The limited role of serum neurofilament light chain in predicting pain severity of patients with diabetic polyneuropathy.

Pain is one of many complaints expressed by patients with diabetic polyneuropathy. However, no objective measure for pain severity has been available. Neurofilament light chains have been widely used for assessing axonal damage in the neuronal system. Hence, we sought to investigate whether neurofilament light chains can serve as a marker reflecting pain severity in diabetic polyneuropathy. We enrolled the patients with diabetic polyneuropathy. Serum concentrations of neurofilament light chain were then measured using a single-molecule array. Pain severity was evaluated using painDETECT and the Brief Pain Inventory. Moreover, laboratory results including, serum creatinine, HbA1c, and glomerular filtration rate. A correlation test was used to analyze each variable. A total of 42 patients were enrolled. Neurofilament light chain levels were unable to reflect current neuropathic pain severity. However, high levels of neurofilament light chain were a significant predictor of poor diabetes control (r = 0.41; p = 0.02) and kidney damage (r = 0.45; p = 0.01). Serum levels of neurofilament light chain could not reflect current pain severity but was strongly associated with kidney dysfunction and poor diabetes control. Other biomarkers that could predict pain severity need to be uncovered.

Correlation analysis between the early diagnosis and severity of neuropathic pain and the activation level of NLRP3 inflammasome: A retrospective study.

To investigate the correlation between neuropathic pain's early diagnosis, severity, and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation, we retrospectively evaluated 50 patients with neuropathic pain and 50 healthy individuals. Activation of the NLRP3 inflammasome was measured in blood samples, as well as pain levels and clinical markers. Neuropathic pain patients exhibited elevated NLRP3 inflammasome activation. Pain intensity positively correlated with activation. Correlation was also observed with inflammatory markers and pain-related biomarkers. NLRP3 inflammasome demonstrated high diagnostic sensitivity. In conclusion, NLRP3 inflammasome activation influences neuropathic pain initiation and progression. Measuring activation levels may serve as an early diagnostic indicator and severity gauge for neuropathic pain.

Systematic Review and Metanalysis of the Expression of Blood-Based and Cerebrospinal Fluid-Based Biomarkers Related to Inflammatory Mediators in Neuropathic Pain.

BACKGROUND: The understanding of neuropathic pain remains incomplete, highlighting the need for research on biomarkers for improved diagnosis and treatment. This review focuses on identifying potential biomarkers in blood and cerebrospinal fluid for neuropathic pain in different neuropathies. METHODS: Searches were performed in six databases: PubMed, Web of Science, Scopus, Cochrane Library, EMBASE, and CINAHL. Included were observational studies, namely cross-sectional, cohort, and case-control, that evaluated quantitative biomarkers in blood or cerebrospinal fluid. Data were qualitatively synthesized, and meta-analyses were conducted using R. The study is registered with PROSPERO under the ID CRD42022323769. RESULTS: The literature search resulted in 16 studies for qualitative and 12 for quantitative analysis, covering patients over 18 years of age with painful neuropathies. A total of 1403 subjects were analyzed, identifying no significant differences in levels of C-Reactive Protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-alpha) between patients with and without pain. Despite the high inter-rater reliability and adequate bias assessment, the results suggest negligible differences in inflammatory biomarkers, with noted publication bias and heterogeneity among studies, indicating the need for further research. CONCLUSIONS: Our review underscores the complex nature of neuropathic pain and the challenges in identifying biomarkers, with no significant differences found in CRP, IL-6, and TNF-alpha levels between patients with and without pain. Despite methodological robustness, the results are limited by publication bias and heterogeneity. This emphasizes the need for further research to discover definitive biomarkers for improved diagnosis and personalized treatment of neuropathic pain.

The Identification of Blood Biomarkers of Chronic Neuropathic Pain by Comparative Transcriptomics.

