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Background: Surgical treatment of inguinal hernias in children is one of the most common operative procedures worldwide. During surgery for inguinal hernias in adults, chronic pain develops in approximately 10% of all cases. In children, there has been limited research to determine whether they may also develop this chronic postsurgical inguinal pain (CPIP). The aim of this study was to investigate the prevalence of CPIP in children after open inguinal hernia surgery and to identify possible risk factors and protective factors for the development of CPIP. Methods: A single center retrospective analysis of patients aged 4 to 15 years who underwent inguinal hernia repair from 2020 to 2022 was performed. A detailed analysis based on the local database was used to analyze existing pre-existing conditions, perioperative information and the use of a cauda epidural block. A standardized follow-up questionnaire was used to evaluate the prevalence of CPIP and the duration of postoperative analgesic medication. Results: A total of 176 cases were included in the detailed analysis. 3.4 % of the children complained CPIP 3 months after surgery with a mean follow-up period of 26.4 months. At the time of the survey, 50% of CPIP patients reported a resolving from chronic pain. Our analyzes showed a potential higher CPIP rate in females (83.3%; p=0.040), older children (8.3 years vs. 5 years; p=0.006) and chronic pain history (16.7% vs. 2.4%; p=0.038).Furthermore, Children mitght profit from a intraoperative cauda epidural block since we observed a lower rate of CPIP (66.7% (4/6) vs. 97% (164/170); p=0.019) in these patients. Conclusion: We were able to identify initial risk factors such as female gender, older patient age and a history of chronic pain. In addition, we were able to obtain information on possible protective factors such as an intraoperative cauda epidural block and adequate postoperative analgesia. However, further studies are required to clarify the pathogenesis and to confirm predictors and protective factors in order to improve therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: The risk of persistent postoperative opioid use (PPOU) and its association with the type of surgery are still unclear in Germany. Methods: We conducted a nationwide retrospective cohort study on the basis of claims data from BARMER, a statutory health insurance carrier in Germany. Opioid-naive adults who did not have cancer and who underwent inpatient surgery in 2018 were included in the study. The operations were divided into 103 categories. PPOU was defined as the prescribing of opioids between postoperative days 1 and 90 and also between postoperative days 91 and 180 after hospital discharge. Patient-associated risk factors in the 12 months before surgery were investigated. Results: 203327 patients were included. 1.4% had PPOU (95% confidence interval [1.4; 1.5]). There were major differences between operation groups: major amputations and orthopedic procedures carried the greatest risk for the development of PPOU. The type of surgery had a larger effect on the risk of PPOU than pre-existing risk factors (explained variance 22.3% vs. 14.3%). Among such factors, alcohol abuse and pre-existing treatment with antidepressant drugs were associated with the highest risk for PPOU (odds ratios [OR] 1.515 [1.277; 1.797] and 2.131 [1.943; 2.336]). Conclusion: The incidence of PPOU in Germany is low (1.4%). The type of surgery plays an important role in its development. [ABSTRACT FROM AUTHOR]

Karolin Teichmüller,1,2 Andrea Kübler,2 Heike L Rittner,1 Gudrun-Karin Kindl1 1University Hospital Würzburg, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, Centre for Interdisciplinary Pain Medicine, Würzburg, Germany; 2University of Würzburg, Institute of Psychology, Department of Psychology I, Würzburg, GermanyCorrespondence: Gudrun-Karin Kindl, University Hospital Würzburg, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, Centre for Interdisciplinary Pain Medicine, Oberdürrbacher Str. 6, Würzburg, 97080, Germany, Email Kindl_G@ukw.dePurpose: The Avoidance-Endurance Model postulates fear-avoidance responses and endurance responses as important psychological mechanisms in the development and maintenance of chronic pain. The present study aims to investigate potential differences in avoidance and endurance responses to pain before and with advanced chronification.Patients and Methods: Two samples of adults with non-cancer pain at two different stages of chronicity were compared: One with pain and risk factors for chronicity (n=26, part of the PAIN2020 project) and one with chronic pain (n=33 from a pain day care clinic). The German Pain Questionnaire, the Graded Chronic Pain Scale (GCPS) and medical reports were used to measure duration and severity of pain. Responses to pain were assessed with the Avoidance-Endurance Questionnaire (AEQ) and psychological strain with the Depression, Anxiety and Stress Scales (DASS).Results: Both groups were primarily affected by musculoskeletal pain. Although not yet chronified, the risk group reported comparable GCPS levels of pain intensity and disability. Depression and stress ratings were also similar, except for anxiety, which was significantly elevated in the chronic pain sample (p< .001). The AEQ scales did not differ between groups, neither on any of the fear-avoidance- nor endurance-related dimensions. A post-hoc regression analysis revealed a significant prediction of fear-avoidance by pain-related disability (p< .001). The regression model for endurance responses was not significant.Conclusion: Patients with risk factors of chronification experience substantial pain-related burden. Responses to pain in the realm of the Avoidance-Endurance model do not appear to vary as a function of chronification. While fear-avoidance and pain-related disability correlate positively, endurance could not be associated to any of our variables.Keywords: Avoidance-Endurance Model, fear-avoidance, chronic pain, chronification, PAIN2020

