interleukin-8 and Pain

Inflammatory biomarkers are potentially useful targets for pulpal diagnostic tests that can identify pulp status and predict vital pulp treatment (VPT) outcome, however, their accuracy is unknown.. (1) Calculate sensitivity, specificity and diagnostic odds ratio (DOR) of previously investigated pulpitic biomarkers; (2) Determine if biomarker levels discriminate between clinical diagnoses of pulpitis based on the presence or absence of spontaneous pain (3) Evaluate if biomarker level can predict VPT outcome.. Searches: PubMed/MEDLINE, Ovid SP, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, Embase, Web of Science and Scopus in May 2023.. prospective and retrospective observational studies and randomized trials. Participants were humans with vital permanent teeth and a well-defined pulpal diagnosis.. deciduous teeth, in vitro and animal studies. Risk of bias was assessed with modified-Downs and Black quality assessment checklist. Meta-analysis was performed using bivariate random effect model in Meta-DiSc 2.0 and RevMan and the quality of the evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation.. Fifty-six studies were selected, reporting >70 individual biomolecules investigating pulpal health and disease at the gene and protein level. Most studies were of low and fair quality. Among the biomolecules investigated, IL-8 and IL-6 demonstrated a level of diagnostic accuracy with high sensitivity, specificity and DOR to discriminate between healthy pulps and those exhibiting spontaneous pain suggestive of IRP (low-certainty evidence). However, none was shown to have high DOR and the ability to discriminate between pulpitic states (very low certainty evidence). Limited data suggests high levels of matrix metalloproteinase 9 correlate with poorer outcomes of full pulpotomy.. The inability of identified molecular inflammatory markers to discriminate between dental pulps with spontaneous and non-spontaneous pain should shift the focus to improved study quality or the pursuit of other molecules potentially associated with healing and repair.. Low-quality evidence suggests IL-8 and IL-6 demonstrated level of diagnostic accuracy to discriminate between healthy pulps and those exhibiting spontaneous pain. There is a need for standardized biomarker diagnostic and prognostic studies focusing on solutions that can accurately determine the degree of pulp inflammation.. PROSPERO CRD42021259305.

Topics: Biomarkers; Humans; Interleukin-6; Interleukin-8; Pain; Prospective Studies; Pulpitis; Retrospective Studies

Topics: Acquired Immunodeficiency Syndrome; Animals; Cell Movement; Chemokine CCL2; Chemokine CCL4; Chemokine CCL5; Chemokines; Dendritic Cells; Drug Design; Fibrosis; Humans; Inflammation; Interleukin-8; Lymphatic System; Macrophage Inflammatory Proteins; Pain; Receptors, Chemokine; Th1 Cells; Th2 Cells

Although the exact etiology of patient dissatisfaction in total knee arthroplasty (TKA) is unclear, the inflammatory response precipitated by surgery may be implicated. Robotic TKA has been shown to result in reduced bone and soft-tissue trauma. The objectives of this study were to compare the inflammatory response in conventional jig-based TKA versus robotic-arm-assisted TKA and to examine the relationship with early functional outcomes.. This prospective randomized controlled trial included 15 patients with symptomatic knee osteoarthritis undergoing conventional TKA and 15 undergoing robotic-arm-assisted TKA. Blood samples were collected for up to 28 days postoperatively, and predefined markers of systemic inflammation were measured in serum. The local inflammatory response was assessed by analyzing samples from the intra-articular drain fluid at 6 and 24 hours. Relationships with early functional outcomes were evaluated using the Spearman rank correlation coefficient.. Patients in the robotic TKA group demonstrated lower levels of interleukin (IL)-6 in the drain fluid at 6 hours (798.54 pg/mL versus 5,699.2 pg/mL, p = 0.026) and 24 hours and IL-8 at 6 hours. Robotic TKA was associated with lower pain scores on postoperative days 1, 2, and 7. Patient-reported outcome measures were comparable between the 2 groups at 2 years. Significant correlations were observed between all serum markers except IL-1b and self-reported pain on postoperative day 7; between drain IL-8 levels and pain on postoperative days 1 (r = 0.458), 2, and 7; and between drain IL-6, IL-8, and tumor necrosis factor-alpha levels at 6 hours and knee flexion or extension.. Robotic-arm-assisted TKA was associated with a reduction in the early postoperative local inflammatory response. We also found a moderate relationship between the inflammatory responses and self-reported pain, knee flexion, and knee extension. Further validation of these findings on a larger scale and using longer-term outcomes will be key to developing the optimal TKA procedure.. Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Topics: Arm; Arthroplasty, Replacement, Knee; Humans; Interleukin-8; Knee Joint; Osteoarthritis, Knee; Pain; Prospective Studies; Robotic Surgical Procedures

Regarding the use of intravenous lidocaine in fibromyalgia, there are no well-controlled studies. This study aimed to evaluate the effect of intravenous lidocaine on pain intensity, clinical manifestations and plasma levels of interleukin (IL)-1, IL-6, and IL-8 in fibromyalgia patients.. In a randomized double-blind study, group 1 patients received 240 mg of lidocaine in 125 mL of saline solution, while group 2 patients received 125 mL of saline, both once a week for 4 weeks (T1, T2, T3 and T4). All patients received amitriptyline. The following were assessed: pain intensity before treatment (T0) and at 1, 2, 3, 4 and 8 weeks after treatment; clinical manifestations; the fibromyalgia impact questionnaire (FIQ) before and at 4 and 8 weeks after; the levels of IL 1, 6 and 8 before and at 4 and 8 weeks after treatment.. Lower pain intensity was observed in the lidocaine group at T2, with no difference at the other time points. There was a reduction in pain intensity in both groups. The use of paracetamol and tramadol and plasma levels of IL-1, IL-6 and IL-8 did not differ between the groups. Clinical manifestations and side effects did not differ between groups.. The combination of 240 mg of intravenous lidocaine (once a week for 4 weeks) with 25 mg of amitriptyline for 8 weeks had no meaningful impact in fibromyalgia patients.

Topics: Administration, Intravenous; Adult; Amitriptyline; Anesthetics, Local; Biomarkers; Brazil; Double-Blind Method; Drug Therapy, Combination; Female; Fibromyalgia; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Lidocaine; Male; Middle Aged; Pain; Pain Measurement; Prospective Studies; Surveys and Questionnaires; Time Factors; Treatment Outcome

Systemic inflammation can induce pain hypersensitivity in animal and human experimental models, and has been proposed to be central in clinical pain conditions. Women are overrepresented in many chronic pain conditions, but experimental studies on sex differences in pain regulation during systemic inflammation are still scarce. In two randomized and double blind placebo controlled experiments, we used low doses of lipopolysaccharide (LPS) as an experimental model of systemic inflammation. The first study employed 0.8ng/kg LPS in a within-subject design of 8 individuals (1 woman), and the second study 0.6ng/kg LPS in a between-subject design of 52 participants (29 women). We investigated the effect on (a) pressure, heat, and cold pain thresholds, (b) suprathreshold noxious heat and cold sensitivity, and (c) conditioned pain modulation (CPM), and differences between men and women. LPS induced significantly lower pressure pain thresholds as compared to placebo (mean change with the 0.8ng/kg dose being -64±30kPa P=.04; with the 0.6ng/kg dose -58±55kPa, P<.01, compared to before injection), whereas heat and cold pain thresholds remained unaffected (P's>.70). Suprathreshold noxious pain was not affected by LPS in men (P's⩾.15). However, LPS made women rated suprathreshold noxious heat stimuli as more painful (P=.01), and showed a tendency to rate noxious cold pain as more painful (P=.06) as compared to placebo. Furthermore, LPS impaired conditioned pain modulation, a measure of endogenous pain inhibition, but this effect was also restricted to women (P<.01, for men P=.27). Pain sensitivity correlated positively with plasma IL-6 and IL-8 levels. The results show that inflammation more strongly affects deep pain, rather than cutaneous pain, and suggest that women's pain perception and modulation is more sensitive to immune activation than men's.

Topics: Adult; Cold Temperature; Double-Blind Method; Endotoxemia; Female; Hot Temperature; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Pain; Pain Measurement; Pain Threshold; Pressure; Sex Characteristics; Young Adult

Repeated invasive procedures occur routinely in neonates who require intensive care, causing pain at a time when it is developmentally unexpected. Multiple lines of evidence suggest that repeated and prolonged pain exposure alters their subsequent pain processing, long-term development, and behaviour. Primary outcome of this study was to evaluate the reduction of procedural pain induced by "heel-lances" in preterm newborns with three different treatment [administration of fentanyl (FE, 1-2 μg/kg), facilitated tucking (FT), sensorial saturation (SS)]. Secondary outcome was the measurement of the levels of cytokines as markers of stress correlated to pain. A prospective randomized controlled trial (RCT) comparing three different pharmacological or non-pharmacological treatments was performed involving 150 preterm newborn (gestational age 27-32 weeks). No other analgesic treatment was performed during the study. CRIES score was used to evaluate the procedural pain. The results showed that the reduction in the pain score was greater in FE and SS groups than FS group. The differences were statistically significant (p < 0.01). The levels of IL-6, IL-8, and TNF-α were higher in the FT individuals than in the FE or SS-treated infants at 1 day (p < 0.01), at 3 days (p < 0.01), and at 7 days (p < 0.01) of life.. The findings of this study suggest that FE and SS provide a superior analgesia in preterm neonates during procedural pain. In particular, sensorial saturation seems to be an important non-pharmacological alternative treatment to prevent and reduce the procedural pain in preterm newborn.

