research project 4

Tuning pain sensitivity

 

Stefan Lechner, Nevena Milenkovic, Rui Wang

 

Nociception is describes our ability to respond to potentially or actually damaging stimuli. An important aspect of the biology of nociception is that after injury people and animals become much more sensitive to sensory stimulation than before injury. This phenomenon is sometimes called sensitization and it is often desirable to block this process after inflammation to prevent pain becoming pathologically severe. We are interested in the cellular and molecular basis of sensitization. We recently discovered that some endogenous chemicals, such as ATP and UTP that are released from damaged cells during inflammation can potently increase the magnitude of the mechanosensitive current in sensory neurons. This would have the effect of making nociceptors innervating inflamed tissue more sensitive to mechanical stimuli, and such a phenomenon may underlie the tenderness that follows inflammation. Identification of the mechanotransducer as a target of inflammation indicates that, this as yet unknown ion channel, may be an excellent molecular target to block in order to treat pain after inflammation. Sensitization also happens to heat stimuli, a familiar example is the increased sensitivity to even moderate temperature that we experience following UV induced-sunburn. We recently identified the ligand of the tryosine kinase receptor c-Kit as a very potent factor in increasing the sensitivity of nociceptors to noxious heat. There are already clinically available potent blockers of c-Kit e.g. Gleevec, that are used to treat a variety of cancers. We are present carrying out a patient based study to determine if Gleevec and related compounds have significant a

algesic effects when used in man. This study is being carried out within the ECRC at the MDC and at the Charité university hospital.

 

Selected publications:

1. Lechner, S.G. & Lewin, G.R. Peripheral sensitisation of nociceptors via G-protein-dependent potentiation of mechanotransduction currents. The Journal of physiology 587, 3493-503 (2009).

2. Milenkovic, N., Frahm C, Gassmann M, Griffel C, Erdmann B, Birchmeier C, Lewin GR & Garratt AN. Nociceptive Tuning by Stem Cell Factor/c-Kit Signaling. Neuron 56, 893-906 (2007).

3. Gangadharan V; Wang R; Ulzhoefer B; Luo C; Bardoni R; Bali KK; Agarwal N; Tegeder I; Hildebrandt U; Nagy GG; Todd AJ; Ghirri A; Haeussler A; Sprengel R; Seeburg PH; Macdermott AB; Lewin GR; Kuner R. Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice. Journal of Clinical Investigation,121 (4): 1608-1623 (2011)

4. Wang, R., & Lewin, G.R. The Cav3.2 T-type calcium channel regulates temporal coding in mouse mechanoreceptors. Journal of Physiology 589 (9): 2229-2243 (2011)

5. Tappe-Theodor A; Constantin CE; Tegeder I; Lechner SG; Langeslag M; Lepcynzsky P; Wirotanseng RI; Kurejova M; Agarwal N; Nagy G; Todd A; Wettschureck N; Offermanns S; Kress M; Lewin GR; Kuner R. G{alpha}(q/11) signaling tonically modulates nociceptor function and contributes to activity-dependent sensitization. Pain : (2011-11-07)