Neuropathic pain, caused by a lesion in the somatosensory system, is a severely impairing mostly chronic disease. While its underlying molecular mechanisms are not thoroughly understood, neuroimmune interactions as well as changes in the pain pathway such as sensitization of nociceptors have been implicated. It has been shown that not only are different cell types involved in generation and maintenance of neuropathic pain, like neurons, immune and glial cells, but, also, intact adjacent neurons are relevant to the process. Here, we describe an experimental approach to discriminate damaged from intact adjacent neurons in the same dorsal root ganglion (DRG) using differential fluorescent neuronal labelling and fluorescence-activated cell sorting (FACS). Two fluorescent tracers, Fluoroemerald (FE) and 1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate (DiI), were used, whose properties allow us to distinguish between damaged and intact neurons. Subsequent sorting permitted transcriptional analysis of both groups. Results and qPCR validation show a strong regulation in damaged neurons versus contralateral controls as well as a moderate regulation in adjacent neurons. Data for damaged neurons reveal an mRNA expression pattern consistent with established upregulated genes like galanin, which supports our approach. Moreover, novel genes were found strongly regulated such as corticotropin-releasing hormone (CRH), providing novel targets for further research. Differential fluorescent neuronal labelling and sorting allows for a clear distinction between primarily damaged neuropathic neurons and “bystanders,” thereby facilitating a more detailed understanding of their respective roles in neuropathic processes in the DRG. [ABSTRACT FROM AUTHOR]

In February 2009 a major case of scientific misconduct was discovered. The American pain researcher Dr. S. Reuben had published 21 papers over a period of 15 years that were found to be fraudulent. Suddenly many advances in postoperative pain therapy which had been assumed to be correct seemed questionable. In this review article the lessons which can be learnt from this case are described. This review also reveals that it is almost impossible for reviewers or readers of scientific journals to detect scientific fraud. However, several warning signs can be identified that might be useful when reading clinical papers. In retrospect many of these signs were detectable in Reuben’s studies. Based on the fraudulent papers of Reuben it will be shown how and to what extent falsified results can affect other types of literature, such as practice guidelines, meta-analyses, review articles and oral presentations. [ABSTRACT FROM AUTHOR]

Several in vitro and animal studies have demonstrated the immunosuppressive effects of opioids and an increased risk of infection. The clinical relevance of these findings is unclear. In this review the relevant animal and human studies on the relationship of opioid use and risk of infection are summarized. The areas of retroviral infections (i.e. human immunodeficiency virus, HIV), sepsis and pneumonia, postoperative and chronic pain therapy are covered. In the majority of animal studies an increased risk of infection was demonstrated but in human studies these findings were contradictory. However, these studies were frequently underpowered because they involved small patient collectives and do not reflect the standards of evidence-based medicine. In summary, a causal relationship between opioid therapy and an increased risk of infection could neither be conclusively demonstrated nor fully excluded. [ABSTRACT FROM AUTHOR]

Several in vitro and animal studies have demonstrated the immunosuppressive effects of opioids and an increased risk of infection. The clinical relevance of these findings is unclear. In this review the relevant animal and human studies on the relationship of opioid use and risk of infection are summarized. The areas of retroviral infections (i.e. human immunodeficiency virus, HIV), sepsis and pneumonia, postoperative and chronic pain therapy are covered. In the majority of animal studies an increased risk of infection was demonstrated but in human studies these findings were contradictory. However, these studies were frequently underpowered because they involved small patient collectives and do not reflect the standards of evidence-based medicine. In summary, a causal relationship between opioid therapy and an increased risk of infection could neither be conclusively demonstrated nor fully excluded. [ABSTRACT FROM AUTHOR]

Non-opioid analgesics play a central role in the management of postoperative pain. In this review, the pharmacology, the analgesic efficacy and the side-effects of non-opioid analgesics are summarized. First, the pharmacology of diclofenac, acetyl salicylic acid, dipyrone, acetaminophen and the COX-2 inhibitors is described. Second, the analgesic efficacy of non-opioid analgesics is analyzed for moderate pain (e.g. ambulatory surgery) and for moderate to severe pain (e.g. abdominal surgery-in combination with opioids). There is limited evidence for an additive analgesic effect of two non-opioid analgesics. Third, the major side-effects of non-opioid analgesics are discussed in relation to the pathophysiology, the frequency and the clinical relevance of these effects. In particular, side-effects on the gastrointestinal tract (ulcus formation), on coagulation (bleeding and thrombosis), on the renal (renal insufficiency), the pulmonary (bronchospasm) and the hematopoetic systems (agranulocytosis) are described. Recommendations for the clinical use of non-opioid analgesics for perioperative pain therapy are given. [ABSTRACT FROM AUTHOR]