Topics: Analgesics, Opioid; Biomarkers; Blood Specimen Collection; Facilitated Tucking; Female; Fentanyl; Humans; Infant, Newborn; Infant, Premature; Injections, Intravenous; Interleukin-6; Interleukin-8; Male; Pain; Pain Management; Pain Measurement; Physical Stimulation; Prospective Studies; Stress, Physiological; Treatment Outcome; Tumor Necrosis Factor-alpha

The purpose of this pragmatic preliminary analysis was to examine the effectiveness of a cocoa-based protein and carbohydrate prototype drink on skeletal muscle damage and perceived soreness after exhaustive exercise. A repeated-measures experimental design was used. Common biomarkers indicative of skeletal muscle damage included creatine kinase (CK), urinary isoprostanes and inflammatory markers (IL-6, IL-8, C-Reactive Protein [CRP]). Self-reported perception of postexercise soreness was also evaluated. Seven men participated in an exercise session consisting of a 30-minute run on a declined treadmill (-10% grade). Running speed was adjusted accordingly so that participants consistently maintained 75% maximal heart rate. Drinks were ingested immediately after exercise, 2 hours postexercise, and before bed. Blood draws were sampled 30, 60, 120, and 360 minutes postexercise; urine was collected 24 and 48 hours postexercise. A perceived soreness questionnaire was administered 24 and 48 hours postexercise. The test drink had no effect on IL-6, CK, IL-8, CRP, or urinary isoprostanes (p > 0.05). However, the drink decreased the change in perceived soreness from 24 to 48 hours (p = 0.03). Consuming the drink after exercise resulted in a mean change of 2.6 +/- 6 compared to 13.7 +/- 10 for the control. In summary, the drink was effective in decreasing the level of self-reported perceived soreness after exhaustive exercise.

Topics: Beverages; C-Reactive Protein; Cacao; Creatine Kinase; Dietary Carbohydrates; Exercise; Humans; Interleukin-6; Interleukin-8; Male; Muscle, Skeletal; Pain; Young Adult

Flu-like symptoms are common, early transient side effects of paclitaxel chemotherapy. We hypothesized that these symptoms may be due to release of inflammatory cytokines in response to treatment. The objective of this study was to assess changes in plasma levels of interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12, and TNF-alpha during chemotherapy and to correlate these changes with musculoskeletal symptoms.. Ninety patients with breast cancer were included; 70 patients received single agent paclitaxel either weekly or every 3 weeks and 20 received FAC (5-FU, doxorubicin, cyclophosphamide) chemotherapy. Fifteen healthy volunteers were included as controls. Cytokines and symptoms were measured before starting therapy, on day 3 and on the last day of one treatment cycle.. At baseline, all subjects had measurable levels of IL-8 but only 49% had IL-12, 45% had IL-10, 32% had IL-6, and 21% had IL-1beta or TNF-alpha in their plasma. There was no difference in baseline cytokine levels between cancer patients and the healthy volunteers. Schedule-dependent transient changes in the levels of 3 cytokines were observed in the paclitaxel treated patients. In the every 3-week paclitaxel group, IL-6 and IL-8 increased whereas in the weekly paclitaxel group IL-10 increased significantly compared to baseline. Fatigue and flu-like symptoms were also worse on day 3. In the weekly paclitaxel group, increase in IL-10 level correlated positively with joint pain (p=0.003). In the every 3-week paclitaxel group, increase in IL-8 level correlated positively with flu-like symptom (p=0.008). In the FAC-treated group and among the healthy volunteers none of these cytokines increased significantly.. Weekly paclitaxel induces transient increase in IL-10 levels whereas every 3-week higher dose treatments induce IL-8 and IL-6 in the plasma. These changes correlate with joint pain and flu-like symptoms.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Anxiety; Blood; Breast Neoplasms; Cyclophosphamide; Cytokines; Data Interpretation, Statistical; Doxorubicin; Fatigue; Female; Fluorouracil; Humans; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-6; Interleukin-8; Middle Aged; Nausea; Paclitaxel; Pain; Patient Selection; Quality of Life; Tumor Necrosis Factor-alpha

There is no effective treatment for intractable postherpetic neuralgia. Because there is evidence that postherpetic neuralgia has an inflammatory component, we assessed treatment with intrathecally administered methylprednisolone to reduce pain in patients with this disorder.. We enrolled 277 patients who had had intractable postherpetic neuralgia for at least one year, 270 of whom were followed for two years. The patients were randomly assigned to receive intrathecal methylprednisolone and lidocaine (3 ml of 3 percent lidocaine with 60 mg of methylprednisolone acetate, 89 patients), lidocaine alone (3 ml of 3 percent lidocaine, 91 patients), or no treatment (90 patients) once per week for up to four weeks. Each weekly dose was injected into the lumbar intrathecal space. Pain was evaluated before randomization, at the end of the treatment period, and then four weeks, one year, and two years later. Samples of cerebrospinal fluid were obtained for measurement of interleukin-8 before and at the end of the treatment period.. There was minimal change in the degree of pain in the lidocaine-only and control groups during and after the treatment period. In the methylprednisolone-lidocaine group, the intensity and area of pain decreased, and the use of the nonsteroidal antiinflammatory drug diclofenac declined by more than 70 percent four weeks after the end of treatment. No complications related to intrathecal methylprednisolone were observed. Before treatment, the concentrations of interleukin-8 in the cerebrospinal fluid were inversely related to the duration of neuralgia in all the patients (r=-0.49, P<0.001). In the patients who received methylprednisolone, interleukin-8 concentrations decreased by 50 percent, and this decrease correlated with the duration of neuralgia and with the extent of global pain relief (P<0.001 for both comparisons).. The results of this trial indicate that the intrathecal administration of methylprednisolone is an effective treatment for postherpetic neuralgia.

Topics: Aged; Anesthetics, Local; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Drug Therapy, Combination; Female; Herpes Zoster; Humans; Injections, Spinal; Interleukin-8; Lidocaine; Male; Methylprednisolone; Middle Aged; Neuralgia; Pain; Pain Measurement; Single-Blind Method

High-density lipoprotein (HDL) has been found to neutralize LPS activity in vitro and in animals in vivo. We sought to determine the effects of reconstituted HDL (rHDL) on LPS responsiveness in humans in a double-blind, randomized, placebo-controlled, cross-over study. rHDL, given as a 4-h infusion at 40 mg/kg starting 3.5 h before endotoxin challenge (4 ng/kg), reduced flu-like symptoms during endotoxemia, but did not influence the febrile response. rHDL potently reduced the endotoxin-induced release of TNF, IL-6, and IL-8, while only modestly attenuating the secretion of proinflammatory cytokine inhibitors IL-1ra, soluble TNF receptors and IL-10. In addition, rHDL attenuated LPS-induced changes in leukocyte counts and the enhanced expression of CD11b/CD18 on granulocytes. Importantly, rHDL infusion per se, before LPS administration, was associated with a downregulation of CD14, the main LPS receptor, on monocytes. This effect was biologically relevant, since monocytes isolated from rHDL-treated whole blood showed reduced expression of CD14 and diminished TNF production upon stimulation with LPS. These results suggest that rHDL may inhibit LPS effects in humans in vivo not only by binding and neutralizing LPS but also by reducing CD14 expression on monocytes.

Topics: Adult; Antigens, CD; Apolipoprotein A-I; Cholesterol; Cross-Over Studies; Double-Blind Method; Endotoxemia; Endotoxins; Granulocytes; Humans; Inflammation; Infusions, Intravenous; Interleukin-6; Interleukin-8; Leukocyte Count; Lipopolysaccharides; Lipoproteins, HDL; Male; Monocytes; Nausea; Pain; Phosphatidylcholines; Placebos; Shivering; Time Factors; Tumor Necrosis Factor-alpha; Vomiting

The role of cytokines in the pathophysiology, diagnosis, and prognosis of small fiber neuropathy (SFN) is incompletely understood. We studied expression profiles of selected pro- and anti-inflammatory cytokines in RNA from white blood cells (WBC) of patients with a medical history and a clinical phenotype suggestive for SFN and compared data with healthy controls.. We prospectively recruited 52 patients and 21 age- and sex-matched healthy controls. Study participants were characterized in detail and underwent complete neurological examination. Venous blood was drawn for routine and extended laboratory tests, and for WBC isolation. Systemic RNA expression profiles of the pro-inflammatory cytokines interleukin (IL)-1ß, IL-2, IL-8, tumor necrosis factor-alpha (TNF) and the anti-inflammatory cytokines IL-4, IL-10, transforming growth factor beta-1 (TGF) were analyzed. Protein levels of IL-2, IL-8, and TNF were measured in serum of patients and controls. Receiver operating characteristic (ROC)-curve analysis was used to determine the accuracy of IL-2, IL-8, and TNF in differentiating patients and controls. To compare the potential discriminatory efficacy of single versus combined cytokines, equality of different AUCs was tested.. WBC gene expression of IL-2, IL-8, and TNF was higher in patients compared to healthy controls (IL-2: p = 0.02; IL-8: p = 0.009; TNF: p = 0.03) and discriminated between the groups (area under the curve (AUC) ≥ 0.68 for each cytokine) with highest diagnostic accuracy reached by combining the three cytokines (AUC = 0.81, sensitivity = 70%, specificity = 86%). Subgroup analysis revealed the following differences: IL-8 and TNF gene expression levels were higher in female patients compared to female controls (IL-8: p = 0.01; TNF: p = 0.03). The combination of TNF with IL-2 and TNF with IL-2 and IL-8 discriminated best between the study groups. IL-2 was higher expressed in patients with moderate pain compared to those with severe pain (p = 0.02). Patients with acral pain showed higher IL-10 gene expression compared to patients with generalized pain (p = 0.004). We further found a negative correlation between the relative gene expression of IL-2 and current pain intensity (p = 0.02). Serum protein levels of IL-2, IL-8, and TNF did not differ between patients and controls.. We identified higher systemic gene expression of IL-2, IL-8, and TNF in SFN patients than in controls, which may be of potential relevance for diagnostics and patient stratification.

