Refine
Has Fulltext
- yes (13)
Is part of the Bibliography
- yes (13)
Year of publication
Document Type
- Journal article (13)
Language
- English (13) (remove)
Keywords
- neuropathic pain (4)
- blood-nerve barrier (2)
- claudin-1 (2)
- complex regional pain syndrome (2)
- inflammation (2)
- pain (2)
- Analgesia (1)
- CRPS (1)
- DAMGO (1)
- Endogenous opioids (1)
- Expression (1)
- IENFD (1)
- Inflammatory pain (1)
- Langerhans cells (1)
- MMP9 (1)
- Pain (1)
- RECK (1)
- TRP channel (1)
- TRPA1 (1)
- Toll like receptors (1)
- ZO-1 (1)
- acupuncture (1)
- analgesia (1)
- analysis of variance (1)
- animals (1)
- blood nerve barrier (1)
- calcitonin gene-related peptide (1)
- capsaicin (1)
- chemokines (1)
- chronic constriction injury (1)
- chronic constriction nerve injury (1)
- chronic musculoskeletal pain (1)
- chronic pain (1)
- claudin-5 (1)
- comparison (1)
- cytokines (1)
- dermal B cells (1)
- dorsal root ganglion (1)
- enzyme-linkes immunoassays (1)
- fentanyl (1)
- hypertonic solution (1)
- internalization (1)
- ion channel (1)
- ion channels in the nervous system (1)
- macrophages (1)
- mast cells (1)
- microRNA (1)
- mimetic peptide (1)
- molecular medicine (1)
- nerve injury (1)
- netrin-1 (1)
- nociception (1)
- nociceptive Schwann cells (1)
- opioid peptides (1)
- opioid receptors (1)
- opioids (1)
- oxidised lipids (1)
- oxidized phospholipids (1)
- pain behavior (1)
- pain therapy (1)
- peripheral nerve (1)
- reactive oxygen species (1)
- resolvin (1)
- skin punch biopsy (1)
- targeting (1)
- therapeutic antibody (1)
- tight junction (1)
- tight junction protein (1)
- tight junction proteins (1)
- tissue resident T cells (1)
- transient receptor potential channels (1)
- ultrastructure (1)
- µ-Opioid receptor (1)
Institute
- Klinik und Poliklinik für Anästhesiologie (ab 2004) (13)
- Institut für Klinische Neurobiologie (3)
- Neurologische Klinik und Poliklinik (2)
- Rudolf-Virchow-Zentrum (2)
- Institut für Anatomie und Zellbiologie (1)
- Institut für Pharmakologie und Toxikologie (1)
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (1)
- Neurochirurgische Klinik und Poliklinik (1)
EU-Project number / Contract (GA) number
- 602133 (1)
Peripheral neuropathy is accompanied by changes in the neuronal environment. The blood-nerve barrier (BNB) is crucial in protecting the neural homeostasis: Tight junctions (TJ) seal paracellular spaces and thus prevent external stimuli from entering. In different models of neuropathic pain, the BNB is impaired, thus contributing to local damage, immune cell invasion and, ultimately, the development of neuropathy with its symptoms. In this study, we examined changes in expression and microstructural localization of two key tight junction proteins (TJP), claudin-1 and the cytoplasmic anchoring ZO-1, in the sciatic nerve of mice subjected to chronic constriction injury (CCI). Via qPCR and analysis of fluorescence immunohistochemistry, a marked downregulation of mRNA as well as decreased fluorescence intensity were observed in the nerve for both proteins. Moreover, a distinct zig-zag structure for both proteins located at cell-cell contacts, indicative of the localization of TJs, was observed in the perineurial compartment of sham-operated animals. This microstructural location in cell-cell-contacts was lost in neuropathy as semiquantified via computational analysis, based on a novel algorithm. In summary, we provide evidence that peripheral neuropathy is not only associated with decrease in relevant TJPs but also exhibits alterations in TJP arrangement and loss in barrier tightness, presumably due to internalization. Specifically, semiquantification of TJP in cell-cell-contacts of microcompartments could be used in the future for routine clinical samples of patients with neuropathy.