Abstract Background Leukocytes infiltrating inflamed tissue produce and release opioid peptides such as β-endorphin, which activate opioid receptors on peripheral terminals of sensory nerves resulting in analgesia. Gene therapy is an attractive strategy to enhance continuous production of endogenous opioids. However, classical viral and plasmid vectors for gene delivery are hampered by immunogenicity, recombination, oncogene activation, anti-bacterial antibody production or changes in physiological gene expression. Non-viral, non-plasmid minimalistic, immunologically defined gene expression (MIDGE) vectors may overcome these problems as they carry only elements needed for gene transfer. Here, we investigated the effects of a nuclear localization sequence (NLS)-coupled MIDGE encoding the β-endorphin precursor proopiomelanocortin (POMC) on complete Freund's adjuvant-induced inflammatory pain in rats. Results POMC-MIDGE-NLS injected into inflamed paws appeared to be taken up by leukocytes resulting in higher concentrations of β-endorphin in these cells. POMC-MIDGE-NLS treatment reversed enhanced mechanical sensitivity compared with control MIDGE-NLS. However, both effects were moderate, not always statistically significant or directly correlated with each other. Also, the anti-hyperalgesic actions could not be increased by enhancing β-endorphin secretion or by modifying POMC-MIDGE-NLS to code for multiple copies of β-endorphin. Conclusion Although MIDGE vectors circumvent side-effects associated with classical viral and plasmid vectors, the current POMC-MIDGE-NLS did not result in reliable analgesic effectiveness in our pain model. This was possibly associated with insufficient and variable efficacy in transfection and/or β-endorphin production. Our data point at the importance of the reproducibility of gene therapy strategies for the control of chronic pain.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare, predominantly drug-induced, acute life-threatening diseases of skin and mucosae. SJS and TEN are nowadays considered as variants of one disease entity with varying degrees of severity called epidermal necrolysis (EN). EN is associated with high morbidity and mortality and constitutes a major disease burden for affected patients. The guideline "Diagnosis and treatment of epidermal necrolysis (Stevens-Johnson syndrome and toxic epidermal necrolysis)" was developed under systematic consideration of existing scientific literature and in a formal consensus process according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF) to establish an evidence-based framework to support clinical decision-making. The interdisciplinary guideline commission consisted of representatives from various specialist societies and of patient representatives. The guideline is aimed at specialists in the fields of dermatology, ophthalmology, plastic surgery, intensive care, and pediatrics in hospitals and offices, as well as other medical specialties involved in the diagnosis and treatment of EN. The guideline is also aimed at patients, their relatives, insurance funds, and policymakers. The second part is concerned with the topics of supportive therapy in the acute phase of EN and outpatient follow-up treatment., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare, predominantly drug-induced, acute, life-threatening diseases of skin and mucosae. SJS and TEN are nowadays considered variants of one disease entity with varying degrees of severity called epidermal necrolysis (EN). EN is associated with high morbidity and mortality and constitutes a major disease burden for affected patients. The guideline "Diagnosis and treatment of epidermal necrolysis (Stevens-Johnson syndrome and toxic epidermal necrolysis)" was developed under systematic consideration of existing scientific literature and in a formal consensus process according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF) to establish an evidence-based framework to support clinical decision-making. The interdisciplinary guideline commission consisted of representatives from various specialist societies and patient representatives. The guideline is aimed at specialists in the fields of dermatology, ophthalmology, plastic surgery, intensive care, and pediatrics in hospitals and offices, as well as other medical speciallved in the diagnosis and treatment of EN. The guideline is also aimed at patients, their relatives, insurance funds, and policymakers. This first part focuses on the diagnostic aspects, the initial management as well as the immunomodulating systemic therapy., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Competing Interests: CS has received consulting fees from Algiax, Bayer, Grifols, Immunic, Merz, Roche, and Takeda Pharmaceuticals; and has given educational talks for Teva, CSL Behring, Grifols, GlaxoSmithKline, Takeda Phrarmaceuticals, Pfizer, Amicus, and Alnylam. HR has received consulting fees from Agiax and Orion; and has given a lecture for Grünenthal. Both authors are supported by Deutsche Forschungsgemeinschaft (German Research Foundation; KFO5001).