Topics: Cytokines; Female; Humans; Interleukin-10; Interleukin-2; Interleukin-8; Leukocytes; Pain; RNA; Small Fiber Neuropathy; Tumor Necrosis Factor-alpha

This study aimed to determine the effect of lipopolysaccharide (LPS)-induced mastitis with or without nonsteroidal anti-inflammatory drug (NSAID) on dairy cows' clinical, physiological, and behavioral responses in the milking parlor and freestalls as well as the specificity (Sp) and sensitivity (Se) of behavioral responses in detecting cows with LPS-induced mastitis. Twenty-seven cows received an intramammary infusion of 25 µg of Escherichia coli LPS in 1 healthy quarter. Following LPS infusion, 14 cows received a placebo (LPS cows), and 13 cows received 3 mg/kg of body weight of ketoprofen i.m. (LPS+NSAID cows). Cow response to the challenge was monitored at regular intervals from 24 h before to 48 h postinfusion (hpi) through direct clinical observations, markers of inflammation in milk, and via point-in-time direct behavioral observations in the barn and at milking. In LPS cows, infusion induced a significant increase of plasma cortisol levels at 3 and 8 hpi, milk cortisol levels at 8 hpi, somatic cell counts from 8 to 48 hpi, IL-6 and IL-8 at 8 hpi, milk amyloid A (mAA) and haptoglobin at 8 and 24 hpi, rectal temperature at 8 hpi, and respiratory rate at 8 hpi. Their rumen motility rate decreased at 8 and 32 hpi. Compared with before the challenge, significantly more LPS cows stopped feeding/ruminating and pressed their tail between their legs at 3 and 5 hpi, increased feeding/ruminating at 24 hpi, and had the tendency to be less responsive, dropping their head, and dropping their ears at 5 hpi. At milking, compared with before challenge, significantly more LPS cows lifted their hooves at forestripping at 8 hpi. The 2 groups showed similar patterns of response for milk cortisol, somatic cell count, respiratory rate, mAA, haptoglobin, and IL-6, IL-1β, and IL-8. Compared with LPS cows, LPS+NSAID cows had significantly lower plasma cortisol levels at 3 hpi, their rectal temperature decreased at 8 hpi, their rumen motility rate increased at 8 and 32 hpi, and their heart rate increased at 32 hpi. Compared with LPS cows, a significantly larger proportion of LPS+NSAID cows were feeding/ruminating, a lower proportion had ears down at 5 hpi, and a larger proportion lied down at 24 hpi. At milking, whatever the phase of milking, for "hoof to belly," 9 out of 14 cows did not show this behavior before infusion (Sp = 64%) and 14/14 did not kick during pre-infusion milking (Sp = 100%). Regarding sensitivity, at maximum, 5 cows out of 14 (Se = 36%) displayed "hoof t

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior Observation Techniques; Cattle; Cattle Diseases; Escherichia coli; Female; Haptoglobins; Hydrocortisone; Interleukin-6; Interleukin-8; Lipopolysaccharides; Mastitis, Bovine; Milk; Pain; Serum Amyloid A Protein

To observe the effect of acupuncture at "Houxi"(SI3) and "Huantiao"(GB30) on high mobility group box 1(HMGB1) protein and mRNA in spinal nerve trunk(SNT) of rats with lumbar disc herniation(LDH), so as to explore the mechanisms of acupuncture at this paired points on the treatment for LDH.. SD rats were randomly divided into sham operation, model, conventional acupuncture(CA) and paired points(PP) groups (with 8 rats in each group). The LDH model was established by injection of autologous suspension made from rats' own nucleus pulsus into the epidural space. Rats in the CA group received acupuncture treatment at bilateral "Weizhong"(BL40), "Dachangshu"(BL25) and "Shenshu"(BL23), while rats in the PP group received acupuncture at bilateral SI3 and GB30, 30 min each time, once daily for 14 consecutive days. The thermal pain threshold of bilateral hind feet of rats was detected by thermal pain stimulator. The contents of serum IL-1β, IL-6 and IL-8 of rats were detected by ELISA. Western blot and immunofluorescence were used to detect the expression of HMGB1 protein in the lumbar(L)5 SNT of rats. The relative expression of HMGB1 mRNA in L5 SNT was determined by qPCR. HE staining was used to observe the morphological changes of L5 SNT.. Compared with the sham operation group, the thermal pain threshold of bilateral hind feet in the model group was decreased (. Acupuncture intervention inhibites the expressions of HMGB1 protein and mRNA in rats with LDH, and further reduces the production of IL-1β, IL-6 and IL-8, which is beneficial to inflammatory response inhibition and pain alleviation. The therapeutic effect of the PP group is more obvious than that of the CA group.

Topics: Acupuncture Therapy; Animals; HMGB1 Protein; Interleukin-6; Interleukin-8; Intervertebral Disc Displacement; Pain; Rats; Rats, Sprague-Dawley; Spinal Nerves

Synovial tissue is known to be the origin of inflammation in joint disease. Despite this, synovial fluid is the main biological specimen of choice in temporomandibular joint (TMJ) inflammation and pathology biomarker research. No comparison of TMJ protein content between synovial fluid and synovial tissue has been made.. The aim of this study was to investigate whether cytokine concentrations in synovial fluid can be related to cytokine concentrations in synovial tissue and to analyse correlation of clinical parameters reflecting local inflammation to cytokine concentrations.. Synovial tissue and fluid samples were obtained during the same surgical procedure from a cohort of 101 patients with TMJ disorders. Interleukin (IL) 1β, IL-6, IL-8, IL-10 and tumour necrosis factor α (TNF-α) were analysed in the samples and an intraindividual correlation made. Various patient-specific factors related to TMJ inflammation were associated with the cytokine concentrations in synovial fluid and tissue.. No correlation between cytokine concentration in synovial fluid and synovial tissue was found, except for IL-8 (ρ = .284, p = .024). Synovial tissue cytokines correlated strongly to inflammation-related factors: diagnosis (IL-1β, p = .001; TNF-α, p = .000; IL-10, p = .000), TMJ palpation pain (IL-1β, p = .024; TNF-α, p = .025), synovitis score (IL-1β, p = .015) and subjective TMJ pain (TNF-α, p = .016). Synovial fluid cytokines showed no significant relations to inflammation.. The investigated cytokine concentrations showed weak correlations between synovial fluid and synovial tissue, besides IL-8. Synovial tissue appeared to reflect inflammation to a higher extent than synovial fluid. Thus, suggesting that synovial tissue research should complement synovial fluid in future explorations of TMJ pathology and inflammation.

Topics: Cytokines; Humans; Inflammation; Interleukin-10; Interleukin-8; Pain; Synovial Fluid; Temporomandibular Joint; Tumor Necrosis Factor-alpha

The purpose of this study was to analyze inflammation- and pain-related molecules in tears of patients suffering from chronic ocular pain associated with dry eye (DE) and/or a previous corneal refractive surgery (RS). Based on history, symptomatology, and clinical signs, the subjects (n = 180, 51.0 ± 14.7 years, 118 females, 62 males) in this cross-sectional study were assigned to one of five groups: DE and chronic ocular pain after RS (P/DE-RS, n = 52); asymptomatic subjects, i.e., without DE and chronic ocular pain, after RS (A-RS, n = 30); DE and chronic ocular pain without previous RS (P/DE-nonRS, n = 31); DE, no pain, and no previous RS (DE-nonRS, n = 35); and asymptomatic subjects with no previous RS (controls, n = 32). The tear concentrations of 20 cytokines and substance P (SP) were analyzed by immunobead-based assay and enzyme-linked immunosorbent assay, respectively. We found that tear levels of interleukin (IL)-10 and SP were increased in the RS groups. There were significant differences in IL-8/CXCL8 among the five groups. Nerve growth factor (NGF) tear levels were significantly higher in P/DE-RS than in DE-nonRS and controls. IL-9 had the highest percentage of detection in the P/DE-RS and P/DE-nonRS groups, while macrophage inflammatory protein (MIP)-1α, IL-2, and interferon (IFN)-γ were higher in the P/DE-RS, A-RS, and P/DE-nonRS groups. IL-17A was detected only in the A-RS group. Moderate correlations were observed in the A-RS, P/DE-nonRS, DE-nonRS and controls groups. A positive correlation was obtained between growth related oncogene concentration and tear break-up time (rho = 0.550; p = 0.012), while negative correlation was found between monocyte chemoattractant protein-3/CCL7 and conjunctival staining (rho = -0.560; p = 0.001), both in the A-RS group. IL-10 correlated positively with ocular pain intensity (rho = 0.513; p = 0.003) in the P/DE-nonRS group. Regulated on Activation Normal T Cell Expressed and Secreted/CCL5 correlated negatively with conjunctival staining (rho = -0.545; p = 0.001) in the DE-nonRS group. SP correlated negatively with corneal staining (rho = -0.559; p = 0.001) in the controls. In conclusion, chronic ocular pain was associated with higher IL-9 tear levels. IL-10, SP, MIP-1α/CCL3, IL-2, and IFN-γ were associated with previous RS. Higher levels of IL-8/CXCL8, MIP-1α/CCL3, IL-2, and IFN-γ were associated with DE-related inflammation, while NGF levels were related to chronic ocular pain and DE in RS patients. Thes

Topics: Chemokine CCL3; Conjunctiva; Cross-Sectional Studies; Cytokines; Dry Eye Syndromes; Female; Graft vs Host Disease; Humans; Inflammation; Interleukin-10; Interleukin-2; Interleukin-8; Interleukin-9; Male; Nerve Growth Factor; Pain; Tears

Distal transradial access (dTRA) has been proposed as an alternative to traditional transradial access (TRA) in cardiac catheterization.. The study aimed to compare these two transradial approaches: TRA and dTRA in terms of clinical and biochemical aspects.. Two hundred patients who qualified for the elective coronary procedure were included. The patients were assigned to one of the groups depending on their vascular access. The groups were compared in terms of perceived pain using the Visual Analogue Scale (VAS), time of gaining access, need for conversion, and local complications. Additionally, in forty patients circulating endothelial injury markers: endothelin 1 (ET-1), interleukin 8 (IL-8), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were assessed.. Successful cannulation was obtained in 84 (100%) in the TRA group and in 98 (84%) subjects in the dTRA (P <0.001). dTRA was associated with higher level of pain perceived at the time of gaining vascular approach than TRA; median VAS score (interquartile range [IQR]): 4 (2-5) vs. 2 (2-4) (P = 0.04). The mean time (standard deviation [SD]) needed to cannulate the artery in dTRA was longer than in TRA: 81 (8) seconds vs. 50 (4) seconds (P = 0.04). ET-1 concentration was (SD) 2.08 (0.19) pg/ml [dTRA] vs. 2.00 (0.29) [TRA] pg/ml (P = 0.83); sVCAM-1: 12.71 (3.97) ng/ml vs. 12.86 (4.29) ng/ml (P = 0.98); IL-8: 8.81 (0.42) ng/ml vs. 9.15 (0.52) ng/ml (P = 0.62). Th number of complications after procedures did not differ between these two approaches.. Cannulation of dTRA is associated with a lower success rate and higher pain perceived. dTRA is not inferior to TRA when safety issues and vascular injury are considered.