In this study, we recruited 50 chronic pain (neuropathic and nociceptive) and 43 pain-free controls to identify specific blood biomarkers of chronic neuropathic pain (CNP). Affymetrix microarray was carried out on a subset of samples selected 10 CNP and 10 pain-free control participants. The most significant genes were cross-validated using the entire dataset by quantitative real-time PCR (qRT-PCR). In comparative analysis of controls and CNP patients, WLS (P = 4.80 × 10-7), CHPT1 (P = 7.74 × 10-7) and CASP5 (P = 2.30 × 10-5) were highly significant, whilst FGFBP2 (P = 0.00162), STAT1 (P = 0.00223), FCRL6 (P = 0.00335), MYC (P = 0.00335), XCL2 (P = 0.0144) and GZMA (P = 0.0168) were significant in all CNP patients. A three-arm comparative analysis was also carried out with control as the reference group and CNP samples differentiated into two groups of high and low S-LANSS score using a cut-off of 12. STAT1, XCL2 and GZMA were not significant but KIR3DL2 (P = 0.00838), SH2D1B (P = 0.00295) and CXCR31 (P = 0.0136) were significant in CNP high S-LANSS group (S-LANSS score > 12), along with WLS (P = 8.40 × 10-5), CHPT1 (P = 7.89 × 10-4), CASP5 (P = 0.00393), FGFBP2 (P = 8.70 × 10-4) and FCRL6 (P = 0.00199), suggesting involvement of immune pathways in CNP mechanisms. None of the genes was significant in CNP samples with low (< 12) S-LANSS score. The area under the receiver operating characteristic (AUROC) analysis showed that combination of MYC, STAT1, TLR4, CASP5 and WLS gene expression could be potentially used as a biomarker signature of CNP (AUROC - 0.852, (0.773, 0.931 95% CI)).

Influence of Spinal Cord Stimulation on Insulin Sensitivity in Chronic Pain Patients.

BACKGROUND AND OBJECTIVE: This prospective, sham-controlled, randomized, cross-over study (NCT03637075), was designed to test the hypothesis that spinal cord stimulation (SCS) for the treatment of pain can also improve glucose metabolism and insulin sensitivity when compared to sham stimulation. METHODS: Ten non-diabetic participants (5 females, mean age 48.8 years) who had an SCS system implanted for the treatment of chronic neuropathic pain were studied. Whilst applying a hyperinsulinemic-euglycemic clamp, sham-stimulation and tonic stimulation were performed for 45 min (n=4) or 60 min (n=6) in each case randomly. The insulin sensitivity index and pain levels were determined. A second investigation, BurstDR stimulation was also conducted and the result was compared to that of sham stimulation (cross-over design). RESULTS: The insulin sensitivity improved significantly under the tonic stimulation when compared to the sham stimulation (p=0.037). BurstDR stimulation independently did not lead to a significantly improved insulin sensitivity compared to that after sham stimulation (p=0.16). We also examined the pain during the test and found no significant difference between sham and tonic stimulation (p=0.687). CONCLUSION: The results of this study show that tonic stimulation used for the treatment of pain could also improve glucose metabolism and insulin sensitivity. Further investigations are required to investigate the clinical relevance of the role of glucose metabolism in diabetic chronic pain participants and its underlying mechanisms.

Screening of disease-related biomarkers related to neuropathic pain (NP) after spinal cord injury (SCI).

BACKGROUND: Based on the molecular expression level, this paper compares lncRNA and mRNA expressions respectively in peripheral blood samples of the patients after SCI with NP and without NP, and screens disease-related biomarkers related to NP after SCI in peripheral blood samples of patients. METHOD: The expression spectrum of 25 human peripheral blood samples (12 samples of refractory NP patients after SCI) was downloaded and data were normalized. Screening of GO annotations significantly associated with significant differentially expressed mRNAs and significant involvement of the KEGG pathway. The WGCNA algorithm was used to screen for modules and RNAs that were significantly associated with disease characterization. A co-expression network was constructed to extract the genes involved in the disease pathway from the co-expression network, construct a network of SCI pain-related pathways, and screen important disease-related biomarkers. Quantitative real-time PCR was used to detect the mRNA expression of hub genes. RESULTS: Data were normalized and re-annotated by detection of platform information, resulting in a total of 289 lncRNA and 18197 mRNAs. Screening resulted in 338 significant differentially expressed RNAs that met the threshold requirements. Differentially expressed RNAs were significantly enriched with the brown and magenta modules. Six KEGG signaling pathways were screened in the co-expression network, and three KEGG pathways with direct neuropathic pain were identified. The expression levels of E2F1, MAX, MITF, CTNNA1, and ADORA2B in the disease group were all significantly upregulated (p < 0.01). Compared with the normal group, the expression of OXTR was upregulated. CONCLUSION: We speculate that there are 7 genes and 2 lncRNAs directly involved in the pain pathway: E2F1, MAX, MITF, CTNNA1, ADORA2B, GRIK3, OXTR, LINC01119, and LINC02447. These molecules may be important for NP after SCI.