Spatial Transcriptomics (ST), coined as the term for parallel RNA-Seq on cell populations ordered spatially on a histological tissue section, has recently become increasingly popular, especially in experiments where microfluidics-based single-cell sequencing fails, such as assays on neurons. ST platforms, like the 10x Visium technology investigated herein, therefore produce in a single experiment simultaneously thousands of RNA readouts, captured by an array of micrometer scale spots under the histological section. Therefore, a central challenge of analyzing ST experiments consists of analyzing the gene expression morphology of all spots to delineate clusters of similar cell mixtures, which are then compared to each other to identify up- or down-regulated marker genes. Moreover, another level of complexity in ST experiments, compared to traditional RNA-Seq, is imposed by staining the tissue section with protein markers of cells or cell components to identify spots providing relevant information afterward. The corresponding microscopy images need to be analyzed in addition to the RNA-Seq read mappings on the reference genome and transcriptome sequences. Focusing on the software suite provided by the Visium platform manufacturer, we break down the ST analysis pipeline into its four essential steps-the image analysis, the read alignment, the gene quantification, and the spot clustering-and compare results obtained when using reads from different subsets of spots and/or when employing alternative genome or transcriptome references. Our comparative analyses demonstrate the impact of spot selection and the choice of genome/transcriptome references on the analysis results when employing the manufacturer's pipeline., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Bortezomib (BTZ) is a selective and reversible proteasome inhibitor and first line treatment for multiple myeloma (MM). One of the side effects is BTZ-induced peripheral neuropathy (BIPN). Until now there is no biomarker which can predict this side effect and its severity. Neurofilament light chain (NfL) is a neuron specific cytoskeletal protein, of which higher levels can be detected in peripheral blood in case of axon damage. In this study, we aimed to evaluate the relationship between NfL serum levels and characteristics of BIPN., Methods: We performed a first interim analysis of a monocentric, non-randomized, observational clinical trial including 70 patients (DRKS00025422) diagnosed with MM in the inclusion period of June 2021 until March 2022. Two groups of patients-one with ongoing BTZ treatment at the time of recruiting, and one with BTZ treatment in the past-were compared to controls. NfL in serum was analyzed via the ELLA™ device., Results: Both patients with previous and ongoing BTZ treatment had higher serum NfL levels than controls, and patients with ongoing BTZ treatment had higher NfL levels than patients with BTZ treatment in the past. Serum NfL levels correlated with electrophysiological measures of axonal damage in the group with ongoing BTZ treatment., Conclusion: Elevated NfL levels indicate acute axonal damage under BTZ in MM patients., (© 2023. The Author(s).)

Introduction: In patients with peripheral neuropathies (PNP), neuropathic pain is present in 50% of the cases, independent of the etiology. The pathophysiology of pain is poorly understood, and inflammatory processes have been found to be involved in neuro-degeneration, -regeneration and pain. While previous studies have found a local upregulation of inflammatory mediators in patients with PNP, there is a high variability described in the cytokines present systemically in sera and cerebrospinal fluid (CSF). We hypothesized that the development of PNP and neuropathic pain is associated with enhanced systemic inflammation., Methods: To test our hypothesis, we performed a comprehensive analysis of the protein, lipid and gene expression of different pro- and anti-inflammatory markers in blood and CSF from patients with PNP and controls., Results: While we found differences between PNP and controls in specific cytokines or lipids, such as CCL2 or oleoylcarnitine, PNP patients and controls did not present major differences in systemic inflammatory markers in general. IL-10 and CCL2 levels were related to measures of axonal damage and neuropathic pain. Lastly, we describe a strong interaction between inflammation and neurodegeneration at the nerve roots in a specific subgroup of PNP patients with blood-CSF barrier dysfunction., Conclusion: In patients with PNP systemic inflammatory, markers in blood or CSF do not differ from controls in general, but specific cytokines or lipids do. Our findings further highlight the importance of CSF analysis in patients with peripheral neuropathies., Competing Interests: Author CS has been a consultant for Merz, Omega, Ipsen and Bayer on the subject of neuropathic pain. She has given educational talks for GSK and Pfizer. Authors KS and AN are employed by Bionorica research GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 García-Fernández, Höfflin, Rausch, Strommer, Neumann, Cebulla, Reinhold, Rittner, Üçeyler and Sommer.)

In a previous study, we demonstrated that the serum peptidase system might be less efficient in complex regional pain syndrome (CRPS). Since the neuropeptide substanc P (SP) contributes to inflammation in CRPS, we now investigated the metabolism of SP in CRPS specifically. An SP metabolism assay was performed in 24 CRPS patients, which constitute a subgroup of our previous investigation on BK degradation. In addition, we included 26 healthy controls (24 newly recruited plus 2 from our previous investigation), and 13 patients after limb trauma, who did not fulfil the CRPS diagnostic criteria (trauma controls, TC) were included. We adapted a thin layer chromatography assay (TLC) to quantify SP disappearance after incubation with 7.5 µL of serum. These results were compared with bradykinin (BK) metabolization to BK1-8 and BK1-5 fragments from our previous study. In addition, TC were clinically and quantitative sensory testing (QST) phenotyped; the phenotyping of CRPS patients was retrieved from our existing database. SP metabolism was less efficient in CRPS and TC patient serum vs human control (HC) serum (P < .03) suggesting reduced activity of the neutral endopeptidase (NEP) and/or the angiotensin converting enzyme (ACE). Together with the decreased occurrence of BK1-5 fragment in CRPS and TC, this suggests a reduced activation of the angiotensin converting enzyme (ACE). There was no clear clinical phenotype related to impaired SP degradation; duration of disease and gender were also not associated. Most importantly, results in TC did not differ from CRPS. Collectively, our current and previous experimental results suggest that limb trauma reduces serum peptidase metabolism of SP ex vivo, specifically serum ACE activity. However, this finding is not CRPS-specific and seems to be rather a long-term consequence of the trauma itself. PERSPECTIVE: The experimental data from this study further support the hypothesis that impaired metabolism of inflammatory peptides potentially contribute to the development of posttraumatic pain in CRPS or limb trauma patients., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