Topics: Cardiac Catheterization; Coronary Angiography; Humans; Interleukin-8; Pain; Percutaneous Coronary Intervention; Radial Artery; Treatment Outcome

The increase of individuals with Osteoarthritis (OA) has generated an increase in public spending in the treatments, which are still not that effective. So, the purpose of this study was to analyze and compare four types of interventions: platelet-rich plasma (PRP), adipose-derived stem cells (ADSCs), ADSCs + PRP and the standard surgical video arthroscopy (All groups passed through standard arthroscopy before intervention). The evaluation was performed by applying the questionnaires Western Ontario McMaster Universities, Short Form Health Survey 36 and Visual Analog Pain Scale, also by analyzing the synovial fluid (inflammatory cytokines, enzymatic, colorimetric and viscosity analysis), this evaluation happened in two moments: before the surgical procedures and after 6 months of the interventions and also was made a comparison to standard arthroscopy. The questionnaires results showed a greater improvement in the scores of the domains analyzed in the ADSCs + PRP group, followed by the ADSCs and PRP group. In the evaluation of inflammatory cytokines, there was a significant reduction in the cytokine IL-1b only in the ADSCs + PRP group (46%) and ADSCs (31%), of IL-6 in the ADSCs + PRP group (72%), of IL-8 in the ADSCs + PRP group (50%) and ADSCs (31%), and TNF in the ADSCs + PRP group (46%). There was also a significant increase in the amount of total proteins (79%) in the control group and polymorphonuclear cells (47%) in the ADSCs + PRP group. Taking all the results into account, we infer that therapies with ADSCs + PRP and only ADSCs are safe and effective over 6 months for the improvement of pain, functional capacity and joint inflammation in volunteers with OA. It is also considered that the use of ADSCs + PRP, particularly, is a promising alternative to help manage this disease, due to the better results presented among the four propose interventions.

Topics: Humans; Hyaluronic Acid; Inflammation; Injections, Intra-Articular; Interleukin-6; Interleukin-8; Osteoarthritis, Knee; Pain; Platelet-Rich Plasma; Stem Cells; Treatment Outcome

Inflammation is proposed to influence tumor response in radiotherapy (RT). Clinical studies to investigate the relationship between inflammatory markers and RT response is warranted to understand the variable RT efficacy in patients with painful bone metastases.. To evaluate the association between inflammatory markers and analgesic response to RT in patients with painful bone metastases.. Adult patients from 7 European study sites undergoing RT for painful bone metastases were included in this prospective and longitudinal analysis. The association between RT response and 17 inflammatory markers at baseline, as well as the association between RT response and the changes observed in inflammatory markers between baseline and three and eight weeks after RT, was analyzed with univariate regression analyses. Baseline analyses were adjusted for potential clinical predictors of RT response.. None of the inflammatory markers were significantly associated with an upcoming RT response in the analysis of 448 patients with complete baseline data. In patients available for follow-up, the three-week change in TNF (P 0.017), IL-8 (P 0.028), IP-10 (P 0.032), eotaxin (P 0.043), G-CSF (P 0.033) and MCP-1 (P 0.002) were positively associated with RT response, while the three-week change in CRP (P 0.006) was negatively associated.. Results from this study show an association between RT response and change in pro-inflammatory mediators and indicate that inflammation may be important to achieve an analgesic RT response in patients with painful bone metastases. None of the investigated inflammatory markers were found to be pre-treatment predictors of RT response.

Topics: Adult; Analgesics; Bone Neoplasms; Chemokine CXCL10; Granulocyte Colony-Stimulating Factor; Humans; Inflammation; Interleukin-8; Pain; Palliative Care; Prospective Studies

Meniscal allograft transplantation (MAT) has been developed as a treatment for meniscal deficiency. Despite promising outcomes, there are no real-time methods to evaluate graft survivorship and predict functional outcomes.. Assessment of serum and urine biomarkers could be used to develop biomarker panels-prognostic (1- and 3-month postsurgical time points) and diagnostic (6-month time point)-based on strong associations with clinically relevant outcome metrics obtained 6 months after surgery.. Descriptive laboratory study.. Twelve adult purpose-bred research hounds were included and underwent medial meniscal release to induce meniscal deficiency. Three months after meniscal release surgery, medial menisci were replaced with fresh-frozen meniscus (n = 4), fresh meniscus (n = 4), or fresh meniscotibial osteochondral allograft (n = 4) such that a spectrum of pain and functional outcomes could be anticipated. Serum and urine from all dogs were collected preoperatively and at 1, 3, and 6 months after MAT surgery. Dogs were assessed for pain-related and functional outcomes at the same time points. To develop a prognostic panel of biomarkers, biomarker data from the 1- and 3-month post-MAT surgery time points were used to model 6-month clinical outcomes. A diagnostic panel of biomarkers was developed using data from the 6-month post-MAT surgery to model 6-month clinical outcomes. Primary outcomes for pain and function were visual analog scale (VAS) and operated limb percentage total pressure index (%TPI), respectively. Using random subject effects, linear mixed models were used to develop prognostic biomarker panels, and linear fixed-effect models were used to develop diagnostic biomarker panels, with variance explained for each panel reported (. Across prognostic biomarker panels, a panel including serum IL-6, IL-8, IL-10, and IL-18 was fit for the primary functional outcome, operated limb %TPI (. Biomarker panels of selected serum and/or urine proteins can model clinically relevant metrics for function and pain in a preclinical model of MAT.. Biomarker panels could be used to provide real-time diagnostic and prognostic data regarding outcomes after MAT.

Topics: Allografts; Animals; Biomarkers; Dogs; Follow-Up Studies; Interleukin-8; Menisci, Tibial; Meniscus; Pain; Tissue Inhibitor of Metalloproteinase-1

Anti- and proinflammatory cytokines and plasma high-sensitivity C-reactive protein (hs-CRP) are used to assess inflammatory stress response (ISR) following surgery. However, the serum IL-18 (interleukin-18) cytokine values versus numeric rating scale (NRS) pain score and number of analgesic doses (NAD) postoperatively are unknown.. Blood levels of six interleukins (IL-18, IL-1ra, IL-6, IL-10, IL-1β, and IL-8) and hs-CRP were measured at three time points; before operation (PRE), immediately after operation (POP1), and six hours after operation (POP2) in 114 patients with cholelithiasis.. Following surgery, the blood levels of hs-CRP and IL-1ra, IL-6, IL-10, and IL-1β cytokines had a trend for increase (p<0.001 and p=0.014, respectively). The serum IL-18 concentrations inversely correlated to NRS and NAD during the first 24 h postoperatively.. The correlation of IL-18 levels to NRS and NAD values supports the hypothesis that ISR and pain are related.

Topics: Analgesics; C-Reactive Protein; Cytokines; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-18; Interleukin-6; Interleukin-8; Interleukins; NAD; Pain; Pain, Postoperative

The aim of the study was to identify inflammatory cytokines/chemokines associated with neuroinflammation and periphery-to-CNS inflammatory cross-talk in degenerative disc disease (DDD) and lumbar disc herniation (LDH), common causes of low back pain (LBP). A secondary aim was to investigate the associations between cytokines and symptom severity.. In total, 40 DDD and 40 LDH patients were recruited from a surgical waiting list, as well as 39 healthy controls (HC) and 40 cerebrospinal fluid (CSF) controls. The subjects completed questionnaires and pressure algometry was performed at the lumbar spine and forearm. The CSF, serum and disc tissues were collected during surgery. Inflammatory mediators TNF, INFg, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13 and MCP1 were analysed by immunoassay (Meso Scale Discovery) and quantitative real-time polymerase chain reaction (qPCR) was used for analysis of IL-6, IL-8, MCP1 and TSPO expression in intervertebral discs (IVDs).. In the LDH group, we found elevated IL-8 concentrations in CSF indicating neuroinflammation, while IL-8 and MCP1 concentrations in serum were lower compared to HC. The IVD expression of IL-6, IL-8 and TSPO was lower in LDH patients compared to DDD. LDH patients had a positive correlation between IL-8 concentrations in CSF and serum and IL-8 in CSF was associated with higher pain intensity and increased spinal pressure pain sensitivity. The MCP1 concentration in serum was associated with higher global pain ratings and increased spinal pressure pain sensitivity, while IL-6 serum concentration correlated with the intensity of the neuropathic pain component (leg pain) in LDH patients. IVD expression of TSPO in LDH patients was associated with increased intensity of back pain. No differences were found in cytokine CSF concentrations between DDD patients and CSF controls, but DDD patients had lower IL-8 and MCP1 serum concentrations than HC. In female DDD patients, IL-8 and MCP1 concentrations in serum were associated with increased intensity of back pain.. Our results suggest that neuroinflammation mediated by elevated IL-8 concentrations in CSF and IL-8 mediated periphery-to-CNS inflammatory cross-talk contributes to pain in LDH patients and suggest a link between TSPO expression in discs and low back pain.

