Team Prof. Dr. Halina Machelska

Contact

Pain Research Laboratory
Klinik für Anaesthesiologie mit Schwerpunkt operative Intensivmedizin
Charité-Universitätsmedizin
Campus Benjamin Franklin
Hindenburgdamm 30
12203 Berlin, Germany

t: +49 30 8445 3851
f: +49 30 8445 4469
halina.machelska(at)charite.de

Team members

Ozgur Celik | t: +49 30 8445 3168
Ph.D. Student
Dr. rer. nat. Dominika Labuz | t: +49 30 8445 3867
PhD
Dr. rer.nat Yvonne Schmidt | t: +49 30 8445 2131

Previous Team Members

Karen Henning
M.Sc. student
Dr. rer. nat. Anja Schreiter

Projects

Immune cell-derived opioids and neuropathic pain

Neuropathic pain is a common consequence of peripheral nerve injuries such as amputation, diabetes, entrapment or compression, and represents one of the most devastating forms of chronic pain. Such pain can persist long after the initiating nerve damaging event has healed, and is often refractory to conventional pain treatments. In addition to neuronal changes activation of the immune system is gaining increasing attention as a component of nerve injury. Interestingly, the currently prevalent opinion points to immune cells as generators of neuropathic pain. In contrast, we have recently shown that leukocytes (CD45+ hematopoetic cells) containing opioid peptides participate in the attenuation of pain in neuritis. In a mouse model of neuropathic pain we demonstrated that these cells infiltrate the site of nerve damage and they co-express receptors for corticotropin-releasing factor (CRF), an important physiological agent releasing opioids from immune cells. Application of CRF at the site of nerve injury resulted in full reversibility of mechanical hypersensitivity that was dependent on locally expressed CRF receptors, opioid peptides (beta-endorphin, Met-enkephalin, dynorphin A) and receptors (mu, delta, kappa), and on intercellular adhesion molecule-1-mediated accumulation of opioid-containing leukocytes (Labuz et al., 2009). Moreover, we found that T lymphocytes represent an essential CD45+ cell population, which mediates analgesia in advanced neuropathy. Thus, T cells expressing CRF receptors and opioid peptide beta-endorphin were absent at the damaged nerve in mice with severe combined immunodeficiency (SCID). Consequently, these animals had substantially reduced CRF-induced analgesia, which could be restored with T cells transferred from wild type mice (Labuz et al., 2010). These data defined opioid peptide-containing immune cells as a new component of beneficial effects of neuroinflammation.  

Group members involved:
Dominika Labuz, Yvonne Schmidt, Anja Schreiter, Lisa Cardnuff

Extramural funding:
DFG, KFO 100/2, Project 1 (H. Machelska).

Labuz D, Schmidt Y, Schreiter A, Rittner HL, Mousa SA, Machelska H.
Immune cell-derived opioids protect against neuropathic pain.
J Clin Invest 2009; 119(2):278-286.
Labuz D, Schreiter A, Schmidt Y, Brack A, Machelska H.
T lymphocytes containing β-endorphin ameliorate mechanical hypersensitivity following nerve injury .
Brain Behav Immun 2010 ; 24(7): 1045-53 .

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Enhancement of endogenous opioid function in experimental inflammatory pain (with Christoph Stein)

This project explores novel ways of pain control without adverse effects associated with classical anti-inflammatory drugs and centrally acting opioids. Immune cells infiltrating inflamed tissue produce and release opioid peptides. These peptides activate opioid receptors on peripheral terminals of sensory nerves and inhibit neuronal excitability, resulting in analgesia. Compared to conventional exogenous agonists, endogenous opioids have a reduced potential of inducing receptor downregulation, tolerance or paradoxical excitatory effects due to unphysiologically high exogenous agonist concentrations at the receptor. In this project we aim at producing analgesia by enhancing the function of endogenous opioid peptides.

Group members involved:
Anja Schreiter, Stephanie Miceli, Dominika Labuz

Collaborators:
B. Roques (Université Paris Descartes, 4 avenue de l’Observatoire, Paris, France), J. Sieper (Rheumatologie, Charité Campus Benjamin Franklin, Berlin, Germany), M. Schmelz (Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum, Fakultät für Klinische Medizin Mannheim, Universität Heidelberg, Germany)

Extramural funding:
DFG, MA 243/2-1 (H. Machelska) and STE 477/9-1 (C. Stein)

Contribution of opioid peptides and receptors in immune cells to exogenous opioid control of neuropathic pain

Neuropathic pain results from nerve injury, which can lead to inflammation (neuritis). Recently we showed that damaged nerves express opioid receptors and are infiltrated by opioid peptide-containing leukocytes (see project 1). Although, opioid receptors are also present in immune cells, their significance to pain transmission has not been addressed so far. In this project we aim at elucidating the contribution of leukocytic opioid peptides and receptors to peripheral opioid antinociception in painful neuropathy. These studies will provide new insights into mechanisms of analgesic actions based on the interplay between endogenous and exogenous opioids acting at their receptors in immune cells. By promoting the use of natural opioidergic pain killers and their peripheral sensory and leukocytic receptors, our studies offer a potential approach for efficient and safe control of painful inflammatory neuropathies.

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

Collaborators:
A. Zimmer (Institute of Molecular Psychiatry, Universitätsklinikum Bonn, Germany), B. Kieffer and C. Gavériaux-Ruff (Institut de Genetique et de Biologie Moleculaire et Cellulaire, NRS/INSERM/ULP, Strasbourg, France)

Extramural funding:
DFG, MA 2437/4-1 (H. Machelska)

Opioid actions on nociceptors following nerve damage

Here we focus on opioid receptor functioning after nerve injury. We employ electrophysiological recordings in a mouse model of neuropathic pain. The goal is to examine how nerve damage affects properties of peripheral sensory fibers and how opioids modulate these properties. 

Group members involved:
Yvonne Schmidt