How homeostatic ER calcium fluxes shape cellular calcium signals is still poorly understood. Here we used dual-color calcium imaging (ER-cytosol) and transcriptome analysis to link candidates of the calcium toolkit of astrocytes with homeostatic calcium signals. We found molecular and pharmacological evidence that P/Q-type channel Cacna1a contributes to depolarization-dependent calcium entry in astrocytes. For stimulated ER calcium release, the cells express the phospholipase Cb3, IP 3 receptors Itpr1 and Itpr2, but no ryanodine receptors (Ryr1-3). After IP 3 -induced calcium release, Stim1/2 - Orai1/2/3 most likely mediate SOCE. The Serca2 (Atp2a2) is the candidate for refilling of the ER calcium store. The cells highly express adenosine receptor Adora1a for IP 3 -induced calcium release. Accordingly, adenosine induces fast ER calcium release and subsequent ER calcium oscillations. After stimulation, calcium refilling of the ER depends on extracellular calcium. In response to SOCE, astrocytes show calcium-induced calcium release, notably even after ER calcium was depleted by extracellular calcium removal in unstimulated cells. In contrast, spontaneous ER-cytosol calcium oscillations were not fully dependent on extracellular calcium, as ER calcium oscillations could persist over minutes in calcium-free solution. Additionally, cell-autonomous calcium oscillations show a second-long spatial and temporal delay in the signal dynamics of ER and cytosolic calcium. Our data reveal a rather strong contribution of homeostatic calcium fluxes in shaping IP 3 -induced and calcium-induced calcium release as well as spatiotemporal components of intracellular calcium oscillations., (Copyright © 2021. Published by Elsevier Ltd.)

Future or reality? Treating acute and chronic pain is a part of the daily routine of clinical anesthesiologists. Commonly used analgesics have unwanted side effects or may even be insufficient as in chronic pain treatment. Virtual Reality (VR) could be a promising new approach which offers noninvasive therapy options for the treatment of pain. In case of the opioid misuse the adjunctive treatment is mandatory. Various phenomena occur in VR, such as immersion, presence, embodiment and Proteus effect, which can cause a change in body awareness and behavior. Experimental and clinical studies already yielded some promising results for analgesic effects for acute and chronic pain conditions using VR simulation. Potential analgesic mechanisms include distraction, cognitive behavioral change, and distance from reality, leading to neurophysiological changes at the cortical level. The quality of the virtual environment, personalized avatars, as well as the possibility of interaction and multisensory input can increase immersion, which leads to a state of presence, and thus effective VR. VR can be used as an immersive extension or alternative to mirror therapy, especially for pain disorders such as complex regional pain syndrome (CRPS) or phantom limb pain. VR can be supplemented by gamification, which increases intrinsic motivation, well-being and adherence to therapy. In summary, VR could be an effective and realistic therapy option for acute and chronic pain in clinical and home settings in the future., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: nein; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: nein; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein. Erklärung zu nichtfinanziellen Interessen Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Introduction: The B-cell chemoattractant CXCL13 has been suggested as a cerebrospinal fluid (CSF) biomarker for Lyme neuroborreliosis (LNB). Our aim was to substantiate the value of CXCL13 in a large unselected cohort and determine a practical cut-off value to diagnose LNB., Methods: We retrospectively studied clinical and CSF data of consecutive patients who underwent CSF CXCL13 testing over a period of three years (February 2015 to January 2018) at our academic teaching hospital. Patients were classified into 12 groups according to their final diagnosis. To diagnose LNB (definite or probable/possible), definitions of the respective guideline of the German Neurological Society were applied., Results: Of 1410 patients, 29 were diagnosed with definite LNB and 9 with probable/possible LNB. Median CXCL13 levels were highly elevated in both LNB groups (554 pg/mL and 649 pg/mL, respectively) and the group with bacterial/fungal CNS infections (410 pg/mL; n = 6), while all other groups had markedly lower median CXCL13 levels (p < .001). For definite LNB, the best CXCL13 test cut-off was 55.5 pg/mL with a sensitivity of 96.6% (95% confidence interval, CI, 80.4%-99.8%) and a specificity of 94.9% (95% CI 93.5%-95.9%). All patients with LNB showed clinical improvement after antibiotic treatment., Conclusion: In this large monocentric cohort, CSF CXCL13 was found to be a highly sensitive and useful marker for LNB. In conditions with low index of suspicion for LNB, CXCL13 testing may be unwarranted. A review of the literature on the sensitivity and specificity of CSF CXCL13 in the differential of LNB is provided., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A variety of barriers ensures the protection of the peripheral nervous system from noxious blood-borne or surrounding stimuli. In this review, anatomy and functioning of the blood nerve barrier (BNB) and the blood DRG barrier (BDB) will be presented and key tight junction proteins described: ZO-1, claudin-1, -3, -5, -11, -12, -19, occludin, and tricellulin. Different diseases can lead to or be accompanied by nerve barrier disruption; impairment of nerve barriers in turn worsens pathology. Peripheral nerve injury, diabetic neuropathy and inflammatory polyneuropathy cause an increased permeability of BNB and BDB. Knowledge and understanding of these mechanisms might ultimately lead to the invention of drugs to control barrier function and help ameliorating neurological diseases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Complex regional pain syndrome (CRPS) develops after fracture. The acute CRPS phenotype resembles exaggerated inflammation, which is explained by local and systemic activation of a proinflammatory network including peptides and cytokines. Epidemiologic data suggest that inactivation of the peptidase angiotensin-converting enzyme in patients treated for hypertension increases the odds to develop CRPS. This hint leads us to investigate the serum protease network activity in patients with CRPS vs respective controls. For this purpose, we developed a dabsyl-bradykinin (DBK)-based assay and used it to investigate patients with CRPS, as well as healthy and pain (painful diabetic neuropathy [dPNP]) controls. The major result is that the degradation of DBK to fragments 1-8 and 1-5 in healthy control and dPNP is shifted to higher values for DBK1-8 and lower values for DBK1-5 at 1 hour of incubation in patients with CRPS. Using this novel reporter peptide assay, we have been able to show that the resolving protease network for mediators such as BK might be different in patients with CRPS; having a look at the clinical signs, which resemble inflammation, this resolving protease network is probably less effective in CRPS.

