@article{KressHuettenhoferLandryetal.2013, author = {Kress, Michaela and H{\"u}ttenhofer, Alexander and Landry, Marc and Kuner, Rohini and Favereaux, Alexandre and Greenberg, David and Bednarik, Josef and Heppenstall, Paul and Kronenberg, Florian and Malcangio, Marzia and Rittner, Heike and {\"U}{\c{c}}eyler, Nurcan and Trajanoski, Zlatko and Mouritzen, Peter and Birklein, Frank and Sommer, Claudia and Soreq, Hermona}, title = {microRNAs in nociceptive circuits as predictors of future clinical applications}, series = {Frontiers in Molecular Neuroscience}, volume = {6}, journal = {Frontiers in Molecular Neuroscience}, number = {33}, doi = {10.3389/fnmol.2013.00033}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154597}, year = {2013}, abstract = {Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs - and microRNAs (miRNAs) in particular - regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesized as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioral components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals.}, language = {en} } @article{MambrettiKistnerMayeretal.2016, author = {Mambretti, Egle M. and Kistner, Katrin and Mayer, Stefanie and Massotte, Dominique and Kieffer, Brigitte L. and Hoffmann, Carsten and Reeh, Peter W. and Brack, Alexander and Asan, Esther and Rittner, Heike L.}, title = {Functional and structural characterization of axonal opioid receptors as targets for analgesia}, series = {Molecular Pain}, journal = {Molecular Pain}, number = {12}, doi = {10.1177/1744806916628734}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145917}, pages = {1-17}, year = {2016}, abstract = {Background Opioids are the gold standard for the treatment of acute pain despite serious side effects in the central and enteric nervous system. µ-opioid receptors (MOPs) are expressed and functional at the terminals of sensory axons, when activated by exogenous or endogenous ligands. However, the presence and function of MOP along nociceptive axons remains controversial particularly in na{\"i}ve animals. Here, we characterized axonal MOPs by immunofluorescence, ultrastructural, and functional analyses. Furthermore, we evaluated hypertonic saline as a possible enhancer of opioid receptor function. Results Comparative immunolabeling showed that, among several tested antibodies, which all provided specific MOP detection in the rat central nervous system (CNS), only one monoclonal MOP-antibody yielded specificity and reproducibility for MOP detection in the rat peripheral nervous system including the sciatic nerve. Double immunolabeling documented that MOP immunoreactivity was confined to calcitonin gene-related peptide (CGRP) positive fibers and fiber bundles. Almost identical labeling and double labeling patterns were found using mcherry-immunolabeling on sciatic nerves of mice producing a MOP-mcherry fusion protein (MOP-mcherry knock-in mice). Preembedding immunogold electron microscopy on MOP-mcherry knock-in sciatic nerves indicated presence of MOP in cytoplasm and at membranes of unmyelinated axons. Application of [D-Ala\(^2\), N-MePhe\(^4\), Gly-ol]-enkephalin (DAMGO) or fentanyl dose-dependently inhibited depolarization-induced CGRP release from rat sciatic nerve axons ex vivo, which was blocked by naloxone. When the lipophilic opioid fentanyl was applied perisciatically in na{\"i}ve Wistar rats, mechanical nociceptive thresholds increased. Subthreshold doses of fentanyl or the hydrophilic opioid DAMGO were only effective if injected together with hypertonic saline. In vitro, using β-arrestin-2/MOP double-transfected human embryonic kidney cells, DAMGO as well as fentanyl lead to a recruitment of β-arrestin-2 to the membrane followed by a β-arrestin-2 reappearance in the cytosol and MOP internalization. Pretreatment with hypertonic saline prevented MOP internalization. Conclusion MOPs are present and functional in the axonal membrane from na{\"i}ve animals. Hypertonic saline acutely decreases ligand-induced internalization of MOP and thereby might improve MOP function. Further studies should explore potential clinical applications of opioids together with enhancers for regional analgesia.