Serum brain-derived neurotrophic factor levels in patients with diabetic neuropathic pain.

OBJECTIVE: Diabetic neuropathic pain (DNP) is one of the most common and severe complications in patients with diabetes. This study aimed to investigate serum brain-derived neurotrophic factor (BDNF) levels in patients with DNP and to evaluate the association between BDNF and disease severity. METHODS: A total of 143 T2DM patients were included, according to clinical characteristics and douleur neuropathique 4 (DN4) questionnaire are divided into the DNP group (n = 78) and without the DNP group (n = 65). BDNF levels were measured by an enzyme-linked immunosorbent assay. Additionally, other biochemical characteristics were measured using routine laboratory methods. RESULTS: Serum levels of BDNF was increased significantly in the DNP group compared to without DNP group. Meanwhile, a binary logistic regression model identified as revealed BDNF (OR = 1.178, 95 %CI = 1.064-1.305,p = 0.002) was a risk factor in T2DM patients. Furthermore, the serum BDNF levels positively correlated with VAS score in the DNP patients. CONCLUSIONS: Serum BDNF was elevated in DNP patients and increased gradually with the VAS score. BDNF was identified as risk factors for pain in all T2DM patients.

Association of time in range, as assessed by continuous glucose monitoring, with painful diabetic polyneuropathy.

AIMS/INTRODUCTION: This study aimed to evaluate the association between time in range (TIR) obtained from continuous glucose monitoring and the prevalence and degree of painful diabetic neuropathy. MATERIALS AND METHODS: A total of 364 individuals with diabetic peripheral neuropathy were enrolled in this study. Sensor-based flash glucose monitoring systems were used to monitor the participants' glucose levels, and the glycemic variability metrics were calculated, including the TIR, glucose coefficient of variation, standard deviation and the mean amplitude of glycemic excursions. The participants were asked to record any form of pain during the 2 weeks of monitoring, and score the pain every day on a numerical rating scale. Based on the numerical rating scale, the patients were divided into the pain-free group, mild pain group and moderate/severe pain group. RESULTS: Overall, 51.92% (189/364) of the participants were diagnosed with painful diabetic neuropathy. Compared with the pain-free group, the level of TIR decreased significantly in the mild pain and moderate/severe pain groups (P < 0.05). The prevalence of mild pain and moderate/severe pain decreased with increasing TIR quartiles (all P < 0.05). Multiple linear regression analysis showed that TIR was significantly negatively correlated with the numerical rating scale score after adjustment for glycated hemoglobin, glycemic variability indicators and other risk factors (P < 0.05). Logistic regression analysis showed that a decreasing level of TIR was significantly associated with an increasing risk of any pain and moderate/severe pain (P < 0.05). CONCLUSIONS: TIR is correlated with painful diabetic neuropathy and is underscored as a valuable clinical evaluation measure.

Correlates of diabetic polyneuropathy of the elderly in Sub-Saharan Africa.