Background: Pathological pain conditions can be triggered after peripheral nerve injury and/or inflammation. It is a major clinical problem that is poorly treated with available therapeutics. Curcumin is a phenolic compound derived from Curcuma longa, being widely used for its antioxidant, anti-inflammatory and immunomodulatory effects., Purpose: This review systematically summarized updated information on the traditional uses of curcumin in order to explore antinociceptive effects in pathological pain and evaluate future therapeutic opportunities clinically. Moreover, some structure-activity relationships would greatly enrich the opportunity of finding new and promising lead compounds and promote the reasonable development of curcumin., Methods: PubMed were searched and the literature from the year 1976 to January 2018 was retrieved using keywords pain and curcumin., Results: This review systematically summarized updated information on the traditional uses, chemical constituents and bioactivities of curcumin, and highlights the recent development of the mechanisms of curcumin in the pathological pain by sciatic nerve injury, spinal cord injury, diabetic neuropathy, alcoholic neuropathy, chemotherapy induced peripheral neuroinflammtion, complete Freund's adjuvant (CFA) injection or carrageenan injection. Importantly, the clinical studies provide a compelling justification for its use as a dietary adjunct for pain relief. And we also present multiple approaches to improve bioavailability of curcumin for the treatment of pathological pain., Conclusion: This review focuses on pre-clinical and clinical studies in the treatment of pathological pain. Although the mechanisms of pain mitigating effects are not very clear, there is compelling evidence proved that curcumin plays an essential role. However, further high-quality clinical studies should be undertaken to establish the clinical effectiveness of curcumin in patients suffering from pathological pain. Potential methods of increase the water solubility and bioavailability of curcumin still need to be studied. These approaches will help in establishing it as remedy for pathological pain., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Cancer-induced bone pain (CIBP) is a frequent complication in patients suffering from bone metastases. Previous studies have demonstrated a pivotal role of reactive oxygen species (ROS) in inflammatory and neuropathic pain, and ROS scavengers exhibited potent antinociceptive effect. However, the role of spinal ROS remains unclear. In this study, we investigated the analgesic effect of two ROS scavengers in a well-established CIBP model. Our results found that intraperitoneal injection of N-tert-Butyl-α-phenylnitrone (PBN, 50 and 100mg/kg) and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol, 100 and 200mg/kg) significantly suppressed the established mechanical allodynia in CIBP rats. Moreover, repeated injection of PBN and Tempol showed cumulative analgesic effect without tolerance. However, early treatment with PBN and Tempol failed to prevent the development of CIBP. Naive rats received repetitive injection of PBN and Tempol showed no significant change regarding the nociceptive responses. Finally, PBN and Tempol treatment notably suppressed the activation of spinal microglia in CIBP rats. In conclusion, ROS scavengers attenuated established CIBP by suppressing the activation of microglia in the spinal cord., (Copyright © 2017. Published by Elsevier B.V.)

Cancer-induced bone pain (CIBP) remains a major challenge in advanced cancer patients because of our lack of understanding of its mechanisms. Previous studies have shown the vital role of γ-aminobutyric acid B receptors (GABABRs) in regulating nociception and various neuropathic pain models have shown diminished activity of GABABRs. However, the role of spinal GABABRs in CIBP remains largely unknown. In this study, we investigated the specific cellular mechanisms of GABABRs in the development and maintenance of CIBP in rats. Our behavioral results show that acute as well as chronic intrathecal treatment with baclofen, a GABABR agonist, significantly attenuated CIBP-induced mechanical allodynia and ambulatory pain. The expression levels of GABABRs were significantly decreased in a time-dependent manner and colocalized mostly with neurons and a minority with astrocytes and microglia. Chronic treatment with baclofen restored the expression of GABABRs and markedly inhibited the activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase and the cAMP-response element-binding protein signaling pathway., Perspective: Our findings provide, to our knowledge, the first evidence that downregulation of GABABRs contribute to the development and maintenance of CIBP and restored diminished GABABRs attenuate CIBP-induced pain behaviors at least partially by inhibiting the protein kinase/cAMP-response element-binding protein signaling pathway. Therefore, spinal GABABR may become a potential therapeutic target for the management of CIBP., (Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.)