}, language = {en} } @article{EnigkWagnerSamapatietal.2014, author = {Enigk, Fabian and Wagner, Antje and Samapati, Rudi and Rittner, Heike and Brack, Alexander and Mousa, Shaaban A. and Sch{\"a}fer, Michael and Habazettl, Helmut and Sch{\"a}per, J{\"o}rn}, title = {Thoracic epidural anesthesia decreases endotoxin-induced endothelial injury}, series = {BMC Anesthesiology}, volume = {14}, journal = {BMC Anesthesiology}, number = {23}, doi = {10.1186/1471-2253-14-23}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116787}, year = {2014}, abstract = {Background: The sympathetic nervous system is considered to modulate the endotoxin-induced activation of immune cells. Here we investigate whether thoracic epidural anesthesia with its regional symapathetic blocking effect alters endotoxin-induced leukocyte-endothelium activation and interaction with subsequent endothelial injury. Methods: Sprague Dawley rats were anesthetized, cannulated and hemodynamically monitored. E. coli lipopolysaccharide (Serotype 0127: B8, 1.5 mg x kg(-1) x h(-1)) or isotonic saline (controls) was infused for 300 minutes. An epidural catheter was inserted for continuous application of lidocaine or normal saline in endotoxemic animals and saline in controls. After 300 minutes we measured catecholamine and cytokine plasma concentrations, adhesion molecule expression, leukocyte adhesion, and intestinal tissue edema. Results: In endotoxemic animals with epidural saline, LPS significantly increased the interleukin-1 beta plasma concentration (48\%), the expression of endothelial adhesion molecules E-selectin (34\%) and ICAM-1 (42\%), and the number of adherent leukocytes (40\%) with an increase in intestinal myeloperoxidase activity (26\%) and tissue edema (75\%) when compared to healthy controls. In endotoxemic animals with epidural infusion of lidocaine the values were similar to those in control animals, while epinephrine plasma concentration was 32\% lower compared to endotoxemic animals with epidural saline. Conclusions: Thoracic epidural anesthesia attenuated the endotoxin-induced increase of IL-1 beta concentration, adhesion molecule expression and leukocyte-adhesion with subsequent endothelial injury. A potential mechanism is the reduction in the plasma concentration of epinephrine.}, language = {en} } @article{RittnerWangGehringeretal.2014, author = {Rittner, Heike L. and Wang, Ying and Gehringer, Rebekka and Mousa, Shaaban A. and Hackel, Dagmar and Brack, Alexander}, title = {CXCL10 Controls Inflammatory Pain via Opioid Peptide- Containing Macrophages in Electroacupuncture}, doi = {10.1371/journal.pone.0094696}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112979}, year = {2014}, abstract = {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.}, language = {en} } @article{RittnerHackelPflueckeetal.2013, author = {Rittner, Heike Lydia and Hackel, Dagmar and Pfl{\"u}cke, Diana and Neumann, Annick and Viebahn, Johannes and Mousa, Shaaban and Wischmeyer, Erhard and Roewer, Norbert and Brack, Alexander}, title = {The Connection of Monocytes and Reactive Oxygen Species in Pain}, series = {PLoS ONE}, journal = {PLoS ONE}, doi = {10.1371/journal.pone.0063564}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96669}, year = {2013}, abstract = {The interplay of specific leukocyte subpopulations, resident cells and proalgesic mediators results in pain in inflammation. Proalgesic mediators like reactive oxygen species (ROS) and downstream products elicit pain by stimulation of transient receptor potential (TRP) channels. The contribution of leukocyte subpopulations however is less clear. Local injection of neutrophilic chemokines elicits neutrophil recruitment but no hyperalgesia in rats. In meta-analyses the monocytic chemoattractant, CCL2 (monocyte chemoattractant protein-1; MCP-1), was identified as an important factor in the pathophysiology of human and animal pain. In this study, intraplantar injection of CCL2 elicited thermal and mechanical pain in Wistar but not in Dark Agouti (DA) rats, which lack p47phox, a part of the NADPH oxidase complex. Inflammatory hyperalgesia after complete Freund's adjuvant (CFA) as well as capsaicin-induced hyperalgesia and capsaicin-induced current flow in dorsal root ganglion neurons in DA were comparable to Wistar rats. Macrophages from DA expressed lower levels of CCR2 and thereby migrated less towards CCL2 and formed limited amounts of ROS in vitro and 4-hydroxynonenal (4-HNE) in the tissue in response to CCL2 compared to Wistar rats. Local adoptive transfer of peritoneal macrophages from Wistar but not from DA rats reconstituted CCL2-triggered hyperalgesia in leukocyte-depleted DA and Wistar rats. A pharmacological stimulator of ROS production (phytol) restored CCL2-induced hyperalgesia in vivo in DA rats. In Wistar rats, CCL2-induced hyperalgesia was completely blocked by superoxide dismutase (SOD), catalase or tempol. Likewise, inhibition of NADPH oxidase by apocynin reduced CCL2-elicited hyperalgesia but not CFA-induced inflammatory hyperalgesia. In summary, we provide a link between CCL2, CCR2 expression on macrophages, NADPH oxidase, ROS and the development CCL2-triggered hyperalgesia, which is different from CFA-induced hyperalgesia. The study further supports the impact of CCL2 and ROS as potential targets in pain therapy.