BACKGROUND: Diabetic polyneuropathy is associated with significant physical disability among older adults. However, their frequency and correlates are not well known in the older adults in Sub-Saharan-Africa. The objectives were to evaluate the hospital-based prevalence of diabetic polyneuropathy and identify its correlates in older adults. METHODS: Over a period of 5 months, a cross-sectional survey was carried out at Douala Laquintinie Hospital (DLH), a main reference hospital in Douala, the economic capital of Cameroon. Participants in our study group comprised all patients with type 2 diabetes, whatever the reason for their reporting to the hospital. Diabetic Polyneuropathy was defined according to a Diabetic Neuropathy Examination score > 3/16. RESULTS: A total of 159 older adults with diabetes were examined during this recruitment period, among whom 106 (66.7%) were women. The mean age was 68.3 ± 6.5 years. Diabetes median duration was 108 months. For all patients assessed using the Diabetic Neuropathy Examination score, polyneuropathy was reported in 31.4%; among them, polyneuropathy proved symptomatic in 78% of them. Correlates of polyneuropathy were glycated hemoglobin (p = 0.049), HIV infection (p = 0.031) and albuminuria (p< 0.001), even after adjustment for age, gender and duration of diabetes. CONCLUSION: A third of older adults with diabetes who visited our hospital were diagnosed with prevalent diabetes-related polyneuropathy. It shows that early detection is required through routine screening and regular follow-up examinations in order to reduce the risk of disability and improve the quality of life in elderly diabetics.

Correlation between CGRP Levels and the Neuropathic and Inflammatory Component of Postoperative Pain.

INTRODUCTION: In surgical procedures, tissue damage results in the release of a number of bioactive substances. Calcitonin gene-related peptide (CGRP) is a peptide released from sensory nerves, which determines its role in pain sensation. Its distribution in tissues deter-mines its role as a primary afferent neurotransmitter. AIM: To determine the effect of CGRP on postoperative pain and reactive inflammatory process after surgical removal of impacted mandibular third molars, as well as the factors that have influence upon the perception of pain. MATERIALS AND METHODS: Forty patients with bilaterally impacted mandibular third molars were included in the study. Venous blood samples were collected before and 24 hours after the surgical procedure in order to test their serum levels of CGRP and procalcitonin. Two weeks later the procedure was repeated. The difficulty of the surgical procedure, its duration and complications were assessed in all patients. RESULTS: The influence of some of the studied factors upon postoperative pain was established. Differences in the sensation of pain between the two sexes were found when comparing pain intensity reported by the patients. Significant difference between pain inten-sity after the 1st and 2nd surgical procedures (6 hours) was found in females (Z=2.63, p=0.009;), whereas in males the difference was observed at 24 hours (Z=1.99; p=0.047). Regarding the existence of sex-related association, а significant, strong positive correlation between CGRP levels after the 1st and 2nd surgical procedures (24 hours) was found in males (rxy=0.78; p=0.004), whereas in females this correlation was also significant, although moderately significant (rxy=0.44; p=0.020). CGRP levels at the first and second extractions were generally similar in males, and not as much in females. We proved significantly moderate positive association between CGRP and pulse levels measured before the second surgery (rxy=0.37, p=0.021). CONCLUSION: The results of our study suggest a significant role of CGRP in reactive (neurogenic) inflammation.

Painful trigeminal neuropathy associated with anti-Plexin D1 antibody.

OBJECTIVE: To determine whether anti-Plexin D1 antibody (Plexin D1-immunoglobulin G [IgG]), which is associated with limb and trunk neuropathic pain (NP) and binds to pain-conducting small unmyelinated dorsal root ganglion (DRG) neurons, exists in patients with idiopathic painful trigeminal neuropathy (IPTN) and whether Plexin D1-IgG binds to trigeminal ganglion (TG) neurons. METHODS: We enrolled 21 consecutive patients with IPTN and 35 age- and sex-matched controls without NP (25 healthy persons and 10 with neurodegenerative diseases). We measured serum Plexin D1-IgG using a mouse DRG tissue-based indirect immunofluorescence assay (IFA) and by Western blotting (WB) using a recombinant human Plexin D1 (rhPlexin D1) accompanied by immunoadsorption tests with rhPlexin D1. The reactivity of Plexin D1-IgG toward mouse TG, brain, heart, and kidney was assessed by tissue-based IFAs. RESULTS: Serum Plexin D1-IgG was detected more frequently in IPTN than in controls by both IFA and WB (14.3% vs 0%, p = 0.048). Three Plexin D1-IgG-positive patients also had limb or trunk NP and commonly showed tongue pain. In tissue-based IFAs, IgG from 2 Plexin D1-IgG-positive patients immunostained small TG neurons, which was prevented by preincubation with rhPlexin D1. Moreover, Plexin D1-IgG immunostaining mostly colocalized with isolectin B4-positive pain-conducting unmyelinated TG neurons. IFAs of other tissues with the same IgG revealed weak immunoreactivity only in endothelial cells, which was prevented by preincubation with rhPlexin D1. CONCLUSIONS: Plexin D1-IgG, which binds to pain-conducting small TG neurons in addition to DRG neurons, can be present in IPTN as well as limb and trunk NP.