Topics: Adult; Aged; Chemokines; Cytokines; Female; Humans; Interleukin-6; Interleukin-8; Intervertebral Disc; Intervertebral Disc Degeneration; Intervertebral Disc Displacement; Low Back Pain; Lumbar Vertebrae; Male; Middle Aged; Neuroimmunomodulation; Pain; Receptors, GABA

Ibuprofen is a widely used non-steroidal anti-inflammatory drug (NSAID) that exerts analgesic and anti-inflammatory actions. The transient receptor potential ankyrin 1 (TRPA1) channel, expressed primarily in nociceptors, mediates the action of proalgesic and inflammatory agents. Ibuprofen metabolism yields the reactive compound, ibuprofen-acyl glucuronide, which, like other TRPA1 ligands, covalently interacts with macromolecules. To explore whether ibuprofen-acyl glucuronide contributes to the ibuprofen analgesic and anti-inflammatory actions by targeting TRPA1, we used in vitro tools (TRPA1-expressing human and rodent cells) and in vivo mouse models of inflammatory pain. Ibuprofen-acyl glucuronide, but not ibuprofen, inhibited calcium responses evoked by reactive TRPA1 agonists, including allyl isothiocyanate (AITC), in cells expressing the recombinant and native human channel and in cultured rat primary sensory neurons. Responses by the non-reactive agonist, menthol, in a mutant human TRPA1 lacking key cysteine-lysine residues, were not affected. In addition, molecular modeling studies evaluating the covalent interaction of ibuprofen-acyl glucuronide with TRPA1 suggested the key cysteine residue C621 as a probable alkylation site for the ligand. Local administration of ibuprofen-acyl glucuronide, but not ibuprofen, in the mouse hind paw attenuated nociception by AITC and other TRPA1 agonists and the early nociceptive response (phase I) to formalin. Systemic ibuprofen-acyl glucuronide and ibuprofen, but not indomethacin, reduced phase I of the formalin response. Carrageenan-evoked allodynia in mice was reduced by local ibuprofen-acyl glucuronide, but not by ibuprofen, whereas both drugs attenuated PGE

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcium; Cell Line; Dinoprostone; Epithelial Cells; Glucuronates; Humans; Hyperalgesia; Ibuprofen; Interleukin-8; Male; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pain; Rats, Sprague-Dawley; TRPA1 Cation Channel

Burning mouth syndrome (BMS) is a neuropathic orofacial pain condition of unknown aetiology that encompasses intra-oral burning pain without abnormal clinical findings. Psychological, neural and inflammatory processes are associated with BMS pathogenesis. Currently, studies characterising plasma cytokine/chemokine profiles with pain and depression in patients with BMS are lacking. Considering that inflammation is associated with the pathophysiology of BMS, and that inflammation is closely associated with pain and depression, we aimed to correlate depressive symptomatology and oral cavity pain with plasma cytokine/chemokine signatures in a cohort of patients with BMS.. In this study, plasma protein levels of Th1 cytokines (IFN-γ, IL-2, IL-12p70, TNF-α), Th2 cytokines (IL-4, IL-10, IL-6, IL-13) and the chemokine IL-8 were assessed in patients with BMS (n = 10) and healthy volunteers (n = 10), using pro-inflammatory-10-plex assays. Clinical histories, alongside self-rated oral cavity pain intensities and depressive symptomatology were assessed using a visual analogue scale and the 16-item Quick Inventory of Depressive Symptomatology questionnaires, respectively.. We present evidence that BMS is associated with increased depressive symptomatology and enhanced oral cavity pain. Plasma isolated from BMS patients display enhanced expression of the pro-inflammatory chemokine IL-8, when compared to plasma from healthy individuals. Plasma IL-8 signature correlates with pain and depressive symptomatology in the study cohort.. Overall, these findings indicate that plasma IL-8 profiles are dysregulated in BMS and that modulation of IL-8 production in the disorder may be a tool in the management of BMS symptomatology.

Topics: Adult; Aged; Burning Mouth Syndrome; Chemokines; Cohort Studies; Cytokines; Depression; Female; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Mouth; Pain; Pain Measurement; Pilot Projects; Surveys and Questionnaires; Th1 Cells; Th2 Cells

Oral cancer is a multifactorial disease process and involves complex interactions between gene to gene and gene to environmental factors. Interleukin 8 (IL-8), a pro-inflammatory cytokine, having angiogenic activity with elevated expression in tumor cells, is reported to play an essential role in oral cancer development. This study was conducted with the aim to investigate the role of IL-8 (-A251T) gene polymorphism in susceptibility, progression, and self-reporting pain in oral cancer. The single nucleotide polymorphisms of the IL-8 (-A251T) gene were screened in 300 patients with oral cancer and 300 healthy controls, by polymerase chain reaction-restriction fragment length polymorphism. Genotype and allele frequencies were evaluated by chi-square test and odds ratio (OR) with 95% confidence intervals (CIs) were used to evaluate the strength of associations. The results of the study demonstrated that IL-8 (-A251T) gene polymorphism was significantly associated with susceptibility of oral cancer, whereas its correlation with clinico-pathological status or pain due to oral cancer could not be established. The AT heterozygous (OR 5.31; CI 3.38-8.34; p 0.0001) and AA homozygous (OR 2.89; CI 1.76-4.75; p 0.0001) had a greater risk for oral cancer compared to TT homozygous. Furthermore, significantly increased values of A allele frequencies compared to T allele were observed in all patients (OR 1.56; CI 1.24-1.96; p 0.0002). Tobacco chewing and smoking were also found to influence the development of oral cancer and increased the incidence of pain in oral cancer patients. The findings of this study suggest that the IL-8 (-A251T) gene polymorphism may be associated with increased risk of oral cancer.

Topics: Adult; Case-Control Studies; Female; Humans; Interleukin-8; Male; Middle Aged; Mouth Neoplasms; Pain; Polymorphism, Single Nucleotide

The purpose of this study was to relate central inflammation to autonomic activity (heart rate variability (HRV)) in patients with rheumatoid arthritis (RA) and fibromyalgia (FM). RA patients had reduced parasympathetic activity and FM patients had increased sympathetic activity compared to healthy controls. Comparisons between RA and FM showed higher cerebrospinal fluid (CSF) interleukin (IL)-1β inversely correlated to parasympathetic activity in RA. The FM patients had higher concentrations of CSF IL-8, IL-1Ra, IL-4 and IL-10, but none of these cytokines correlated with HRV. In conclusion, we found different profiles of central cytokines, i.e., elevated IL-1β in inflammatory pain (RA) and elevated IL-8 in dysfunctional pain (FM).

Topics: Adult; Arthritis, Rheumatoid; Autonomic Nervous System; Cytokines; Female; Fibromyalgia; Heart Rate; Humans; Interleukin-1beta; Interleukin-8; Middle Aged; Pain; Pain Measurement; Radioimmunoassay; Spinal Puncture; Statistics, Nonparametric

Older adults are at an increased risk to develop frequent and prolonged pain. Emerging evidence proposes a link between immune changes and pain, which is consistent with the inflammation theory of aging and the increased incidence of age-related diseases. This study tested the hypothesis that older adults show greater immune responses to experimental pain compared to younger individuals. Study subjects (8 younger and 9 older healthy adults) underwent 3 experimental sessions using well-validated human experimental pain models: the cold pressor task (CPT), focal heat pain (FHP), and a non-painful thermal control. Blood was collected through an indwelling catheter at baseline and 3, 15, 30, 45, 60, and 90 min post-stimuli administration. Pro-inflammatory cytokines (TNF-α IL-6 and IL-8) peaked at the same time points for both groups, with greater elevations among older subjects for TNF-α and IL-8 in both pain models and elevations in IL-6 only for CPT. Anti-inflammatory cytokines (IL-4, IL-5, and IL-10) generally peaked later for the older subjects, with increased elevations for FHP but not the CPT. These data are consistent with the assertion that age-related immune system dysregulation may account for the increased prevalence of pain in older adults.

Topics: Adolescent; Adult; Aged; Aging; Biomarkers; Cytokines; Female; Healthy Volunteers; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Middle Aged; Pain; Pain Measurement; Tumor Necrosis Factor-alpha; Young Adult

Laboratory study.. To evaluate expression of chemokine regulated and normal T cell expressed and secreted (RANTES)/C-C motif ligand 5 (CCL5) and interleukins in intervertebral discs (IVDs) specimens from patients with discogram-proven painful degeneration.. Discogenic back pain results in tremendous costs related to treatment and lost productivity. The relationship between inflammation, degeneration (IVD), and cytokine upregulation is well established, but other mediators of the inflammatory cascade are not well characterized.. Painful IVDs were taken from 18 patients undergoing surgery for discogenic pain with positive preoperative discogram. Painless control tissue was taken at autopsy from patients without back pain/spinal pathology or spinal levels with negative discograms resected for deformity.Quantitative real time polymerase chain reaction (qRT-PCR) was performed to evaluate RANTES, IL-1β, IL-6, and IL-8 expression in painful and control discs. RANTES and interleukin expression were analyzed on the basis of Pfirrmann grade.Disc cells were cultured in alginate beads using 2 groups: an untreated group and a group treated with 10 ng/mL IL-1β, 10 ng/mL TNF-α, and 1% fetal bovine serum to induce a degenerative phenotype.. Nine painless IVD specimens and 7 painful IVD specimens were collected. RANTES expression demonstrated a 3.60-fold increase in painful discs versus painless discs, a significant difference (P = 0.049). IL-1β expression demonstrated significantly higher expression in painful discs (P = 0.03). RANTES expression data demonstrated significant upregulation with increasing Pfirrmann grade (P = 0.045). RANTES expression correlated significantly with IL-1β expression (ρ = 0.67, P < 0.0001). RANTES expression increased more than 200-fold in the alginate culture model in cells treated with IL-1β/TNF-α, 1% fetal bovine serum (P < 0.001).. RANTES and IL-1β expression was significantly elevated in painful IVDs after careful selection of painless versus painful IVD tissue. RANTES expression was found to correlate significantly with expression of IL-1β. RANTES was upregulated by IL-1β/TNF-α/1% fetal bovine serum an in vitro treatment to induce a degenerative phenotype.

Topics: Adult; Aged; Animals; Cattle; Cells, Cultured; Chemokine CCL5; Cohort Studies; Culture Media; Fetal Blood; Gene Expression; Humans; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Interleukin-8; Intervertebral Disc; Intervertebral Disc Degeneration; Middle Aged; Pain; Reverse Transcriptase Polymerase Chain Reaction; Serum; Tumor Necrosis Factor-alpha; Up-Regulation

A report by the National Cancer Institute identified that an important gap in symptom research is the investigation of multiple symptoms of cancer that might identify common biological mechanisms among cancer-related symptoms.. We applied novel statistical methods to assess whether variants of 37 inflammation genes may serve as biologic markers of risk for severe pain, depressed mood, and fatigue in non-Hispanic white patients with non-small cell lung cancer.. Pain, fatigue, and depressed mood were assessed before cancer treatment. We used a generalized, multivariate, classification tree approach to explore the influence of single-nucleotide polymorphisms in the inflammation genes in pain, depressed mood, and fatigue in lung cancer patients.. Among patients with advanced-stage disease, interleukin (IL)-8-T251A was the most relevant genetic factor for pain (odds ratio [OR] = 2.18, 95% CI = 1.34-3.55, P = 0.001), depressed mood (OR = 0.37, 95% CI = 0.14-1.0), and fatigue (OR = 2.07, 95% CI = 1.16-3.70). Among those with early-stage non-small cell lung cancer, variants in the IL-10 receptor were relevant for fatigue among women. Specifically, women with Lys_Glu or Glu_Glu genotype in the IL-10 gene had a 0.49 times lower risk of severe fatigue compared with those with Lys_Lys genotype (OR = 0.49, 95% CI = 0.25-0.92, P = 0.027). Among men with early-stage lung cancer, a marginal significance was observed for IL-1A C-889T, C/T, or T/T genotypes. These men had a lower risk of severe fatigue compared with those with C/C genotype (OR = 0.38, 95% CI = 0.13-1.06).. The interaction of multiple inflammation genes, along with nongenetic factors, underlies the occurrence of symptoms. IL-8 and IL-10 may serve as potential targets for treating multiple symptoms of cancer.

