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Molecular Medicine Partnership UnitResearch Groups

Molecular Mediators of Chronic Pain

Paul Heppenstall, Rohini Kuner and Jan Siemens

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.

Background

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.

Goals

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 and electrophysiology. 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.

Selected Publications

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.

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
B
atti 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

 

Research group's link to University Hospital web page