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

Paul Heppenstall, Rohini Kuner and Jan Siemens

MMPU Group 2011 – 2019

Project Summary

Chronic pain is a devastating and widespread problem that affects one in five adults across Europe. For the most part, the underlying causes of chronic pain are poorly understood making treatment difficult and often ineffective. Our research focuses on understanding the cellular and molecular mechanisms behind chronic pain with the aim of developing new strategies to treat this debilitating condition.


Many chronic pain states originate from the aberrant function of peripheral sensory neurons that become damaged during metabolic disease, cancer or mechanical injury. We study the molecular adaptations that occur in these neurons following injury, concentrating on how they contribute to chronic pain. We focus our activities on two major research areas which could offer significant therapeutic potential for treating chronic pain; the identification of key signaling pathways that promote chronic pain and the analysis of plasticity in regenerating sensory neurons.


The goal of our collaboration is to combine our expertise on the analysis of experimental models of chronic pain. We use transgenic mouse models that serve both as a means of disrupting novel pain pathways and as reporters for imaging of cellular events associated with chronic pain. Furthermore we develop sophisticated methodology including behavioral monitoring, in vivo imaging, electrophysiology and metabolic analysis. Our aim is to uncover novel mechanisms that play a causative role in the pathophysiology of chronic pain.

Research Focus 1: Signaling Pathways and their Effectors in Chronic Pain

Rohini Kuner is interested in a number of key intracellular signaling pathways that are altered in peripheral sensory neurons in chronic pain states. The endpoints of many of these pathways are ion channels expressed in neuronal membranes. Paul Heppenstall and Jan Siemens have a longstanding interest in sensory ion channel function, in particular in those channels that act as transducers of the physical forces that make up our sense of touch and temperature. In this project, we investigate the interplay between intracellular signaling pathways and ion channel activity. We use electrophysiology and molecular genetics to examine how altered signaling can impact on ion channel function and study how these pathophysiological alterations impact on sensitivity to pain via behavioral analyses.

Research Focus 2: Plasticity and Reorganization in Chronic Pain

Neuronal plasticity is a key mechanism underlying chronic pain. Tremendous potential for plasticity exists at the level of sensory neuron connectivity. Using transgenic reporter mouse models and advanced image analysis, we examine causative links between plasticity and chronic pain and whether perturbation of critical molecules can rescue defective connectivity in regenerating sensory neurons.

A recent new interest has become to advance our understanding how aberrant neuronal activity and plasticity –that drives persistent forms of pain– is altering metabolic flux in glia and neurons to fuel these pathological changes.

Selected publications

The impact of Semaphorin 4C/Plexin-B2 signaling on fear memory via remodeling of neuronal and synaptic morphology.
Simonetti M, Paldy E, Njoo C, Bali KK, Worzfeld T, Pitzer C, Kuner T, Offermanns S, Mauceri D, Kuner R.
Mol Psychiatry. 2019 Aug 23. doi: 10.1038/s41380-019-0491-4. [Epub ahead of print] PMID:31444474

Interleukin-31-mediated photoablation of pruritogenic epidermal neurons reduces itch-associated behaviours in mice.
Nocchi L, Roy N, D’Attilia M, Dhandapani R, Maffei M, Traista A, Castaldi L, Perlas E, Chadick CH, Heppenstall PA.
Nat Biomed Eng. 2019 Feb;3(2):114-125. doi: 10.1038/s41551-018-0328-5. Epub 2018 Dec 17. PMID:30944432

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 Chemogenetic Approach for the Optical Monitoring of Voltage in Neurons.
Sundukova M, Prifti E, Bucci A, Kirillova K, Serrao J, Reymond L, Umebayashi M, Hovius R, Riezman H, Johnsson K, Heppenstall PA.
Angew Chem Int Ed Engl. 2019 Feb 18;58(8):2341-2344. doi: 10.1002/anie.201812967. Epub 2019 Jan 25. PMID:30569539

Peripheral Kappa Opioid Receptor Signaling Takes on a Central Role.
Naser PV, Kuner R.
Neuron. 2018 Sep 19;99(6):1102-1104. doi: 10.1016/j.neuron.2018.09.006. PMID:30236278

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.

Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons.
Dhandapani R, Arokiaraj CM, Taberner FJ, Pacifico P, Raja S, Nocchi L, Portulano C, Franciosa F, Maffei M, Hussain AF, de Castro Reis F, Reymond L, Perlas E, Garcovich S, Barth S, Johnsson K, Lechner SG, Heppenstall PA.
Nat Commun. 2018 Apr 24;9(1):1640. doi: 10.1038/s41467-018-04049-3. PMID:29691410

Cellular populations and thermosensing mechanisms of the hypothalamic thermoregulatory center.
Siemens J, Kamm GB.
Pflugers Arch. 2018 Jan 27. doi: 10.1007/s00424-017-2101-0. [Epub ahead of print] Review. PMID: 29374307

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

Therapeutic potential for leukocyte elastase in chronic pain states harboring a neuropathic component.
Bali KK, Kuner R.
Pain. 2017 Nov;158(11):2243-2258. doi: 10.1097/j.pain.0000000000001032. PMID: 28837503

miR-34c-5p functions as pronociceptive microRNA in cancer pain by targeting Cav2.3 containing calcium channels.
Gandla J, Lomada SK, Lu J, Kuner R, Bali KK.
Pain. 2017 Sep;158(9):1765-1779. doi: 10.1097/j.pain.0000000000000971. PMID: 28614186

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 

A mouse model for pain and neuroplastic changes associated with pancreatic ductal adenocarcinoma.
Selvaraj D, Hirth M, Gandla J, Kuner R.
Pain. 2017 Aug;158(8):1609-1621. doi: 10.1097/j.pain.0000000000000956. PMID: 28715356

A checkpoint to pain.
Hirth M, Gandla J, Kuner R.
Nat Neurosci. 2017 Jun 27;20(7):897-899. doi: 10.1038/nn.4586. No abstract available. PMID: 28653690

Structural plasticity and reorganisation in chronic pain.
Kuner R, Flor H.
Nat Rev Neurosci. 2016 Dec 15;18(1):20-30. doi: 10.1038/nrn.2016.162. Review.

Acetylated tubulin is essential for touch sensation in mice.
Morley SJ, Qi Y, Iovino L, Andolfi L, Guo D, Kalebic N, Castaldi L, Tischer C, Portulano C, Bolasco G, Shirlekar K, Fusco CM, Asaro A, Fermani F, Sundukova M, Matti U, Reymond L, De Ninno A, Businaro L, Johnsson K, Lazzarino M, Ries J, Schwab Y, Hu J, Heppenstall PA.
Elife. 2016 Dec 13;5. pii: e20813. doi: 10.7554/eLife.20813.
PMID: 27976998

The TRPM2 channel is a hypothalamic heat sensor that limits fever and can drive hypothermia.
Song K, Wang H, Kamm GB, Pohle J, de Castro Reis F, Heppenstall P, Wende H, Siemens J.
Science. 2016 Aug 25. pii: aaf7537. [Epub ahead of print] PMID: 27562954

TMEM16F Regulates Spinal Microglial Function in Neuropathic Pain States.
Batti L, Sundukova M, Murana E, Pimpinella S, De Castro Reis F, Pagani F, Wang H, Pellegrino E, Perlas E, Di Angelantonio S, Ragozzino D, Heppenstall PA.
Cell Rep. 2016 Jun 21;15(12):2608-15. doi: 10.1016/j.celrep.2016.05.039. PMID: 27332874

A subpopulation of itch-sensing neurons marked by Ret and somatostatin expression.
Stantcheva KK, Iovino L, Dhandapani R, Martinez C, Castaldi L, Nocchi L, Perlas E, Portulano C, Pesaresi M, Shirlekar KS, de Castro Reis F, Paparountas T, Bilbao D, Heppenstall PA.
EMBO Rep. 2016 Apr;17(4):585-600. doi: 10.15252/embr.201540983. Epub 2016 Feb 29. PMID: 26929027