Topics: Aged; Aged, 80 and over; Causality; Comorbidity; Cytokines; Depression; Fatigue; Female; Genetic Association Studies; Genetic Markers; Genetic Predisposition to Disease; Humans; Interleukin-10; Interleukin-8; Lung Neoplasms; Male; Middle Aged; Pain; Polymorphism, Single Nucleotide; Prevalence; Risk Factors; Texas

Interleukin-8 (IL-8) is known for its roles in inflammation and plays critical roles in the development of pain. Its expression increases in the brain after peripheral inflammation. Prefrontal cortex, including the anterior cingulate cortex (ACC), is a forebrain structure known for its roles in pain transmission and modulation. Painful stimuli potentiate the prefrontal synaptic transmission, however, little is known about the expression of IL-8 and its role in the enhanced ACC synaptic transmission in animals with persistent inflammatory pain.. In the present study, we examined IL-8 expression in the ACC, somatosensory cortex (SSC), and the dorsal horn of lumbar spinal cord following hind-paw administration of complete Freund's adjuvant (CFA) in mice and its effects on the ACC synaptic transmission. Quantification of IL-8 at protein level (by ELISA) revealed enhanced expression in the ACC and spinal cord during the chronic phases of CFA-induced peripheral inflammation. In vitro whole-cell patch-clamp recordings revealed that IL-8 significantly enhanced synaptic transmission through increased probability of neurotransmitter release in the ACC slice. ACC local infusion of repertaxin, a non-competitive allosteric blocker of IL-8 receptors, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in mice.. Our findings suggest that up-regulation of IL-8 in the ACC partly attributable to the enhanced prefrontal synaptic transmission in the mice with persistent inflammatory pain.

Topics: Animals; Freund's Adjuvant; Glutamates; Gyrus Cinguli; Hyperalgesia; In Vitro Techniques; Inflammation; Interleukin-8; Mice; Mice, Inbred C57BL; Pain; Prefrontal Cortex; Receptors, N-Methyl-D-Aspartate; Sulfonamides; Synaptic Transmission

We report the design, the synthesis and the biological evaluation of the analgesic and anti-inflammatory activities of furoxanyl N-acylhydrazones (furoxanyl-NAH) by applying molecular hybridization approach. Hybrid compounds with IL-8-release inhibition capabilities were identified. Among them, furoxanyl-NAH, 17, and benzofuroxanyl-derivative, 24, together with furoxanyl-NAH derivative, 31, without IL-8 inhibition displayed both orally analgesic and anti-inflammatory activities. These hybrid derivatives do not have additional LOX- or COX-inhibition activities. For instance, LOX-inhibition by furoxanyl-NAH derivative, 42, emerged as a structural lead to develop new inhibitors. The lack of mutagenicity of the active derivatives 17, 31, and 42, allow us to propose them as candidates for further clinical studies. These results confirmed the success in the exploitation of hybridization strategy for identification of novel N-acylhydrazones (NAH) with optimized activities.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Cell Line; Cyclooxygenase Inhibitors; Drug Design; Female; Humans; Hydrazones; Inflammation; Interleukin-8; Lipoxygenase Inhibitors; Male; Mice; Oxadiazoles; Pain; Rats

Kaurenoic acid [ent-kaur-16-en-19-oic acid (1)] is a diterpene present in several plants including Sphagneticola trilobata. The only documented evidence for its antinociceptive effect is that it inhibits the writhing response induced by acetic acid in mice. Therefore, the analgesic effect of 1 in different models of pain and its mechanisms in mice were investigated further. Intraperitoneal and oral treatment with 1 dose-dependently inhibited inflammatory nociception induced by acetic acid. Oral treatment with 1 also inhibited overt nociception-like behavior induced by phenyl-p-benzoquinone, complete Freund's adjuvant (CFA), and both phases of the formalin test. Compound 1 also inhibited acute carrageenin- and PGE(2)-induced and chronic CFA-induced inflammatory mechanical hyperalgesia. Mechanistically, 1 inhibited the production of the hyperalgesic cytokines TNF-α and IL-1β. Furthermore, the analgesic effect of 1 was inhibited by l-NAME, ODQ, KT5823, and glybenclamide treatment, demonstrating that such activity also depends on activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway, respectively. These results demonstrate that 1 exhibits an analgesic effect in a consistent manner and that its mechanisms involve the inhibition of cytokine production and activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway.

Topics: Acetic Acid; Administration, Oral; Animals; Asteraceae; Carbazoles; Cyclic GMP-Dependent Protein Kinases; Cytokines; Diterpenes; Dose-Response Relationship, Drug; Formaldehyde; Freund's Adjuvant; Glyburide; Inflammation; Injections, Intraperitoneal; Interleukin-8; KATP Channels; Mice; Molecular Structure; NG-Nitroarginine Methyl Ester; Pain; Tumor Necrosis Factor-alpha

Autologous nucleus pulposus obtained from coccygeal intervertebral discs was grafted on the proximal of L5 dorsal root ganglion. Pain behavior, mRNA expression of Interleukin-8 (IL-8), and immunohistochemical changes were assessed.. The purpose of this study is to investigate temporal changes of IL-8 expression in the spinal cord and dorsal root ganglion and the pain-related behaviors with time course and to elucidate whether repertaxin (IL-8 receptor inhibitor) attenuates pain-related behaviors in a rat model of lumbar disc herniation.. Inflammatory mediators like cytokines and chemokines have been implicated in radicular pain because of disc herniation. IL-8, known as CXCL8, is a chemokine, which has been reported to be associated with painful degenerative disc disorders and chronic inflammatory pain states.. Lumbar disc herniated rat model was made by implantation of the autologous nucleus pulposus, harvested from the coccygeal vertebra of each tail, on the left L5 nerve root just proximal to the dorsal root ganglion. Rats were tested for mechanical allodynia and thermal hyperalgesia at 2 days before surgery, and on days 1, 5, 10, 20, 30, 40, 50, and 60 postoperatively. Experimental group was intrathecally injected with the IL-8 receptor inhibitor at L5 level on postoperative day 10. Mechanical allodynia of the plantar surface of both hindpaw was tested on 30 minutes, 1, 3 hours, 1, 3, 5, and 10 days after administration. For the staining of astrocytes and microglia, immunohistochemical study was done 20 days after surgery.. Mechanical allodynia in ipsilateral hindpaw developed 1 day after surgery and lasted until 60 days and thermal withdrawal latency decreased significantly on the ipsilateral side 10 days after surgery and gradually increased through day 60. The IL-8 receptor inhibitor attenuated the mechanical allodynia caused by nucleus pulposus when it was administered on postoperative day 10 and reduced microglial activation and phosphorylated form of mitogen-activated protein kinase (pERK) expression in the spinal dorsal horn.. IL-8 might be a potential therapeutic target in chronic radicular neuropathic pain because of disc herniation, CXCL8 inhibitor could be one of its promising therapeutic agents.

Topics: Animals; Chemokine CXCL1; Disease Models, Animal; Ganglia, Spinal; Gene Expression; Hyperalgesia; Immunohistochemistry; Interleukin-8; Intervertebral Disc Displacement; Lumbar Vertebrae; Male; Pain; Pain Measurement; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-8A; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spinal Cord; Sulfonamides; Time Factors

Descriptive and mechanistic investigation of the anti-inflammatory and anticatabolic effect of resveratrol in intervertebral discs (IVDs) in vitro and of the analgetic effect in vivo.. To determine whether resveratrol may be useful in treating nucleus pulposus (NP)-mediated pain.. Proinflammatory cytokines seem to be key mediators in the development of NP-mediated pain. Patients with discogenic or radiculopathic pain may substantially benefit from anti-inflammatory substances that could be used in a minimal-invasive treatment approach. Resveratrol, a polyphenolic phytoalexin found in red wine exhibits anti-inflammatory effects in various cell types and tissues, but no data exists so far with regards to the IVD in the context of low back and leg pain.. In part 1, the anti-inflammatory and anticatabolic effect of resveratrol was investigated in a cell culture model on interleukin 1β (IL-1β) prestimulated human IVD cells on the gene and protein expression level. In part 2, the molecular mechanisms underlying the effects observed upon resveratrol treatment were investigated (toll-like receptors, nuclear factor κB, sirtuin 1 (SIRT1), mitogen-activated protein (MAP) kinases p38/ERK/JNK). In part 3, the analgetic effects of resveratrol were investigated in vivo using a rodent model of radiculopathy and von Frey filament testing. All quantitative data were statistically evaluated either by Mann-Whitney U test or by one-way analysis of variance and Bonferroni post hoc testing (P < 0.05).. In vitro, resveratrol exhibited an anti-inflammatory and anticatabolic effect on the messenger RNA and protein level for IL-6, IL-8, MMP1, MMP3 and MMP13. This effect does not seem to be mediated via the MAP kinase pathways (p38, ERK, JNK) or via the NF-κB/SIRT1 pathway, although toll-like receptor 2 was regulated to a minor extent. In vivo, resveratrol significantly reduced pain behavior triggered by application of NP tissue on the dorsal root ganglion for up to 14 days.. Resveratrol was able to reduce levels of proinflammatory cytokines in vitro and showed analgetic potential in vivo. A decrease in proinflammatory cytokines may possibly be the underlying mechanism of pain reduction observed in vivo. Resveratrol seems to have considerable potential for the treatment of NP-mediated pain and may thus be an alternative to other currently discussed (biological) treatment options.