}, language = {en} } @article{RittnerSauerHackeletal.2014, author = {Rittner, Heike L. and Sauer, Reine-Solange and Hackel, Dagmar and Morschel, Laura and Sahlbach, Henrike and Wang, Ying and Mousa, Shaaban A. and Roewer, Norbert and Brack, Alexander}, title = {Toll like receptor (TLR)-4 as a regulator of peripheral endogenous opioid-mediated analgesia in inflammation}, doi = {10.1186/1744-8069-10-10}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110193}, year = {2014}, abstract = {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.}, language = {en} } @article{ReinholdSchwabeLuxetal.2018, author = {Reinhold, Ann Kristin and Schwabe, Joachim and Lux, Thomas J. and Salvador, Ellaine and Rittner, Heike L.}, title = {Quantitative and Microstructural Changes of the Blood-Nerve Barrier in Peripheral Neuropathy}, series = {Frontiers in Neuroscience}, volume = {12}, journal = {Frontiers in Neuroscience}, doi = {10.3389/fnins.2018.00936}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225179}, pages = {936, 1-9}, year = {2018}, abstract = {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.}, language = {en} } @article{OehlerKlokaMohammadietal.2020, author = {Oehler, Beatrice and Kloka, Jan and Mohammadi, Milad and Ben-Kraiem, Adel and Rittner, Heike L.}, title = {D-4F, an ApoA-I mimetic peptide ameliorating TRPA1-mediated nocifensive behaviour in a model of neurogenic inflammation}, series = {Molecular Pain}, volume = {16}, journal = {Molecular Pain}, doi = {10.1177/1744806920903848}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236061}, pages = {1-11}, year = {2020}, abstract = {Background High doses of capsaicin are recommended for the treatment of neuropathic pain. However, low doses evoke mechanical hypersensitivity. Activation of the capsaicin chemosensor transient receptor potential vanilloid 1 (TRPV1) induces neurogenic inflammation. In addition to the release of pro-inflammatory mediators, reactive oxygen species are produced. These highly reactive molecules generate oxidised phospholipids and 4-hydroxynonenal (4-HNE) which then directly activate TRP ankyrin 1 (TRPA1). The apolipoprotein A-I mimetic peptide D-4F neutralises oxidised phospholipids. Here, we asked whether D-4F ameliorates neurogenic hypersensitivity in rodents by targeting reactive oxygen species and 4-HNE in the capsaicin-evoked pain model. Results Co-application of D-4F ameliorated capsaicin-induced mechanical hypersensitivity and allodynia as well as persistent heat hypersensitivity measured by Randell-Selitto, von Frey and Hargreaves test, respectively. In addition, mechanical hypersensitivity was blocked after co-injection of D-4F with the reactive oxygen species analogue H2O2 or 4-HNE. In vitro studies on dorsal root ganglion neurons and stably transfected cell lines revealed a TRPA1-dependent inhibition of the calcium influx when agonists were pre-incubated with D-4F. The capsaicin-induced calcium influx in TRPV1-expressing cell lines and dorsal root ganglion neurons sustained in the presence of D-4F. Conclusions D-4F is a promising compound to ameliorate TRPA1-dependent hypersensitivity during neurogenic inflammation.}, language = {en} } @article{ReinholdKrugSalvadoretal.2022, author = {Reinhold, Ann Kristin and Krug, Susanne M. and Salvador, Ellaine and Sauer, Reine S. and Karl-Sch{\"o}ller, Franziska and Malcangio, Marzia and Sommer, Claudia and Rittner, Heike L.}, title = {MicroRNA-21-5p functions via RECK/MMP9 as a proalgesic regulator of the blood nerve barrier in nerve injury}, series = {Annals of the New York Academy of Sciences}, volume = {1515}, journal = {Annals of the New York Academy of Sciences}, number = {1}, doi = {10.1111/nyas.14816}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318226}, pages = {184 -- 195}, year = {2022}, abstract = {Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired—partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA-21-5p (miR-21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR-21 in neuropathic pain and its impact on the BNB in a human-murine back translational approach. MiR-21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin-1 in both injured and spared nerves. Moreover, the putative miR-21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb. In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR-21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB. Perineurial miR-21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR-21 after nerve injury reversed it. In summary, the data support a novel role for miR-21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9.