Martin Lohse, Christof Schütte, Christoph Stein, Marcus Weber, Stefanie Winkelmann (since January 2021)
Vikram Sunkara (till January 2021, FU), Noureldin Saleh (till August 2019, ZIB), Sourav Ray (from January 2020, ZIB)
First funding period: 01.01.2019 – 31.12.2020; Second funding period: 01.01.21 – 31.12.2022
FU Berlin / ZIB
This project aims at understanding the effects of drugs inducing pain relief (painkillers) via activation of opioid receptors on the molecular and cellular level. Our previous mathematical results helped to uncover that changes in pH encountered in painfully injured tissues cannot fully explain the increased activation rates of mu-opioid receptors (MOR) in the injured/inflamed environment. Other inflammatory components (e.g. radicals such as H2O2) need to be included. We have now extended our models by integrating stochastic components describing localized chemical reactions at the receptor and altered signaling processes (e.g. G-protein activation, cAMP production, membrane ion currents).
A German documentary about pain relief can be accessed here. M. Weber and C. Stein have contributed to this ARTE TV documentary in 02/2020.
M. Weber and C. Stein have presented a common outreach talk at URANIA in 03/2020. The link is here.
There is a ZIB webpage about this project here.
A website showing the clinical relevance and the experimental anesthesiology approach at Charité can be found here.
Different binding modes at only one pH value
Simulation of protonation states
We were able to explain the outcome of clinical tests on the basis of this dependence.
There is a translational challenge in going from in vitro to in situ. We bridging this gap by developing mathematical models to capture the spatio-temporal dynamics of the opioid in situ.
Our recent in vitro studies on MOR expressed in transfected cells have yielded the following results: H2O2 did not interfere with binding of the standard MOR ligand DAMGO. Higher H2O2 concentrations decreased G-protein coupling (measured by binding of [35S]-GTPγS) induced by the standard MOR agonist fentanyl. At acidic pH, the pH-dependent ligand NFEPP (but not fentanyl) more potently activated MOR-dependent G-protein coupling. H2O2 did not influence fentanyl-induced inhibition of forskolin-stimulated cAMP production. These results will be complemented by measurements of membrane ion currents.
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