Treatment induced neuropathy of diabetes.

BACKGROUND: Treatment induced neuropathy of diabetes (TIND) is an iatrogenic painful sensory and autonomic neuropathy. Although the prevalence is not known, it is seen in up to 10% of tertiary cases referred for evaluation of diabetic neuropathy. EVIDENCE: TIND is associated with a decrease in the glycosylated hemoglobin A1C in individuals with longstanding hyperglycemia. TIND is more common in individuals with type 1 diabetes, but can occur in anyone with diabetes through the use of insulin, oral hypoglycemic medications or diet control. There is an acute or subacute onset of neuropathy that is linked to the change in glucose control. Although the primary clinical manifestation is neuropathic pain there is a concurrent development of autonomic dysfunction, retinopathy and nephropathy. CONCLUSION: TIND is more common than previously suspected. The number of cases reported over the past 10 years is much greater than historical literature predicted. Increased attention to target glucose control as a physician metric could suggest a possible explanation for the increased in TIND cases reported in recent years. At present, supportive care is the only recommended treatment. Future research is necessary to define the underlying mechanism, prevent development and to guide treatment recommendations.

Effect of crocin on morphine tolerance and serum BDNF levels in a rat model of neuropathic pain.

BACKGROUND: Chronic use of morphine treatment for neuropathic pain leads to morphine-induced analgesic tolerance. Crocin contained in Crocus sativus L., exerts anti-inflammatory and analgesic effects. This study examined the effects of crocin on morphine tolerance and serum BDNF levels on neuropathic pain induced by chronic constriction injury (CCI) in rats. METHODS: CCI model of neuropathic pain was done in male Wistar rats (200-250 g). Rats were treated with crocin (15 or 30 mg/kg, intraperitoneally) alone or simultaneously with morphine (10 mg/kg, subcutaneously) during or after induction of CCI. Pain behavioral responses including mechanical allodynia and thermal hyperalgesia were measured from days of 15-27 after CCI. Then, rats were evaluated for serum BDNF levels on days 14 and/or 27. RESULTS: We found that morphine tolerance developed after the induction of neuropathic pain. The injection of crocin (15 and 30 mg/kg) was able to enhance analgesic effect of morphine by reduction of mechanical allodynia on days 15-27 post-surgery in CCI rats. While preemptive administration of crocin at a lower dose (15 mg/kg) maintained the analgesic effect of morphine. Morphine injection and/or co-administration with crocin (15, 30 mg/kg) decreased serum BDNF levels in CCI rats. CONCLUSION: These findings indicate that crocin may have a therapeutic effect to maintain morphine analgesic efficacy and also to prevent the development of morphine tolerance in neuropathic pain, but probably not through BDNF.

Cytokine Levels in Neural Pain in Leprosy.