}, language = {en} } @article{OehlerBrackBlumetal.2021, author = {Oehler, Beatrice and Brack, Alexander and Blum, Robert and Rittner, Heike L.}, title = {Pain Control by Targeting Oxidized Phospholipids: Functions, Mechanisms, Perspectives}, series = {Frontiers in Endocrinology}, volume = {11}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2020.613868}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223432}, year = {2021}, abstract = {Within the lipidome oxidized phospholipids (OxPL) form a class of chemically highly reactive metabolites. OxPL are acutely produced in inflamed tissue and act as endogenous, proalgesic (pain-inducing) metabolites. They excite sensory, nociceptive neurons by activating transient receptor potential ion channels, specifically TRPA1 and TRPV1. Under inflammatory conditions, OxPL-mediated receptor potentials even potentiate the action potential firing rate of nociceptors. Targeting OxPL with D-4F, an apolipoprotein A-I mimetic peptide or antibodies like E06, specifically binding oxidized headgroups of phospholipids, can be used to control acute, inflammatory pain syndromes, at least in rodents. With a focus on proalgesic specificities of OxPL, this article discusses, how targeting defined substances of the epilipidome can contribute to mechanism-based therapies against primary and secondary chronic inflammatory or possibly also neuropathic pain.}, language = {en} } @article{LuxHuBenKraiemetal.2019, author = {Lux, Thomas J. and Hu, Xiawei and Ben-Kraiem, Adel and Blum, Robert and Chen, Jeremy Tsung-Chieh and Rittner, Heike L.}, title = {Regional differences in tight junction protein expression in the blood-DRG barrier and their alterations after nerve traumatic injury in rats}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {1}, issn = {1422-0067}, doi = {10.3390/ijms21010270}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285029}, year = {2019}, abstract = {The nervous system is shielded by special barriers. Nerve injury results in blood-nerve barrier breakdown with downregulation of certain tight junction proteins accompanying the painful neuropathic phenotype. The dorsal root ganglion (DRG) consists of a neuron-rich region (NRR, somata of somatosensory and nociceptive neurons) and a fibre-rich region (FRR), and their putative epi-/perineurium (EPN). Here, we analysed blood-DRG barrier (BDB) properties in these physiologically distinct regions in Wistar rats after chronic constriction injury (CCI). Cldn5, Cldn12, and Tjp1 (rats) mRNA were downregulated 1 week after traumatic nerve injury. Claudin-1 immunoreactivity (IR) found in the EPN, claudin-19-IR in the FRR, and ZO-1-IR in FRR-EPN were unaltered after CCI. However, laser-assisted, vessel specific qPCR, and IR studies confirmed a significant loss of claudin-5 in the NRR. The NRR was three-times more permeable compared to the FRR for high and low molecular weight markers. NRR permeability was not further increased 1-week after CCI, but significantly more CD68\(^+\) macrophages had migrated into the NRR. In summary, NRR and FRR are different in na{\"i}ve rats. Short-term traumatic nerve injury leaves the already highly permeable BDB in the NRR unaltered for small and large molecules. Claudin-5 is downregulated in the NRR. This could facilitate macrophage invasion, and thereby neuronal sensitisation and hyperalgesia. Targeting the stabilisation of claudin-5 in microvessels and the BDB barrier could be a future approach for neuropathic pain therapy.}, language = {en} } @article{OehlerKistnerMartinetal.2017, author = {Oehler, Beatrice and Kistner, Katrin and Martin, Corinna and Schiller, J{\"u}rgen and Mayer, Rafaela and Mohammadi, Milad and Sauer, Reine-Solange and Filipovic, Milos R. and Nieto, Francisco R. and Kloka, Jan and Pfl{\"u}cke, Diana and Hill, Kerstin and Schaefer, Michael and Malcangio, Marzia and Reeh, Peter W. and Brack, Alexander and Blum, Robert and Rittner, Heike L.