current projects

Development of novel analgesics without side effects

Figure signaling Fluorfentanyl pH

Christoph Stein, Halina Machelska 

Currently available drugs to treat severe pain are mu-opioid receptor ligands (e.g., morphine, fentanyl) that are limited by adverse effects such as sedation, cognitive impairment, apnoea, addiction, and constipation. In this project our goal is to develop new painkillers devoid of the untoward side effects (Stein, Annu Rev Med 2016). We use mathematical modelling and nanotechnology to design drugs, which will be then examined in vitro and in vivo in models of pathological pain.

Group members involved: Viola Spahn, Dominika Labuz, Antonio Rodriguez-Gaztelumendi, Giovanna Del Vecchio, Sara Gonzalez-Rodriguez, Julia Temp, Michael Kloner

Collaborators: R. Haag (Chemistry, Freie Universität Berlin), M. Weber, O. Scharkoi, P. Deuflhard (Mathematics, Zuse Institut, Berlin)

Funding: BMBF, Focus Area DynAge (Freie Universität, Charité)

To top

Regulation of µ-opioid receptor function in inflammation

Figure_MOR_periphery_inflammation

Christoph Stein

The analgesic potency of peripherally applied opioids is strongly increased in inflamed tissue. In this project we investigate how the function of the µ-opioid receptor is modulated by changes in pH as observed in the patho-physiological state of inflammation. Following a multidisciplinary approach we combine methods from molecular and cellular biology with molecular simulations to elucidate the mechanisms underlying observations from behavioral experiments. Identifying disease-specific regulatory mechanisms will help to design novel opioids with reduced side-effects.

Group members involved: Johanna Meyer, Giovanna Del Vecchio, Viola Spahn

Collaborator: M. Weber (Mathematics, Zuse Institute, Berlin)

 

Control of pain in experimental osteoarthritis

Figure Osteoarthritis

Halina Machelska

Osteoarthritis (OA) is a common chronic degenerative disease of the joints, and the knee is most often affected. OA affects millions of people worldwide and its risk increases with age. Pain is the major debilitating sign of OA; it impairs function and quality of life. Current pharmacological and surgical treatments are unsatisfactory and produce serious complications. In this project we focus on a non-pharmacological, non-invasive approach to ameliorate OA pain, namely vibration-based exercise. We aim to elucidate the mechanisms underlying the analgesia resulting from whole body vibration. Since OA pain involves peripheral and central nervous system mechanisms, we investigate the impact of vibration on pain-promoting and pain-inhibiting mediators in the knee, peripheral neurons, spinal cord, and brain.

Group members involved: Julia Temp, Dominika Labuz, Özgür Celik

Collaborators: W. Ertel, J.Becker, T. Haase (Orthopedic surgery, Charité Campus Benjamin Franklin), M. von Kleist (Mathematics, Freie Universität Berlin)

Funding: BMBF (OVERLOAD-Prev-OP)

To top

Regulation of neuropathic pain by opioid peptides and receptors in immune cells

Figure_Leukocyte-opioids-calcium

Halina Machelska

Neuropathic pain often results from nerve injury (e.g., amputation, compression), which can lead to inflammation (neuritis). Previously we found that damaged nerves express opioid receptors and are infiltrated by opioid peptide-containing immune cells (Labuz et al., J Clin Invest 2009; Labuz et al., Brain Behav Immun 2010; Schmidt et al., PloS One 2013). The traditional view is that opioids produce analgesia by exclusively acting at opioid receptors expressed in neurons. We have now discovered that pain can be inhibited by activation of opioid receptors in immune cells. In contrast to the action of neuronal opioid receptors which is based on the inhibition of the release of pain-inducing mediators (e.g., substance P, calcitonin gene-related peptide), the activation of leukocyte opioid receptors results in the secretion of opioid peptides. The released opioid peptides subsequently act at local neuronal opioid receptors and decrease neuropathy-triggered mechanical, but not heat pain (Celik et al., Brain Behav Immun 2016; Labuz et al., Sci Rep 2016). These data offer a previously unknown explanation for the effective analgesia of opioids applied to tissue abundantly infiltrated by opioid peptide-expressing immune cells in patients with postoperative pain and in animal models of neuropathic pain (Stein et al., J Clin Invest 1996; Labuz et al., J Pharmacol Exp Ther 2013). Our findings may have wide clinical implications, since the majority of painful conditions are associated with immune responses, including inflammatory neuropathies, arthritis, cancer, and postoperative pain. In several ongoing projects we investigate various populations of immune cells, including pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages.

