Research Report 2010 - MDC

distinct developmental mechanisms are used to inducesuch competence in neurons that underlie touch sensationas opposed to nociception (Painful stimuli). Forexample, we have shown that NGF plays a critical role inthe acquisition of transduction competence by nociceptors.Tuning pain sensitivityStefan Lechner, Nevena Milenkovic, Rui WangNociception is describes our ability to respond to potentiallyor actually damaging stimuli. An important aspectof the biology of nociception is that after injury peopleand animals become much more sensitive to sensorystimulation than before injury. This phenomenon issometimes called sensitization and it is often desirableto block this process after inflammation to prevent painbecoming pathologically severe. We are interested inthe cellular and molecular basis of sensitization. Werecently discovered that some endogenous chemicals,such as ATP and UTP that are released from damagedcells during inflammation can potently increase themagnitude of the mechanosensitive current in sensoryneurons. This would have the effect of making nociceptorsinnervating inflamed tissue more sensitive tomechanical stimuli, and such a phenomenon mayunderlie the tenderness that follows inflammation.Identification of the mechanotransducer as a target ofinflammation indicates that, this as yet unknown ionchannel, may be an excellent molecular target to blockin order to treat pain after inflammation.Sensitization also happens to heat stimuli, a familiarexample is the increased sensitivity to even moderatetemperature that we experience following UV inducedsunburn.We recently identified the ligand of the tryosinekinase receptor c-Kit as a very potent factor inincreasing the sensitivity of nociceptors to noxiousheat. There are already clinically available potent blockersof c-Kit e.g. Gleevec, that are used to treat a varietyof cancers. We are present carrying out a patient basedstudy to determine if Gleevec and related compoundshave significant analgesic effects when used in man.This study is being carried out within the ECRC at theMDC and at the Charité university hospital.The naked mole rat is an unusual subterranean rodentin many respects. It is the only known poikilothermicmammal (ie. cold blooded), it lives in colonies with aninsect-like social structure, and it is also the longestlivedrodent species known (lifetimes in excess of 25yrs). Interestingly, although this animal has normalacute pain responses it displays no hypersensitivity (socalled hyperalgesia) to a variety of inflammatory andchemical stimuli. What is particularly striking in thenaked mole rat is that the animals completely lack aneuronal or behavioral response to acid. We suspectthat at the heart of this specialized adaptation lies indistinct gene variants encoding ion channels and associatedchannels that are required for the transductionof painful stimuli.We are at present cloning and characterizinggenes coding ion channels from the nakedmole rat to address this issue. We have cloned andstarted to characterize the naked mole rat capsaicinreceptor, an ion channel called TRPV1 as well as the tyrosinekinase receptor trkA the activation of which by NGFcan potently potentiate TRPV1. We are presentlyembarking on a large scale molecular characterizationof the naked mole rat transcriptome using so-calleddeep sequencing technologies (In collaboration withWei Chen, BIMSB).Selected PublicationsLechner SG, Frenzel H, Wang R & Lewin GR. (2009). Developmental wavesof mechanosensitivity acquisition in sensory neuron subtypes duringembryonic development. Embo J 28, 1479-1491.Lechner SG & Lewin GR. (2009). Peripheral sensitisation of nociceptors viaG-protein-dependent potentiation of mechanotransduction currents. JPhysiol 587, 3493-3503.Milenkovic N, Frahm C, Gassmann M, Griffel C, Erdmann B, Birchmeier C,Lewin GR & Garratt AN. (2007). Nociceptive tuning by stem cell factor/c-Kit signaling. Neuron 56, 893-906.Park TJ, Lu Y, Juttner R, Smith ES, Hu J, Brand A, Wetzel C, Milenkovic N,Erdmann B, Heppenstall PA, Laurito CE, Wilson SP & Lewin GR. (2008).Selective inflammatory pain insensitivity in the African naked mole-rat(Heterocephalus glaber). PLoS Biol 6, e13.Wetzel C, Hu J, Riethmacher D, Benckendorff A, Harder L, Eilers A,Moshourab R, Kozlenkov A, Labuz D, Caspani O, Erdmann B, Machelska H,Heppenstall PA & Lewin GR. (2007). A stomatin-domain protein essentialfor touch sensation in the mouse. Nature 445, 206-209.The Naked Mole Rat a pain free mammal?Damir Omerbasic, Ewan St. John SmithFunction and Dysfunction of the Nervous System 165