The peripheral (PNS) and central nervous system (CNS) are delicate structures, highly sensitive to homeostatic changes-and crucial for basic vital functions. Thus, a selection of barriers ensures the protection of the nervous system from noxious blood-borne or surrounding stimuli. In this chapter, anatomy and functioning of the blood-nerve (BNB), the blood-brain (BBB), and the blood-spinal cord barriers (BSCB) are presented and the key tight junction (TJ) proteins described: claudin-1, claudin-3, claudin-5, claudin-11, claudin-12, claudin-19, occludin, Zona occludens-1 (ZO-1), and tricellulin are by now identified as relevant for nerval barriers. Different diseases can lead to or be accompanied by neural barrier disruption, and impairment of these barriers worsens pathology. Peripheral nerve injury and inflammatory polyneuropathy cause an increased permeability of BNB as well as BSCB, while, e.g., diseases of the CNS such as amyotrophic lateral sclerosis, multiple sclerosis, spinal cord injury, or Alzheimer's disease can progress and worsen through barrier dysfunction. Moreover, the complex role and regulation of the BBB after ischemic stroke is described. On the other side, PNS and CNS barriers hamper the delivery of drugs in diseases when the barrier is intact, e.g., in certain neurodegenerative diseases or inflammatory pain. Understanding of the barrier - regulating processes has already lead to the discovery of new molecules as drug enhancers. In summary, the knowledge of all of these mechanisms might ultimately lead to the invention of drugs to control barrier function to help ameliorating or curing neurological diseases.

Fibromyalgia syndrome (FMS) is a chronic widespread pain condition probably comprising subgroups with different underlying pathomechanisms. There is increasing evidence for small nerve fiber impairment in subgroups of patients with FMS. MicroRNAs (miRNAs) regulate molecular factors determining nerve de- and re-generation. We investigated whether systemic and cutaneous miRNA expression in patients with FMS is related to small nerve fiber pathology. We confirmed previous findings of disturbed small fiber function and reduced intraepidermal nerve fiber density in subgroups of patients with FMS. We found 51 aberrantly expressed miRNAs in white blood cells of patients with FMS, of which miR-let-7d correlated with reduced small nerve fiber density in patients with FMS. Furthermore, we demonstrated miR-let-7d and its downstream target insulin-like growth factor-1 receptor as being aberrantly expressed in skin of patients with FMS with small nerve fiber impairment. Our study gives further evidence of small nerve fiber pathology in FMS subgroups and provides a missing link in the pathomechanism that may lead to small fiber loss in subgroups of patients with FMS.

Unlabelled: The paracellular cleft within epithelia/endothelia is sealed by tight junction (TJ) proteins. Their extracellular loops (ECLs) are assumed to control paracellular permeability and are targets of pathogenes. We demonstrated that claudin-1 is crucial for paracellular tightening. Its ECL1 is essential for the sealing and contains two cysteines conserved throughout all claudins., Aims: We prove the hypothesis that this cysteine motif forms a redox-sensitive intramolecular disulfide bridge and, hence, the claudin-1-ECL1 constitutes a functional structure which is associated to ECLs of this and other TJ proteins., Results: The structure and function of claudin-1-ECL1 was elucidated by investigating sequences of this ECL as synthetic peptides, C1C2, and as recombinant proteins, and exhibited a β-sheet binding surface flanked by an α-helix. These sequences bound to different claudins, their ECL1, and peptides with nanomolar binding constants. C-terminally truncated C1C2 (-4aaC) opened cellular barriers and the perineurium. Recombinant ECL1 formed oligomers, and bound to claudin-1 expressing cells. Oligomerization and claudin association were abolished by reducing agents, indicating intraloop disulfide bridging and redox sensitivity., Innovation: The structural and functional model based on our in vitro and in vivo investigations suggested that claudin-1-ECL1 constitutes a functional and ECL-binding β-sheet, stabilized by a shielded and redox-sensitive disulfide bond., Conclusion: Since the β-sheet represents a consensus sequence of claudins and further junctional proteins, a general structural feature is implied. Therefore, our model is of general relevance for the TJ assembly in normal and pathological conditions. C1C2-4aaC is a new drug enhancer that is used to improve pharmacological treatment through tissue barriers.

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-1β 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-1β concentration, adhesion molecule expression and leukocyte-adhesion with subsequent endothelial injury. A potential mechanism is the reduction in the plasma concentration of epinephrine.

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.

