Ein optogenetischer Ansatz zur Untersuchung der zellulären und molekularen Mechanismen von A-Faser-Nozizeptor induziertem Akutschmerz und Entzündungsschmerzen
Zusammenfassung der Projektergebnisse
Noxious mechanical stimuli activate multiple peripheral sensory afferent subtypes, thus generating a plethora of sensory information that is simultaneously transmitted to the central nervous system. Accordingly, there is an intense debate about whether different forms of pain arise from sensory input from single afferent subpopulations that are particularly sensitive to certain types of stimuli, or whether pain requires the integration of inputs from multiple afferent subtypes. Hitherto, addressing this question has been hampered by the lack of tools and the scarcity of genetic markers that would allow for subtype-specific manipulation of sensory neuron function. In study 1 we utilized optogenetics to generate mouse lines that allowed us to selectively control neural activity in different subpopulations of A-fibre nociceptors and touch receptors. We demonstrate that pain intensity is not exclusively determined by the firing rate of nociceptors, but rather depends on the balance of noxious and tactile sensory input. Moreover, we show that nociceptive paw withdrawal – an essential reflex that protects the organism from potentially harmful stimuli – is triggered by as little as a single action potential in fast conducting A-fibre nociceptors, but additional tactile sensory input is required for normal well-coordinated reflex execution. Hence our study demonstrates that the integration of noxious and tactile information plays a crucial role in acute mechanical pain signalling, which finally confirms one of the central predictions of the classical Gate Control Theory of pain that was proposed some 50 years. In study 2 we considered the role of NGF in the modulation of nociceptor sensitivity. NGF plays a central role in the induction and maintenance of chronic pain associated with, for example, osteoarthritis, low back pain, bladder pain syndrome and irritable bowel syndrome. Numerous clinical trials have shown great efficacy of anti-NGF antibodies in alleviating pain associated with these diseases, but the problematic side effect profile of these antibodies calls for alternative, more sensory neuron-specific anti-NGF drugs. However, alternative targets for anti-NGF drugs are rare, because neither the precise cell types nor the downstream targets of NGF-signaling that mediate pain hypersensitivity are fully understood. Here we provide a detailed comparison of the expression patterns and the electrophysiological properties of voltage-gated sodium channels in three physiologically important subpopulations of nociceptors – i.e. A-fibre nociceptors that signal pinprick pain, mechanically insensitive ‘silent’ nociceptor, which are the most abundant nociceptors in viscera and deep somatic tissue as well as polymodal C-fibre nociceptors. Moreover, we demonstrate that NGF differentially modulates voltage-gated sodium currents in these three nociceptor subtypes. Hence, our results exemplarily show that the effects of a given inflammatory mediator on a given protein may differ between cell types and thus highlight the importance of studying mechanisms of peripheral sensitization in a cell type-specific manner. In study 3 we examined the mechanogating mechanism of the mechanically activated ion channel PIEZO2. We identified a gating particle that controls ion permeation and discovered an intramolecular force transmission pathway that relays force from the periphery of the channel to the pore region, which leads to opening of the channel. PIEZO channels do not only confer mechanosensitivity to sensory neurons but also to many other cell types, all of which are exposed to mechanical stimuli of some kind. Accordingly, mutations in PIEZO channels have been linked to numerous diseases such as dehydrated hereditary stomatocytosis, congenital lymphatic dysplasia and several arthrogryposis disorders, just to name a few. Hence, understanding how cells convert mechanical stimuli into electrical signals that trigger a cellular or systemic response are detected by cells is of fundamental interest and the results of study 3 have provided novel insights into this important biological process.
Projektbezogene Publikationen (Auswahl)
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(2017). Touch Receptor-Derived Sensory Information Alleviates Acute Pain Signaling and Fine-Tunes Nociceptive Reflex Coordination. Neuron 93, 179–193
Arcourt, A., Gorham, L., Dhandapani, R., Prato, V., Taberner, F.J., Wende, H., Gangadharan, V., Birchmeier, C., Heppenstall, P.A., and Lechner, S.G.
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(2018). Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons. Nat Commun 9, 1640
Dhandapani, R., Arokiaraj, C.M., Taberner, F.J., Pacifico, P., Raja, S., Nocchi, L., Portulano, C., Franciosa, F., Maffei, M., Hussain, A.F., Reis, F. de C., Reymond, L., Perlas, E., Garcovich, S., Barth, S., Johnsson, K., Lechner, S.G. & Heppenstall, P.A.
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(2018). Differential modulation of voltage-gated sodium channels by nerve growth factor in three major subsets of TrkA-expressing nociceptors. Mol Pain 14, 1744806918814640
Schaefer, I., Prato, V., Arcourt, A., Taberner, F.J., and Lechner, S.G.
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(2019). Structure-guided examination of the mechanogating mechanism of PIEZO2. PNAS 116, 14260–14269
Taberner, F.J., Prato, V., Schaefer, I., Schrenk-Siemens, K., Heppenstall, P.A., and Lechner, S.G.