A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing.
Eliava M, Melchior M, Knobloch-Bollmann HS, Wahis J, da Silva Gouveia M, Tang Y, Ciobanu AC, Triana del Rio R, Roth LC, Althammer F, Chavant V, Goumon Y, Gruber T, Petit-Demoulière N, Busnelli M, Chini B, Tan LL, Mitre M, Froemke RC, Chao MV, Giese G, Sprengel R, Kuner R, Poisbeau P, Seeburg PH, Stoop R, Charlet A, Grinevich V.
Neuron. 2016 Mar 16;89(6):1291-304. doi: 10.1016/j.neuron.2016.01.041.

Functional characterization of a mouse model for central post-stroke pain.
Gritsch S, Bali KK, Kuner R, Vardeh D.
Mol Pain. 2016 Mar 8;12. pii: 1744806916629049. doi: 10.1177/1744806916629049.

The Cannabinoid Receptor CB1 Interacts with the WAVE1 Complex and Plays a Role in Actin Dynamics and Structural Plasticity in Neurons.
Njoo C, Agarwal N, Lutz B, Kuner R.
PLoS Biol. 2015 Oct 23;13(10):e1002286. doi: 10.1371/journal.pbio.1002286. eCollection 2015 Oct. PMID: 26496209

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.

TRP ion channels in thermosensation, thermoregulation and metabolism
Hong Wang & Jan Siemens
Temperature, 2015, 2, 178-187

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.

A role for Kalirin-7 in nociceptive sensitization via activity-dependent modulation of spinal synapses.
Lu J, Luo C, Bali KK, Xie RG, Mains RE, Eipper BA, Kuner R.
Nat Commun. 2015 Apr 13;6:6820. doi: 10.1038/ncomms7820.

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):759-70. doi: 10.1016/j.cell.2015.01.022.

Genetic targeting of chemical indicators in vivo.
Yang G, de Castro Reis F, Sundukova M, Pimpinella S, Asaro A, Castaldi L, Batti L, Bilbao D, Reymond L, Johnsson K, Heppenstall PA.
Nat Methods. 2015 Feb;12(2):137-9. doi: 10.1038/nmeth.3207. Epub 2014 Dec 8.

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.

Oligodendrocyte ablation triggers central pain independently of innate or adaptive immune responses in mice.
Gritsch S, Lu J, Thilemann S, Wörtge S, Möbius W, Bruttger J, Karram K, Ruhwedel T, Blanfeld M, Vardeh D, Waisman A, Nave KA, Kuner R
Nature Communications 2014 Dec 1;5:5472.

Wnt-Fzd signaling sensitizes peripheral sensory neurons via distinct noncanonical pathways.
Simonetti M, Agarwal N, Stösser S, Bali KK, Karaulanov E, Kamble R,
Pospisilova B, Kurejova M, Birchmeier W, Niehrs C, Heppenstall P, Kuner R.
Neuron. 2014 Jul 2;83(1):104-21. doi: 10.1016/j.neuron.2014.05.037.

Noncoding RNAs: key molecules in understanding and treating pain.
Bali KK, Kuner R.
Trends Mol Med. 2014 Aug;20(8):437-448. doi: 10.1016/j.molmed.2014.05.006. Epub 2014 Jun 28. Review.

Studying ongoing and spontaneous pain in rodents–challenges and opportunities.
Tappe-Theodor A, Kuner R.
Eur J Neurosci. 2014 Jun;39(11):1881-90. doi: 10.1111/ejn.12643. Epub 2014 May 29.

Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain.
Bali KK, Selvaraj D, Satagopam VP, Lu J, Schneider R, Kuner R.
EMBO Mol Med. 2013 Nov;5(11):1740-58. doi: 10.1002/emmm.201302797. Epub 2013 Oct 18.