Topics: Adult; Aged; Analgesics; Animals; Anti-Inflammatory Agents; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation; Humans; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Interleukin-8; Intervertebral Disc; JNK Mitogen-Activated Protein Kinases; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; Middle Aged; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Pain; Pain Measurement; Radiculopathy; Rats; Rats, Sprague-Dawley; Resveratrol; RNA, Messenger; Signal Transduction; Sirtuin 1; Stilbenes; Time Factors; Toll-Like Receptor 2; Wine; Young Adult

Although fibromyalgia (FM) is traditionally a non-inflammatory condition, emerging data also suggest that FM has an immunologic component. Previous studies have reported that peripheral blood concentrations of two chemokines (i.e., interleukin-8 [IL-8] and monocyte chemotactic protein-1 [MCP-1]) were elevated in FM patients compared with normal controls. We sought to determine the longitudinal relationships of changes in the levels (picogram/mL) of IL-8 and MCP-1 with changes in the severity of FM-related pain.. Secondary data analysis of a cohort of 16 FM subjects who provided blood samples at two time points: week 1 and week 12. Setting.  Urban rheumatology clinic practices.. Individuals who met the American College of Rheumatology 1990 criteria for FM.. Changes from week 1 to week 12 of the following variables: Brief Pain Inventory (BPI) pain severity and plasma concentrations of IL-8 and MCP-1..   Change in BPI pain severity was significantly associated with changes in IL-8 and MCP-1 plasma concentrations. Specifically, for each unit increase in the change of BPI pain severity, IL-8 increased by 2.5 pg/mL (P = 0.03) and MCP-1 increased by 9.4 pg/mL (P = 0.006). None of the covariates (i.e., body mass index, medications, severity of depression, and overall FM burden) were significantly associated with either chemokines..   Although preliminary, our findings raise the hypothesis that IL-8 and MCP-1 may be involved in the pathogenesis of FM. If replicated in a larger study, IL-8 and MCP-1 may assist in determining prognosis and in monitoring of treatment response.

Topics: Biomarkers; Chemokine CCL2; Cognitive Behavioral Therapy; Female; Fibromyalgia; Humans; Interleukin-8; Middle Aged; Pain; Pain Measurement; Pilot Projects; Randomized Controlled Trials as Topic; Surveys and Questionnaires

In this prospective longitudinal clinical study, we evaluated the role of proinflammatory cytokine IL-8 and its clinical relevance in patients with fibromyalgia (FM) who fulfilled clearly defined inclusion and exclusion criteria and underwent a 3-week inpatients multidisciplinary pain therapy.. IL-8 in sera was measured in 20 patients with FM and 80 healthy participants at 4 fixed time points: at the beginning of the study, at 10 days, 21 days, and 6 months, respectively. Pain intensity, back function, depression, nicotine/alcohol consumption, and medication were assessed in the patient group and correlated with IL-8 levels.. Before and during the inpatient therapy, the serum level of IL-8 was significantly higher in patients with FM compared with controls (P<0.001), but did not correlated with pain intensity and medication. Already at T1 there was a significant reduction of IL-8 serum level (P=0.023) in patient group. Six months after multidisciplinary pain therapy, IL-8 serum level in FM patients was still significantly higher than controls (P=0.044) but reduced approximately to normal range and correlated significantly negatively with pain intensity (r=-0.782, P=0.001). Patients with FM had significantly less pain (P<0.001) and better back function (P<0.001) at day 2 than at day 0. In addition, in patients with FM, IL-8 serum level correlated with nicotine consumption (r=0.471, P=0.042).. Our results suggest that IL-8 level contributes in patients with FM whose pain intensity and back function can be improved under influence of multidisciplinary pain therapy without need of an anti-IL-8 therapy.

Topics: Aging; Alcohol Drinking; Back; Biomarkers; Body Mass Index; Combined Modality Therapy; Depression; Female; Fibromyalgia; Humans; Interleukin-8; Longitudinal Studies; Male; Middle Aged; Pain; Pain Measurement; Prospective Studies; Sex Characteristics; Surveys and Questionnaires; Tobacco Use Disorder; Treatment Outcome

Circulating endothelial progenitor cells (EPCs) counts were determined in patients with sickle cell disease (SCD) to elucidate their role in SCD-related ischemia-induced angiogenesis and reendothelialization.. Circulating EPC counts (KDR(+)/CD34(+)/Cd45(dim) cells) and their relation to serum levels of EPC mobilizing growth factors erythropoietin, vascular endothelial growth factor, and interleukin-8 were investigated in SCD patients during asymptomatic state (n=66) and painful crisis (n=36) and compared to healthy controls (n=13).. EPC counts were comparable between controls (0; range, 0-1.1 cells/mL) and patients (0; range, 0-0 cells/mL) in asymptomatic state, but were significantly higher during painful crisis (41.7; range, 0-186 cells/mL; p<0.05). Also in a paired analysis of 12 patients who were included both during asymptomatic state and painful crisis, EPC counts increased significantly during painful crisis (from 0 [range, 0-0] to 26 [range, 0-149 cell/mL; p<0.05). EPC counts were not related to any of the measured growth factors.. The higher EPC counts during painful crisis might indicate a role for EPC mobilization in reendothelialization. As a relationship of EPCs with the established mobilizing growth factors, measured in this study was not observed, the mechanism of EPC mobilization in SCD remains to be elucidated.

Topics: Adult; Anemia, Sickle Cell; Endothelial Cells; Erythropoietin; Female; Humans; Interleukin-8; Ischemia; Leukocyte Count; Male; Neovascularization, Pathologic; Pain; Stem Cells; Vascular Endothelial Growth Factor A

We previously showed that select cytokine gene polymorphisms are a significant predictor for pain reported at initial presentation in 446 white patients newly diagnosed with non-small cell lung cancer. This follow-up study explores the extent to which polymorphisms in tumor necrosis factor-alpha (TNF- alpha-308 G/A), interleukin (IL)-6 -174G/C, and IL-8 -251T/A could explain variability in pain and analgesic response among those patients (n = 140) subsequently referred for pain treatment.. Pain severity (0, no pain; 10, worst pain) was assessed at initial consultation and at follow-up visit. The total dose of opioids at the time of first-follow up visit (30 days postconsult) was converted to an equivalent dose of parenteral morphine.. Forty-one percent (57 of 140) of the patients reported severe pain (score > 7/10) at initial consultation (mean, 5.5), which significantly decreased to 25% (mean, 4) at first follow-up visit (McNemar = P < 0.001). Polymorphisms in TNF and IL-6 were significantly associated with pain severity (for TNF GG, 4.12; GA, 5.38; AA, 5.50; P = 0.04) and with morphine equivalent daily dose (IL-6 GG, 69.61; GC, 73.17; CC, 181.67; P = 0.004), respectively. Adjusting for demographic and clinical variables, variant alleles in TNFalpha -308 G/A remained significantly associated with pain severity (b = 0.226; P = 0.036) and carriers of the IL-6 -174C/C genotypes required 4.7 times higher dose of opioids for pain relief (odds ratio, 4.7; 95% confidence interval, 1.2;15.0) relative to GG and GC genotypes.. We provide preliminary evidence of the influence of cytokine genes on pain and response to analgesia in lung cancer patients. Additional studies are needed to validate our findings. The long-term application is to tailored pain therapies.

Topics: Analgesics; Analysis of Variance; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Chi-Square Distribution; Female; Genetic Variation; Genotype; Humans; Interleukin-6; Interleukin-8; Lung Neoplasms; Male; Pain; Pain Measurement; Palliative Care; Polymorphism, Genetic; Tumor Necrosis Factor-alpha

Cytokines, aberrantly produced by cancer cells, have recently been implicated in the severity of cancer-related pain. We explored if polymorphisms in candidate cytokine genes could explain variability in self-reported pain in lung cancer patients of all stages.. Pain, clinical, and demographic variables were assessed at presentation and before any cancer treatment in 446 Whites, 125 African-Americans, and 35 Hispanics with newly diagnosed non-small cell lung cancer. We genotyped functional single nucleotide polymorphisms in tumor necrosis factor-alpha (TNF-alpha -308 G/A), interleukin-6 (IL-6) -174G/C, and IL-8 -251T/A and determined their associations with pain severity.. More African-Americans (35.5%) reported severe pain (score > or = 7 on a 0-10 scale) relative to Hispanics (20%) and Whites (17%; P < 0.001). We did not observe any significant association between genotypes in TNF-alpha, IL-6, and IL-8 and severe pain for either African-Americans or Hispanics, possibly due to small sample sizes. However, we observed that IL-8 (TT, 13%; TA + AA, 87%; P = 0.04) was significantly associated with severe pain among White patients. Logistic regression analyses showed that after controlling for epidemiologic (age and sex), clinical (stage of disease, comorbidities), and symptom (depressed mood and fatigue) variables known to influence pain severity, variant alleles in IL-8 -251T/A [odds ratio (OR), 2.35; 95% confidence interval (95% CI), 1.10-5.03; P = 0.03] persisted as a significant factor for severe pain for White patients.. In this preliminary analysis, we found evidence of the influence of cytokine genes on pain in White patients with lung cancer. Additional larger studies are needed to validate our findings. The long-term application is to tailored pain therapies.

Topics: Black or African American; Carcinoma, Non-Small-Cell Lung; Genotype; Hispanic or Latino; Humans; Interleukin-6; Interleukin-8; Lung Neoplasms; Pain; Polymorphism, Single Nucleotide; Tumor Necrosis Factor-alpha; White People

Irritable bowel syndrome (IBS) is a functional disorder with an etiology that has been linked to both psychological stress and infection. The primary aim of this study was to examine the hypothalamic-pituitary-adrenal axis in patients with IBS and to relate such response to plasma cytokine profiles.. A total of 151 subjects, 76 patients and 75 controls, were recruited. The patients with IBS were diagnosed according to Rome II criteria. Forty-nine patients and 48 matched controls had cytokine levels measured, and a subset of 21 patients and 21 controls also underwent a corticotropin-releasing hormone (CRH) stimulation test with plasma levels of adrenocorticotropic hormone (ACTH) and cortisol measured. The remaining 27 patients and 27 controls underwent a dexamethasone (1 mg) challenge.. Cortisol and the proinflammatory cytokines interleukin (IL)-6 (together with its soluble receptor) and IL-8 were elevated in all IBS subgroups (diarrhea predominant, constipated, and alternators), although the elevation was most marked in the constipated subgroup. There was no alteration in the anti-inflammatory cytokine IL-10. Following CRH infusion, an exaggerated release of both ACTH and cortisol was observed in patients with IBS. There was a significant correlation between the ACTH response (deltaACTH) and the IL-6 levels. A similar relationship existed between the deltaACTH/deltacortisol ratio and the IL-6 levels. Dexamethasone suppression of cortisol was similar in patients and controls.. IBS is characterized by an overactivation of the hypothalamic-pituitary-adrenal axis and a proinflammatory cytokine increase.