Pain is a frequent symptom in leprosy patients. It may be predominantly nociceptive, as in neuritis, or neuropathic, due to injury or nerve dysfunction. The differential diagnosis of these two forms of pain is a challenge in clinical practice, especially because it is quite common for a patient to suffer from both types of pain. A better understanding of cytokine profile may serve as a tool in assessing patients and also help to comprehend pathophysiology of leprosy pain. Patients with leprosy and neural pain (n = 22), neuropathic pain (n = 18), neuritis (nociceptive pain) (n = 4), or no pain (n = 17), further to those with diabetic neuropathy and neuropathic pain (n = 17) were recruited at Souza Araujo Out-Patient Unit (Fiocruz, Rio de Janeiro, RJ, Brazil). Serum levels of IL1ß, IL-6, IL-10, IL-17, TNF, CCL-2/MCP-1, IFN-γ, CXCL-10/IP-10, and TGF-ß were evaluated in the different Groups. Impairment in thermal or pain sensitivity was the most frequent clinical finding (95.5%) in leprosy neuropathy patients with and without pain, but less frequent in Diabetic Group (88.2%). Previous reactional episodes have occurred in patients in the leprosy and Pain Group (p = 0.027) more often. Analysis of cytokine levels have demonstrated that the concentrations of IL-1ß, TNF, TGF-ß, and IL-17 in serum samples of patients having leprosy neuropathy in combination with neuropathic or nociceptive pain were higher when compared to the samples of leprosy neuropathy patients without pain. In addition, these cytokine levels were significantly augmented in leprosy patients with neuropathic pain in relation to those with neuropathic pain due to diabetes. IL-1ß levels are an independent variable associated with both types of pain in patients with leprosy neuropathy. IL-6 concentration was increased in both groups with pain. Moreover, CCL-2/MCP-1 and CXCL-10/IP-10 levels were higher in patients with diabetic neuropathy over those with leprosy neuropathy. In brief, IL-1ß is an independent variable related to neuropathic and nociceptive pain in patients with leprosy, and could be an important biomarker for patient follow-up. IL-6 was higher in both groups with pain (leprosy and diabetic patients), and could be a therapeutic target in pain control.

Catecholaminergic and opioidergic system mediated effects of reboxetine on diabetic neuropathic pain.

RATIONALE: Current data indicate that the noradrenergic system plays a critical role in neuropathic pain treatment. Notably, drugs that directly affect this system may have curative potential in neuropathy-associated pain. OBJECTIVES: The aim of this study was to evaluate the potential therapeutic efficacy of reboxetine, a potent and selective noradrenaline reuptake inhibitor, on hyperalgesia and allodynia responses in rats with experimental diabetes. Furthermore, mechanistic studies were performed to elucidate the possible mode of actions. METHODS: Experimental diabetes was induced by a single dose of streptozotocin. Mechanical hyperalgesia, mechanical allodynia, thermal hyperalgesia, and thermal allodynia responses in diabetic rats were evaluated by Randall-Selitto, dynamic plantar, Hargreaves, and warm plate tests, respectively. RESULTS: Reboxetine treatment (8 and 16 mg/kg for 2 weeks) demonstrated an effect comparable to that of the reference drug, pregabalin, improving the hyperalgesic and allodynic responses secondary to diabetes mellitus. Pretreatment with phentolamine, metoprolol, SR 59230A, and atropine did not alter the abovementioned effects of reboxetine; however, the administration of α-methyl-para-tyrosine methyl ester, propranolol, ICI-118,551, SCH-23390, sulpiride, and naltrindole significantly inhibited these effects. Moreover, reboxetine did not induce a significant difference in the rat plasma glucose levels. CONCLUSIONS: Our findings indicate that the antihyperalgesic and antiallodynic effects of reboxetine are mediated by the catecholaminergic system; ß2-adrenoceptors; D1-, D2/D3-dopaminergic receptors; and δ-opioid receptors. The results suggest that this analgesic effect of reboxetine, besides its neutral profile on glycemic control, may be advantageous in the pharmacotherapy of diabetic neuropathy-induced pain.

Identifying Plasma Derived Extracellular Vesicle (EV) Contained Biomarkers in the Development of Chronic Neuropathic Pain.