}, title = {Inflammatory pain control by blocking oxidized phospholipid-mediated TRP channel activation}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {5447}, doi = {10.1038/s41598-017-05348-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158536}, year = {2017}, abstract = {Phospholipids occurring in cell membranes and lipoproteins are converted into oxidized phospholipids (OxPL) by oxidative stress promoting atherosclerotic plaque formation. Here, OxPL were characterized as novel targets in acute and chronic inflammatory pain. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) and its derivatives were identified in inflamed tissue by mass spectrometry and binding assays. They elicited calcium influx, hyperalgesia and induced pro-nociceptive peptide release. Genetic, pharmacological and mass spectrometric evidence in vivo as well as in vitro confirmed the role of transient receptor potential channels (TRPA1 and TRPV1) as OxPAPC targets. Treatment with the monoclonal antibody E06 or with apolipoprotein A-I mimetic peptide D-4F, capturing OxPAPC in atherosclerosis, prevented inflammatory hyperalgesia, and in vitro TRPA1 activation. Administration of D-4F or E06 to rats profoundly ameliorated mechanical hyperalgesia and inflammation in collagen-induced arthritis. These data reveal a clinically relevant role for OxPAPC in inflammation offering therapy for acute and chronic inflammatory pain treatment by scavenging OxPAPC.}, language = {en} } @article{KindlTeichmuellerEscolanoLozanoetal.2022, author = {Kindl, Gudrun and Teichm{\"u}ller, Karolin and Escolano-Lozano, Fabiola and Birklein, Frank and Rittner, Heike L.}, title = {Pain, disability, and lifestyle: Patients with complex regional pain syndrome compared to chronic musculoskeletal pain-A retrospective analysis}, series = {European Journal of Pain}, volume = {26}, journal = {European Journal of Pain}, number = {3}, doi = {10.1002/ejp.1900}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318200}, pages = {719 -- 728}, year = {2022}, abstract = {Background Complex regional pain syndrome (CRPS) is an orphan disease occurring as a complication after trauma. Due to its acute onset and the typical clinical presentation of the inflammatory and autonomous signs, it is an eye-catching chronic pain disease affecting also young and working people. In social media and the internet, high pain severity and the unfavourable prognosis are often empathized. Methods Here, we compared epidemiological, pain and lifestyle factors of 223 CPRS patients from the "ncRNAPain" cohort with 255 patients with chronic musculoskeletal pain (MSK). MSK patients were recruited at the beginning of a multimodal pain therapy programme. We searched for factors predicting pain intensity. Results Both chronic pain diseases affected women in middle age. Patients with MSK were more obese, drank more alcohol, and were less educated (Pearson chi-square Test or Mann-Whitney/U-Test). Both groups smoked more than healthy people in the OECD (Organization for Economic Cooperation and Development). Mann-Whitney/U-Test confirmed that CRPS patients did not have more severe pain and did not suffer more from pain-related disability than patients with MSK. CRPS patients also had less psychiatric comorbidities. Multiple linear regression analysis revealed that group assignment, depressive characteristics, body mass index, average alcohol consumption and smoking predicted higher pain ratings, while disease duration, anxiety symptoms or gender had no influence on pain intensity. Conclusion In summary, our study supports a more optimistic view on pain in CRPS patients in comparison to MSK and identifies lifestyle factors that might contribute to the pathophysiology like smoking and drinking. Important next steps are the identification of CRPS patients at risk for chronification or—vice versa—with protective factors for pain resolution. Significance This study compares complex regional pain syndrome (CRPS) and chronic musculoskeletal pain and questions previously reported pain, disability and lifestyle factors associated with CRPS.}, language = {en} } @article{OehlerMohammadiPerpinaVicianoetal.2017, author = {Oehler, Beatrice and Mohammadi, Milad and Perpina Viciano, Cristina and Hackel, Dagmar and Hoffmann, Carsten and Brack, Alexander and Rittner, Heike L.