The paracellular flux of solutes through tissue barriers is limited by transmembrane tight junction proteins. Within the family of tight junction proteins, claudin-1 seems to be a key protein for tightness formation and integrity. In the peripheral nervous system, the nerve fibers are surrounded with a barrier formed by the perineurium which expresses claudin-1. To enhance the access of hydrophilic pharmaceutical agents via the paracellular route, a claudin-1 specific modulator was developed. For this purpose, we designed and investigated the claudin-1 derived peptide C1C2. It transiently increased the paracellular permeability for ions and high and low molecular weight compounds through a cellular barrier model. Structural studies revealed a β-sheet potential for the functionality of the peptide. Perineurial injection of C1C2 in rats facilitated the effect of hydrophilic antinociceptive agents and raised mechanical nociceptive thresholds. The mechanism is related to the internalization of C1C2 and to a vesicle-like distribution within the cells. The peptide mainly colocalized with intracellular claudin-1. C1C2 decreased membrane-localized claudin-1 of cells in culture and in vivo in the perineurium of rats after perineurial injection. In conclusion, a novel tool was developed to improve the delivery of pharmaceutical agents through the perineurial barrier by transient modulation of claudin-1.

Patients used to opioids belong to 2 groups: patients under opioid therapy due to tumor pain or chronic non malignant pain and, second, opioid addicts with current uncontrolled abuse, under substitution therapy or former opioid addicts ("clean"). Perioperatively these patients are difficult to manage because of the complex medical as well as psychosocial factors. Despite these problems, these patients have a right to receive sufficient perioperative pain therapy and this should not be withheld. Due to the lack of controlled studies this review summarizes standardized examples and alternatives in the acute pain treatment of patients using opioids. Early interdisciplinary cooperation, prevention of withdrawal through substitution of opioids and alternative treatment strategies like regional analgesia or ketamine as well as carefully titration of opioids are the essential components of the treatment of these patients. Furthermore, these patients require a clear and empathic guidance by medical and nursing staff., (© Georg Thieme Verlag Stuttgart · New York.)

In complete Freund's adjuvants (CFA) inflammation opioid containing neutrophils release opioid peptides upon stimulation and mediate peripheral analgesia. Neutrophil migration is regulated partially by chemokines, but other mediators e.g. formyl peptides could also contribute. In vitro, formyl peptides but not Mycobacterium butyricum (CFA component) induced migration of neutrophils. In contrast, local formyl peptide injection did not induce leukocyte recruitment in vivo due to insufficient up-regulation of adhesion molecule expression. Furthermore, leukocyte recruitment and peripheral opioid-mediated analgesia were unaffected by systemic formyl peptide receptor blockade in CFA inflammation. Thus, while formyl peptides do not regulate migration they directly stimulate opioid peptide release., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Inflammatory pain can be controlled by intraplantar opioid injection or by secretion of endogenous opioid peptides from leukocytes in inflamed rat paws. Antinociception requires binding of opioid peptides to opioid receptors on peripheral sensory nerve terminals. In the absence of inflammation, hydrophilic opioid peptides do not penetrate the perineurial barrier and, thus, do not elicit antinociception. This study was designed to examine the conditions under which endogenous, neutrophil-derived hydrophilic opioid peptides (i.e. Met-Enkephalin and beta-endorphin) can raise nociceptive thresholds in noninflamed tissue in rats. Intraplantar injection of the chemokine CXCL2/3 (macrophage inflammatory protein-2) induced selective neutrophil recruitment without overt signs of inflammation or changes in mechanical nociceptive thresholds (paw pressure threshold). Following intraplantar injection of hypertonic saline, the perineurial barrier was permeable for hours and intraplantar injection of opioid peptides increased mechanical nociceptive thresholds. While formyl-Met-Leu-Phe (fMLP) triggered opioid peptide release from neutrophils in vitro, nociceptive thresholds were unchanged in vivo. In vitro, hypertonicity interfered with fMLP-induced p38 mitogen activated kinase (MAPK) phosphorylation and opioid peptide release from neutrophils. These inhibitory effects were fully reversible by washout. In vivo, return to normotonicity occurred within 30min while the perineurium remained permeable for hours. Under these conditions, fMLP triggered MAPK phosphorylation and induced opioid peptide-mediated increases in nociceptive thresholds in the noninflamed paw. Taken together, antinociception mediated by endogenous opioids in noninflamed tissue has two important requirements: (i) opening of the perineurial barrier for opioid peptide access and (ii) opioid peptide release from neutrophils involving p38 MAPK.

Chemokines are chemotactic mediators controlling cell trafficking under physiological and pathological conditions. Chemokines are not only important under various inflammatory conditions but also play a role in pain and analgesia. While many studies examined the hyperalgesic action of chemokines, recent evidence also points towards antinociceptive effects of chemokines. Such effects are indirect by recruitment of opioid containing leukocytes and stimulation of release of opioid peptides. Opioid peptides then bind to opioid receptors on peripheral sensory neurons eliciting potent analgesia. This review focuses on the analgesic role of chemokines in the periphery under inflammatory and non-inflammatory conditions.