Topics: Adrenocorticotropic Hormone; Adult; Alcohol Drinking; Biomarkers; Cytokines; Dexamethasone; Female; Humans; Hypothalamo-Hypophyseal System; Interleukin-10; Interleukin-6; Interleukin-8; Intestines; Ireland; Irritable Bowel Syndrome; Male; Pain; Reference Values

The chemokines use G protein-coupled receptors to regulate the migratory and proadhesive responses of leukocytes. Based on observations that G protein-coupled receptors undergo heterologous desensitization, we have examined the ability of chemokines to also influence the perception of pain by cross-desensitizing opioid G protein-coupled receptors function in vitro and in vivo. We find that the chemotactic activities of both mu- and delta-opioid receptors are desensitized following activation of the chemokine receptors CCR5, CCR2, CCR7, and CXCR4 but not of the CXCR1 or CXCR2 receptors. Furthermore, we also find that pretreatment with RANTES/CCL5, the ligand for CCR1, and CCR5 or SDF-1alpha/CXCL12, the ligand for CXCR4, followed by opioid administration into the periaqueductal gray matter of the brain results in an increased rat tail flick response to a painful stimulus. Because chemokine administration into the periaqueductal gray matter inhibits opioid-induced analgesia, we propose that the activation of proinflammatory chemokine receptors down-regulates the analgesic functions of opioid receptors, and this enhances the perception of pain at inflammatory sites.

Topics: Analgesics, Opioid; Animals; Cell Line; Cells, Cultured; Chemokine CCL19; Chemokine CXCL12; Chemokines; Chemokines, CC; Chemokines, CXC; Chemotaxis; Enkephalin, D-Penicillamine (2,5)-; Humans; Interleukin-8; Mice; Monocytes; Pain; Receptors, CCR2; Receptors, CCR5; Receptors, CCR7; Receptors, Chemokine; Receptors, CXCR4; Receptors, Opioid, delta; Receptors, Opioid, mu

Intraperitoneal administration of zymosan and acetic acid induced a dose-dependent nociceptive writhing response in mice. Lavage of the peritoneal cavities with saline reduced the number of total resident peritoneal cells and caused a proportional decrease in the nociceptive responses induced by these stimuli. Furthermore, the specific reduction of the peritoneal mast cell population by intraperitoneal administration of compound 48/80 also reduced the nociceptive responses induced by zymosan and acetic acid. In contrast, enhancement of the peritoneal macrophage population by pretreatment of the cavities with thioglycollate caused an increase in the number of writhes induced by both stimuli. These data suggest that the nociceptive responses induced by zymosan and acetic acid are dependent upon the peritoneal resident macrophages and mast cells. These cells modulate the nociceptive response induced by zymosan and acetic acid via release of tumour necrosis factor alpha (TNF-alpha), interleukin 1beta and interleukin 8. This suggestion is supported by the following observations: (a) pretreatment of the peritoneal cavities with antisera against these cytokines reduced the nociceptive responses induced by these stimuli; (b) peritoneal cells harvested from cavities injected with zymosan or acetic acid released both interleukin 1beta and TNF-alpha; (c) although individual injection of TNF-alpha, interleukin 1beta or interleukin 8 did not induce the nociceptive effect, intraperitoneal injection of a mixture of these three recombinant cytokines caused a significant nociceptive writhing response. In conclusion, our results suggest that the nociceptive activity of zymosan and acetic acid in the writhing model is due to the release of TNF-alpha, interleukin 1beta and interleukin 8 by resident peritoneal macrophages and mast cells.

Topics: Acetic Acid; Animals; Cell Count; Cytokines; Dose-Response Relationship, Drug; Iloprost; Immune Sera; Interleukin-1; Interleukin-8; Macrophages, Peritoneal; Male; Mast Cells; Mice; Nociceptors; Pain; Tumor Necrosis Factor-alpha; Zymosan

As a mediator of neurogenic inflammation and pain, we hypothesized that levels of the neuropeptide Substance P (SP) would be elevated in patients with sickle cell disease (SCD) with vaso-occlusive pain crisis. SP is a known stimulator of tumor necrosis factor-alpha (TNF-alpha) release and a promoter of interleukin-8 (IL-8), which are reported to be increased in SCD. These cytokines enhance adhesion of leukocytes to endothelium and may play a role in vaso-occlusive events. Serum levels of IL-8, TNFalpha, and SP were studied in three groups of children aged 2 to 18 years: 30 well children with SCD, 21 with SCD in pain crisis, and 20 healthy age-matched controls. Serum levels of SP were elevated in all SCD patients and were highest in patients in pain crisis. The percentage of sera with detectable levels of IL-8 (>5.0 pmol/L) was increased in SCD patients as compared with the control group. IL-8 levels were similar for well SCD patients and those with pain. TNFalpha levels were not significantly different among the three groups. In three children with SCD, SP was measured at baseline and again during pain crisis. In each case, serum levels during pain crisis were higher than they were when the patient was well. We conclude that levels of SP are high in patients with SCD and increase during pain crisis. These results imply that SP plays a prominent role in the pain and inflammation of SCD and may be a measurable laboratory marker of vaso-occlusive crisis. We speculate that neurokinin receptor antagonists may have a therapeutic potential in the treatment of crisis pain.

Topics: Acute Disease; Adolescent; Anemia, Sickle Cell; Child; Child, Preschool; Female; Humans; Interleukin-8; Ischemia; Male; Pain; Substance P; Tumor Necrosis Factor-alpha

We determined the levels of inflammatory cytokines such as interleukin 6 (IL-6) granulocyte-colony stimulating factor (G-CSF) and IL-8 in the amniotic fluids from women with premature or term delivery. Cytokines were detectable even in the absence of apparent infection (group 1), but much higher cytokine levels were found in cases of intrauterine infection, particularly in cases of premature delivery (group 2). In cases of term delivery (groups 3-5), all of the cytokine levels showed c. 3- to 4-fold increase during labor pain (group 4) and an 8- to 13-fold increase in the presence of endotoxin (group 5), in comparison with the levels in cases where neither factor was present (group 3). Regarding infection, the cytokine levels were 20- to 30-fold higher in chorioamnionitis-positive premature delivery group (group 2), than in the infection-negative group (group 1). All the cytokines were simultaneously induced in amniotic fluid by labor pain and infection, and a significant positive correlation was observed among these three cytokine levels. In-vitro culture system and immunohistochemical study indicated that the cytokines in the amniotic fluid appeared to originate from trophoblasts and decidual cells. Thus, infection and labor pain may trigger the production of inflammatory cytokines at term as well as premature delivery and the determination of these cytokine levels will be a good indication for the prediction of the presence of intrauterine infection.

Topics: Amniotic Fluid; Bacterial Infections; Cells, Cultured; Decidua; Female; Granulocyte Colony-Stimulating Factor; Humans; Immunohistochemistry; Interleukin-6; Interleukin-8; Labor, Obstetric; Obstetric Labor Complications; Obstetric Labor, Premature; Pain; Pregnancy; Trophoblasts

1. The hyperalgesic activities in rats of interleukin-1 beta (IL-1 beta), IL-6, IL-8, tumour necrosis factor alpha (TNF alpha) and carrageenin were investigated. 2. IL-6 activated the previously delineated IL-1/prostaglandin hyperalgesic pathway but not the IL-8/sympathetic mediated hyperalgesic pathway. 3. TNF alpha and carrageenin activated both pathways. 4. Antiserum neutralizing endogenous TNF alpha abolished the response to carrageenin whereas antisera neutralizing endogenous IL-1 beta, IL-6 and IL-8 each partially inhibited the response. 5. The combination of antisera neutralizing endogenous IL-1 beta + IL-8 or IL-6 + IL-8 abolished the response to carrageenin. 6. These results show that TNF alpha has an early and crucial role in the development of inflammatory hyperalgesia. 7. The delineation of the role of TNF alpha, IL-1 beta, IL-6 and IL-8 in the development of inflammatory hyperalgesia taken together with the finding that the production of these cytokines is inhibited by steroidal anti-inflammatory drugs provides a mechanism of action for these drugs in the treatment of inflammatory hyperalgesia.

Topics: Animals; Carrageenan; Indomethacin; Inflammation; Interleukin-1; Interleukin-6; Interleukin-8; Male; Neural Pathways; Nociceptors; Pain; Prostaglandins; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

1. The hyperalgesic effects of interleukin-8 (IL-8), interleukin-1 beta (IL-1 beta) and carrageenin were measured in a rat paw pressure test. 2. IL-8 evoked a dose-dependent hyperalgesia which was attenuated by a specific antiserum, the beta-adrenoceptor antagonists atenolol and propranolol, the dopamine receptor antagonist SCH 23390 and the adrenergic neurone-blocking agent guanethidine. The hyperalgesia was not attenuated by the cyclooxygenase inhibitor indomethacin or the IL-1 beta analogue Lys-D-Pro-Thr. 3. IL-1 beta-evoked hyperalgesia was attenuated by indomethacin and Lys-D-Pro-Thr but not by atenolol or SCH 23390. 4. Carrageenin-evoked hyperalgesia was attenuated by atenolol, indomethacin and anti-IL-8 serum. The effects of atenolol and anti-IL-8 serum were not additive. The effects of indomethacin and anti-IL-8 serum were additive: this combination abolished carrageenin-evoked hyperalgesia. 5. A new biological activity of IL-8 is described, namely the capacity to evoke hyperalgesia by a prostaglandin-independent mechanism. IL-8 is the first endogenous mediator to be identified as evoking hyperalgesia involving the sympathetic nervous system. Since IL-8 is released by activated macrophages and endothelial cells it may be a humoral link between tissue injury and sympathetic hyperalgesia.

Topics: Animals; Atenolol; Benzazepines; Carrageenan; Dinoprostone; Edema; Foot; Guanethidine; Interleukin-1; Interleukin-8; Male; Monocytes; Nociceptors; Pain; Propranolol; Rats; Rats, Inbred Strains; Recombinant Proteins; Sympathetic Nervous System