Background
Leukocytes containing opioid peptides locally control inflammatory pain. In the early phase of complete Freund’s adjuvant (CFA)-induced hind paw inflammation, formyl peptides (derived e.g. from Mycobacterium butyricum) trigger the release of opioid peptides from neutrophils contributing to tonic basal antinociception. In the later phase we hypothesized that toll-like-receptor-(TLR)-4 activation of monocytes/macrophages triggers opioid peptide release and thereby stimulates peripheral opioid-dependent antinociception.
Results
In Wistar rats with CFA hind paw inflammation in the later inflammatory phase (48–96 h) systemic leukocyte depletion by cyclophosphamide (CTX) or locally injected naloxone (NLX) further decreased mechanical and thermal nociceptive thresholds. In vitro β-endorphin (β-END) content increased during human monocyte differentiation as well as in anti-inflammatory CD14+CD16- or non-classical M2 macrophages. Monocytes expressing TLR4 dose-dependently released β-END after stimulation with lipopolysaccharide (LPS) dependent on intracellular calcium. Despite TLR4 expression proinflammatory M1 and anti-inflammatory M2 macrophages only secreted opioid peptides in response to ionomycin, a calcium ionophore. Intraplantar injection of LPS as a TLR4 agonist into the inflamed paw elicited an immediate opioid- and dose-dependent antinociception, which was blocked by TAK-242, a small-molecule inhibitor of TLR4, or by peripheral applied NLX. In the later phase LPS lowered mechanical and thermal nociceptive thresholds. Furthermore, local peripheral TLR4 blockade worsened thermal and mechanical nociceptive pain thresholds in CFA inflammation.
Conclusion
Endogenous opioids from monocytes/macrophages mediate endogenous antinociception in the late phase of inflammation. Peripheral TLR4 stimulation acts as a transient counter-regulatory mechanism for inflammatory pain in vivo, and increases the release of opioid peptides from monocytes in vitro. TLR4 antagonists as new treatments for sepsis and neuropathic pain might unexpectedly transiently enhance pain by impairing peripheral opioid analgesia.
CXCL10 Controls Inflammatory Pain via Opioid Peptide- Containing Macrophages in Electroacupuncture
(2014)
Acupuncture is widely used for pain treatment in patients with osteoarthritis or low back pain, but molecular mechanisms remain largely enigmatic. In the early phase of inflammation neutrophilic chemokines direct opioid-containing neutrophils in the inflamed tissue and stimulate opioid peptide release and antinociception. In this study the molecular pathway and neuroimmune connections in complete Freund's adjuvant (CFA)-induced hind paw inflammation and electroacupuncture for peripheral pain control were analyzed. Free moving Wistar rats with hind paw inflammation were treated twice with electroacupuncture at GB30 (Huan Tiao - gall bladder meridian) (day 0 and 1) and analyzed for mechanical and thermal nociceptive thresholds. The cytokine profiles as well as the expression of opioid peptides were quantified in the inflamed paw. Electroacupuncture elicited long-term antinociception blocked by local injection of anti-opioid peptide antibodies (beta-endorphin, met-enkephalin, dynorphin A). The treatment altered the cytokine profile towards an anti-inflammatory pattern but augmented interferon (IFN)-gamma and the chemokine CXCL10 (IP-10: interferon gamma-inducible protein) protein and mRNA expression with concomitant increased numbers of opioid peptide-containing CXCR3+ macrophages. In rats with CFA hind paw inflammation without acupuncture repeated injection of CXCL10 triggered opioid-mediated antinociception and increase opioid-containing macrophages. Conversely, neutralization of CXCL10 time-dependently decreased electroacupuncture-induced antinociception and the number of infiltrating opioid peptide-expressing CXCR3+ macrophages. In summary, we describe a novel function of the chemokine CXCL10 - as a regulator for an increase of opioid-containing macrophages and antinociceptive mediator in inflammatory pain and as a key chemokine regulated by electroacupuncture.