Group members involved: Özgür Celik, Dominika Labuz, Karen Henning

Collaborators: A. Zimmer (Institute of Molecular Psychiatry, Universitätsklinikum Bonn, Germany), B. Kieffer (McGill University, Montreal, Canada), C. Gavériaux-Ruff (University of Strasbourg, Ilkrich, France)

Funding: DFG

Neuropathic pain: genetic biomarkers and novel analgesics for individualized therapy

Quantitativ sensory testing (QST)

Christoph Stein

Up to 8% of the population suffers from neuropathic pain due to lesions in the peripheral or central nervous system. To enable "personalized" medicine, only a strict separation of neuropathic from other chronic pain syndromes allows individualized therapy. At present, diagnosis is based on medical history, subjective description of somatosensory symptoms and application of non-genetic diagnostic tests. Conventional pain medications are not sufficiently effective and limited by serious side effects. The search for new analgesics is extremely difficult because of the poor predictive validity of animal models and the high inter-individual variability of neuropathic pain manifestations and treatment responses.In collaboration with an interdisciplinary group of European pain researchers (NeuroPain consortium) we pursue the following aims:

  • Examination of phenotype-genotype associations predictive for neuropathic pain by extensive phenotyping
  • Investigation of the analgesic effect of a novel phytocannabinoid in a cohort of HIV-associated painful neuropathy
  • Pharmacogenomic studies in patients to evaluate genetic characteristics of responders and non-responders to this novel substance

 

Group members involved: Simone Scheffel, Luca Eibach

Collaborators: NeuroPain Consortium (particularly Helsinki University Central Hospital, Finland; DeCODE Genetics, Iceland; Imperial College London and GW Pharmaceuticals, England)

Funding: European Commission FP7 (NeuroPain), CRU, BIH

To top

Transcriptional regulation and processing of opioid peptides in immune cells

Figure POMC

Christoph Stein

Immune cell-derived beta-endorphin is a potent inhibitor of inflammatory pain in animals and in patients with arthritis. In lymph nodes of rats draining an inflamed hind paw the amounts of signal sequence-encoding (exon 2-3) proopiomelanocortin (POMC) mRNA and beta-endorphin increase. Little is known about the regulation of opioid peptide expression in leukocytes. We are interested in factors that induce POMC gene expression in immune cells and that regulate posttranslational processing of POMC resulting in the production of beta-endorphin (Sitte et al., J Neuroimmunol 2007; Busch-Dienstfertig et al., Mol Pain 2012; Busch-Dienstfertig and González-Rodríguez, JAKSTAT 2013).

Group members involved: Melanie Busch-Dienstfertig, Santhosh Chandar Maddila, Nicole Vogel, Charlotte Jacobi

Funding: BMBF (NEUROIMPA, ImmunoPain)

Opioid modulation of ion channels in peripheral sensory neurons

Figure GIRK staining

Christoph Stein, Halina Machelska

Opioids such as morphine act through G-inhibitory protein-coupled opioid receptors located on central and peripheral pain-sensing neurons. Mechanisms involved in opioid analgesia include activation of G-protein-gated inwardly rectifying K+ (GIRK) channels and inhibition of voltage-gated Ca2+ channels. We examine GIRK/opioid receptor coupling in peripheral sensory neurons and its impact on peripheral opioid analgesia in inflammatory pain (Nockemann et al., EMBO Mol Med 2013). We also investigate other ion channels such as transient receptor potential A (TRPA) and the interactions between opioid receptors and vanilloid receptor type 1 (TRPV1) during withdrawal of chronically applied opioid as well as in the peripheral inhibition of neuropathic pain. We utilize in vivo analgesia testing, ex vivo electrophysiological patch clamp recordings, Ca2+- and K+-imaging in naïve and pathological pain conditions (Endres-Becker et al., Mol Pharmacol 2007; Zurborg et al., Nat Neurosci 2007; Spahn et al., Pain 2013; Spahn et al., Mol Pharmacol 2014; Spahn et al., Methods Mol Biol 2015; Labuz et al., Neuropharmacology 2016).  

Group members involved: Dinah Nockemann, Viola Spahn, Philip Stötzner

Funding: DFG, BMBF (MedSys, NoPain)

Modeling pain switches

Figure Modelling Pain Switches

Christoph Stein

This program project applies mathematical models of signaling switches involved in pain sensitization, optimizes and expands them by reflection on molecular, cellular as well as behavioral experiments, to finally apply their predictive power to enable a mechanism-based pain therapy in humans. Our project tests mathematical models electrophysiologically in primary sensory neurons and in in vivo models. Ultimately, testing in human patients with suitable sensory modality profiles is anticipated.

Group members involved: Marian Brackmann, Viola Spahn

Collaborators: T. Hucho, H. Seitz (formerly Max Planck Institute Molecular Genetics, Berlin), R. Baron (Neurology, Uni Kiel), P. Reeh (Physiology, Uni Erlangen), W. Marwan (Systems Biology, Magdeburg), J. Schuchhardt (MicroDiscovery GmbH, Berlin), M. Heiner (Computer Science, Uni Cottbus), F. Herberg (Biochemistry, Uni Kassel)

Funding: BMBF (e:Bio)