Transcriptional mechanisms underlying sensitization of peripheral sensory neurons by granulocyte-/granulocyte-macrophage colony stimulating factors.
Bali KK, Venkataramani V, Satagopam VP, Gupta P, Schneider R, Kuner R.
Mol Pain. 2013 Sep 25;9:48. doi: 10.1186/1744-8069-9-48.

The K(+) channel GIRK2 is both necessary and sufficient for peripheral opioid-mediated analgesia.
Nockemann D, Rouault M, Labuz D, Hublitz P, McKnelly K, Reis FC, Stein C, Heppenstall PA.
EMBO Mol Med. 2013 Aug;5(8):1263-77. doi: 10.1002/emmm.201201980. Epub 2013 Jul 1.

A novel biological role for the phospholipid lysophosphatidylinositol in nociceptive sensitization via activation of diverse G-protein signaling pathways in sensory nerves in vivo.
Gangadharan V, Selvaraj D, Kurejova M, Njoo C, Gritsch S, Skoricová D, Horstmann H, Offermanns S, Brown AJ, Kuner T, Tappe-Theodor A, Kuner R.
Pain. 2013 Aug 21. doi:pii: S0304-3959(13)00461-2. 10.1016/j.pain.2013.08.019. [Epub ahead of print]

Pain hypersensitivity mechanisms at a glance.
Gangadharan V, Kuner R.
Dis Model Mech. 2013 Jul-Aug;6(4):889-95. doi: 10.1242/dmm.011502.

αTAT1 is the major α-tubulin acetyltransferase in mice.
Kalebic N, Sorrentino S, Perlas E, Bolasco G, Martinez C, Heppenstall PA.
Nat Commun. 2013 June;4:1962. doi: 10.1038/ncomms2962. PubMed PMID: 23748901

Transgenic mouse lines for non-invasive ratiometric monitoring of intracellular chloride
Batti L, Mukhtarov M, Audero E, Ivanov A, Paolicelli O, Zurborg S, Gross C, Bregestovski P, Heppenstall PA.
Front Mol Neurosci. 2013 May 21;6:11. doi: 10.3389/fnmol.2013.00011. Print 2013. PubMed PMID: 23734096; PubMed Central PMCID: PMC3659292.

Nuclear calcium signaling in spinal neurons drives a genomic program required for persistent inflammatory pain.
Simonetti M, Hagenston AM, Vardeh D, Freitag HE, Mauceri D, Lu J, Satagopam VP, Schneider R, Costigan M, Bading H, Kuner R.
Neuron. 2013 Jan 9;77(1):43-57. doi: 10.1016/j.neuron.2012.10.037

Presynaptically Localized Cyclic GMP-Dependent Protein Kinase 1 Is a Key Determinant of Spinal Synaptic Potentiation and Pain Hypersensitivity
Luo C., Gangadharan V., Bali K., Xie R.G., Agarwal N., Kurejova M., Tappe-Theodor A., Tegeder I., Feil S., Lewin G., Polgar E., Todd A.J., Schlossmann J., Hofmann F., Liu D.L., Hu S.J., Feil R., Kuner T., Kuner R.,
PLoS Biol. 2012 Mar;10(3):e1001283. Epub 2012 Mar 13.

Generation and characterization of an Advillin-Cre driver mouse line.
Zurborg S, Piszczek A, Martínez C, Hublitz P, Al Banchaabouchi M, Moreira P, Perlas P, Heppenstall PA.
Molecular Pain. 2011, Sep 11;7(1):66.

Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice.
Gangadharan V, Wang R, Ulzhöfer B, Luo C, Bardoni R, Bali KK, Agarwal N, Tegeder I, Hildebrandt U, Nagy GG, Todd AJ, Ghirri A, Hussler A, Sprengel R, Seeburg PH, Macdermott AB, Lewin GR, Kuner R.
J Clin Invest. 2011 121(4):1608-23

A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain
Bohlen CJ, Priel A, Zhou S, King D, Siemens J, Julius D.
Cell. 2010 May 28;141(5):834-45

Hematopoietic colony stimulating factors mediate tumor-nerve interactions and bone cancer pain.
Schweizerhof M., Stösser S., Kurejova M., Njoo C., Gangadharan V., Agarwal N., Schmelz, M., Bali K.K., Christoph M., Brugger S., Dickenson A., Simone D., Kuner R. 
Nature Medicine 2009, 15(7):802-7

The AMPA receptor subunits, GluR-A and GluR-B reciprocally modulate spinal synaptic plasticity and inflammatory pain.
Hartmann B, Ahmadi S, Heppenstall P, Zeilhofer HU, Lewin G, Schott C, Seeburg PH, Sprengel R, Kuner R
Neuron. 2004 Nov 18;44(4):637-50

Group Members

in alphabetical order

Muad Abd El Hay, PhD student

Wojciech Ambroziak, PhD, Postdoctoral Fellow

Carolina Araujo Sousa, PhD student (EMBL International PhD Programme – EIPP)

Kiran Kumar Bali, PhD, Postdoctoral Fellow

Laura Batti, PhD, Postdoctoral Fellow

Laura Castaldi, PhD, Postdoctoral Fellow

Fernanda de Castro Reis, Research technician

Rahul Dhandapani, PhD student (EMBL International PhD Programme – EIPP)

Tessa Frank, PhD student

Carolin Escherich, MD Student (JCF, HRCMM)

Jagadeesh Gandla, PhD student

Vijayan Gangadharan, PhD, Postdoctoral Fellow

Christina Hanack, PhD student

Céline Heinl, PhD, Postdoctoral Fellow

Paul Heppenstall, PhD, Group Leader

Christiane Höper, MD student (JCF, HRCMM)

Loredana Iovino, PhD student (EMBL International PhD Programme – EIPP)

Nereo Kalebic , PhD student (EMBL International PhD Programme – EIPP)

Gretel Kamm, PhD, Postdoctoral Fellow

Sanjeev Kaushalya, PhD, Postdoctoral Fellow

Rohini Kuner, PhD, Group Leader

Wanessa Lima, PhD, Postdoctoral Fellow

Shiying Lu, PhD student (EMBL International PhD Programme – EIPP)

Sebastian Marty, PhD Student

Chiara Morelli, PhD student (EMBL International PhD Programme – EIPP)

Shane Morley, PhD student (EMBL International PhD Programme – EIPP)

Paul Naser, MD student (JCF, HRCMM)

Sara Nencini, PhD,Postdoctoral Fellow

Linda Nocchi, PhD, Postdoctoral Fellow

Manfred Oswald, PhD, Postdoctoral Fellow

Jörg Pohle, PhD, Postdoctoral Fellow

Carla Portulano, Postdoctoral Fellow (EIPOD)

Oscar Retana, MD student (JCF, HRCMM)

Charlotte Rostock, PhD student

Katrin Schrenk-Siemens, PhD, Postdoctoral Fellow

Martin Seefeld, PhD student (HBIGS PhD programme, University of Heidelberg)

Deepitha Selvaraj, PhD, Postdoctoral Fellow

Joana Serrao, PhD student (EMBL International PhD Programme – EIPP)

Jan Siemens, PhD, Group Leader

Manuela Simonetti, PhD, Postdoctoral Fellow

Kun Song, PhD student

Kalina Stantcheva, PhD student (EMBL International PhD Programme – EIPP)

Mayya Sundukova, PhD, Postdoctoral Fellow

Linette Tan, PhD, Postdoctoral Fellow (EMBO)

Lucas Vicuna, Ph, Postdoctoral Fellow

Annika von Seggern, Research Technician

Hong Wang, PhD, Postdoctoral Fellow

Hagen Wende, PhD, Postdoctoral Fellow

Guoying Yang, PhD, Postdoctoral Fellow (EIPOD)

Kristina žuža, PhD Student

Jan Siemens and Rohini Kuner