnikova K, Palmer A, Kovalev V, Tarasov A, Stuart L, Nigmetzianov R, Dominik F, Key METASPACE contributors
BioRxiv 539478 (2019)

3D molecular cartography using LC-MS facilitated by Optimus and ‘ili software.
Protsyuk I, Melnik AV, Nothias LF, Rappez L, Phapale P, Aksenov AA, Bouslimani A, Ryazanov S, Dorrestein PC, Alexandrov T.
Nat Protoc. 2018 Jan;13(1):134-154. doi: 10.1038/nprot.2017.122. Epub 2017 Dec 21.PMID: 29266099

FDR-controlled metabolite annotation for high-resolution imaging mass spectrometry.
Palmer A, Phapale P, Chernyavsky I, Lavigne R, Fay D, Tarasov A, Kovalev V, Fuchser J, Nikolenko S, Pineau C, Becker M, Alexandrov T.
Nat Methods. 2017 Jan;14(1):57-60. doi: 10.1038/nmeth.4072. Epub 2016 Nov 14. PMID:27842059

Molecular cartography of the human skin surface in 3D.
Bouslimani A, Porto C, Rath CM, Wang M, Guo Y, Gonzalez A, Berg-Lyon D, Ackermann G, Moeller Christensen GJ, Nakatsuji T, Zhang L, Borkowski AW, Meehan MJ, Dorrestein K, Gallo RL, Bandeira N, Knight R, Alexandrov T, Dorrestein PC.
Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):E2120-9. doi: 10.1073/pnas.1424409112. Epub 2015 Mar 30. PMID:25825778

Siemens Group

Diverging roles of TRPV1 and TRPM2 in warm-temperature detection
Muad Y. Abd El Hay, Gretel B. Kamm, Alejandro Tlaie & Jan Siemens
eLife 13:RP95618 (2024) March 5, doi: 10.7554/eLife.95618.1

Neuron–astrocyte metabolic coupling facilitates spinal plasticity and maintenance of inflammatory pain
Sebastián Marty-Lombardi, Shiying Lu, Wojciech Ambroziak, Katrin Schrenk-Siemens, Jialin Wang, Anna A. DePaoli-Roach, Anna M. Hagenston, Hagen Wende, Anke Tappe-Theodor, Manuela Simonetti, Hilmar Bading, Jürgen G. Okun, Rohini Kuner, Thomas Fleming & Jan Siemens
Nature Metabolism (2024) March 5, doi:10.1038/s42255-024-01001-2

A synaptic temperature sensor for body cooling.
Kamm GB, Boffi JC, Zuza K, Nencini S, Campos J, Schrenk-Siemens K, Sonntag I, Kabaoğlu B, El Hay MYA, Schwarz Y, Tappe-Theodor A, Bruns D, Acuna C, Kuner T, Siemens J.
Neuron. 2021 Oct 20;109(20):3283-3297.e11. doi: 10.1016/j.neuron.2021.10.001. PMID: 34672983

Human vs. Mouse Nociceptors – Similarities and Differences.
Rostock C, Schrenk-Siemens K, Pohle J, Siemens J.
Neuroscience. 2018 Sep 1;387:13-27. doi: 10.1016/j.neuroscience.2017.11.047. Epub 2017 Dec 8. PMID: 29229553

The TRPM2 channel is a hypothalamic heat sensor that limits fever and can drive hypothermia.
Song K, Wang H, Kamm GB, Pohle J, Reis FC, Heppenstall P, Wende H, Siemens J.
Science. 2016 Sep 23;353(6306):1393-1398. Epub 2016 Aug 25. PMID:27562954

GABA blocks pathological but not acute TRPV1 pain signals.
Hanack C, Moroni M, Lima WC, Wende H, Kirchner M, Adelfinger L, Schrenk-Siemens K, Tappe-Theodor A, Wetzel C, Kuich PH, Gassmann M, Roggenkamp D, Bettler B, Lewin GR, Selbach M, Siemens J.
Cell. 2015 Feb 12;160(4):759-770. doi: 10.1016/j.cell.2015.01.022. PMID:25679765

PIEZO2 is required for mechanotransduction in human stem cell-derived touch receptors.
Schrenk-Siemens K, Wende H, Prato V, Song K, Rostock C, Loewer A, Utikal J, Lewin GR, Lechner SG, Siemens J.
Nat Neurosci. 2015 Jan;18(1):10-6. doi: 10.1038/nn.3894. Epub 2014 Dec 3.PMID: 25469543

A somatosensory circuit for cooling perception in mice.
Milenkovic N, Zhao WJ, Walcher J, Albert T, Siemens J, Lewin GR, Poulet JF.
Nat Neurosci. 2014 Nov;17(11):1560-6. doi: 10.1038/nn.3828. Epub 2014 Sep 28. PMID:25262494