}, title = {Peripheral interaction of Resolvin D1 and E1 with opioid receptor antagonists for antinociception in inflammatory pain in rats}, series = {Frontiers in Molecular Neuroscience}, volume = {10}, journal = {Frontiers in Molecular Neuroscience}, number = {242}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158642}, year = {2017}, abstract = {Antinociceptive pathways are activated in the periphery in inflammatory pain, for instance resolvins and opioid peptides. Resolvins are biosynthesized from omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid. Resolvin D1 (RvD1) and resolvin E1 (RvE1) initiate the resolution of inflammation and control of hypersensitivity via induction of anti-inflammatory signaling cascades. RvD1 binds to lipoxin A4/annexin-A1 receptor/formyl-peptide receptor 2 (ALX/FPR2), RvE1 to chemerin receptor 23 (ChemR23). Antinociception of RvD1 is mediated by interaction with transient receptor potential channels ankyrin 1 (TRPA1). Endogenous opioid peptides are synthesized and released from leukocytes in the tissue and bind to opioid receptors on nociceptor terminals. Here, we further explored peripheral mechanisms of RvD1 and chemerin (Chem), the ligand of ChemR23, in complete Freund's adjuvant (CFA)-induced hindpaw inflammation in male Wistar rats. RvD1 and Chem ameliorated CFA-induced hypersensitivity in early and late inflammatory phases. This was prevented by peripheral blockade of the μ-opioid peptide receptor (MOR) using low dose local naloxone or by local injection of anti-β-endorphin and anti-met-enkephalin (anti-ENK) antibodies. Naloxone also hindered antinociception by the TRPA1 inhibitor HC-030031. RvD1 did not stimulate the release of β-endorphin from macrophages and neutrophils, nor did RvD1 itself activate G-proteins coupled MOR or initiate β-arrestin recruitment to the membrane. TRPA1 blockade by HC-030031 in inflammation in vivo as well as inhibition of the TRPA1-mediated calcium influx in dorsal root ganglia neurons in vitro was hampered by naloxone. Peripheral application of naloxone alone in vivo already lowered mechanical nociceptive thresholds. Therefore, either a perturbation of the balance of endogenous pro- and antinociceptive mechanisms in early and late inflammation, or an interaction of TRPA1 and opioid receptors weaken the antinociceptive potency of RvD1 and TRPA1 blockers.}, language = {en} } @article{ChenSchmidtSchuergeretal.2021, author = {Chen, Jeremy Tsung-Chieh and Schmidt, Lea and Sch{\"u}rger, Christina and Hankir, Mohammed K. and Krug, Susanne M. and Rittner, Heike L.}, title = {Netrin-1 as a multitarget barrier stabilizer in the peripheral nerve after injury}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms221810090}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261695}, year = {2021}, abstract = {The blood-nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nervous systems; however, its role in regulating barrier integrity and pain processing after nerve injury is poorly understood. Here, we show that chronic constriction injury (CCI) in Wistar rats reduced netrin-1 protein and the netrin-1 receptor neogenin-1 (Neo1) in the sciatic nerve. Replacement of netrin-1 via systemic or local administration of the recombinant protein rescued injury-induced nociceptive hypersensitivity. This was prevented by siRNA-mediated knockdown of Neo1 in the sciatic nerve. Mechanistically, netrin-1 restored endothelial and myelin, but not perineural, barrier function as measured by fluorescent dye or fibrinogen penetration. Netrin-1 also reversed the decline in the tight junction proteins claudin-5 and claudin-19 in the sciatic nerve caused by CCI. Our findings emphasize the role of the endothelial and myelin barriers in pain processing after nerve damage and reveal that exogenous netrin-1 restores their function to mitigate CCI-induced hypersensitivity via Neo1. The netrin-1-neogenin-1 signaling pathway may thus represent a multi-target barrier protector for the treatment of neuropathic pain.}, language = {en} } @article{BenKraiemSauerNorwigetal.2021, author = {Ben-Kraiem, Adel and Sauer, Reine-Solange and Norwig, Carla and Popp, Maria and Bettenhausen, Anna-Lena and Atalla, Mariam Sobhy and Brack, Alexander and Blum, Robert and Doppler, Kathrin and Rittner, Heike Lydia}, title = {Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy}, series = {Journal of Molecular Medicine}, volume = {99}, journal = {Journal of Molecular Medicine}, number = {9}, doi = {10.1007/s00109-021-02091-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265237}, pages = {1237-1250}, year = {2021}, abstract = {Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26\% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage.}, language = {en} }