Molecular Medicine Partnership UnitResearch Groups
Molecular Mediators of Chronic Pain
Paul Heppenstall, Rohini Kuner and Jan Siemens (joining in April 2013)
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 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.
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