Research into potentially novel biomarkers for chronic pain development is lacking. microRNAs (miRNAs) are attractive candidates as biomarkers due to their conservation across species, stability in liquid biopsies, and variation that corresponds to a pathologic state. miRNAs can be sorted into extracellular vesicles (EVs) within the cell and released from the site of injury. EVs transfer cargo molecules between cells thus affecting key intercellular signaling pathways. The focus of this study was to determine the plasma derived EV miRNA content in a chronic neuropathic pain rat model. This was accomplished by performing either spinal nerve ligation (SNL; n = 6) or sham (n = 6) surgery on anesthetized male Sprague-Dawley rats. Mechanosensitivity was assessed and plasma derived EV RNA was isolated at baseline (BL), day 3, and 15 postnerve injury. EV extracted small RNA was sequenced followed by differentially expressed (DE) miRNAs and gene target enrichment/signaling pathway analysis performed using R packages and TargetScan/Ingenuity pathway analysis (IPA), respectively. Seven of the DE miRNAs were validated by Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR). The data indicated that SNL rats displayed a time-dependent threshold reduction in response to evoked stimuli from day 3 to day 15 postnerve injury. The data also revealed that 22 and 74 miRNAs at day 3 and 15, respectively, and 33 miRNAs at both day 3 and 15 were uniquely DE between the SNL and sham groups. The key findings from this proposal include (1) the majority of the DE EV miRNAs, which normally function to suppress inflammation, were downregulated, and (2) several of the plasma derived DE EV miRNAs reflect previously observed changes in the injured L5 nerve. The plasma derived DE EV miRNAs regulate processes important in the development and maintenance of neuropathic pain states and potentially serve as key regulators, biomarkers, and targets in the progression and treatment of chronic neuropathic pain. PERSPECTIVE: This article describes the DE miRNA content of plasma derived EVs, comparing neuropathic pain to normal conditions. This data indicates that EV miRNAs may be important in nociception and may also serve as biomarkers for chronic pain. These results encourage further research on EV miRNAs in chronic neuropathic pain sufferers.

Deficits in systemic biomarkers of neuroinflammation and growth factors promoting nerve regeneration in patients with type 2 diabetes and polyneuropathy.

Introduction: The determinants and mechanisms contributing to diabetic sensorimotor polyneuropathy (DSPN) remain unclear. Since neuroinflammation and altered nerve regeneration have been implicated in the pathogenesis of both DSPN and neuropathic pain, we hypothesized that the corresponding biomarkers could be associated with DSPN in general and could have the potential to discriminate between the painful and painless DSPN entities. Methods: In a cross-sectional study using multimarker proximity extension assay technology we assessed 71 serum biomarkers including cytokines, chemokines, growth factors, receptors, and others in patients with type 2 diabetes with DSPN (DSPN+) (n=304) or without DSPN (DSPN-) (n=158) and persons with normal glucose tolerance (NGT) without polyneuropathy (n=354). Results: After adjustment for multiple testing and sex, age, body mass index, HbA1c, and smoking, the serum levels of 17 biomarkers (four cytokines, five chemokines, four growth factors, two receptors, two miscellaneous) were lower in DSPN+ than in DSPN- and NGT. In DSPN+, six of these biomarkers were associated with peripheral nerve function. The concentrations of 15 other biomarkers differed between NGT and both DSPN+ and DSPN-, but not between DSPN+ and DSPN-. No differences in biomarker levels were found between patients with painful (n=164) and painless DSPN (n=140). Conclusions: Deficits in systemic cytokines, chemokines, and growth factors promoting nerve regeneration in patients with type 2 diabetes are linked to polyneuropathy in general but not specifically to the painful or painless entity. Trial registration number: NCT02243475.

Current Diagnosis and Treatment of Painful Small Fiber Neuropathy.

PURPOSE OF REVIEW: Small fiber neuropathy (SFN) could cause significant morbidity due to neuropathic pain and autonomic dysfunction. SFN is underdiagnosed and the knowledge on the condition is limited among general public and health care professionals. This review is intended to enhance the understanding of SFN symptoms, causes, diagnostic tools, and therapeutic options. RECENT FINDINGS: There is evidence of SFN in up to 40% patients with fibromyalgia. The causes of SFN are glucose metabolism defect, dysimmune, gluten sensitivity and celiac disease, monoclonal gammopathy, vitamin deficiencies, toxic agents, cancer, and unknown etiology. Auto-antibodies targeting neuronal antigens trisulfated heparin disaccharide (TS-HDS) and fibroblast growth factor 3 (FGFR3) are found in up to 20% of patients with SFN. Treatment of SFN includes treating the etiology and managing symptoms. SFN should be considered in patients with wide-spread body pain. The search for known causes of SFN is a crucial step in disease management.

Neuropathic pain is not associated with serum vitamin D but is associated with female gender in patients with type 2 diabetes mellitus.

Objective: Neuropathic pain is a common complication of diabetes mellitus (DM). Patients may complain of several neuropathic symptoms including impaired peripheral sensation, numbness, tingling, burning, and pain. Because these symptoms may cross with symptoms of vitamin D deficiency, we hypothesized that neuropathic pain and vitamin D deficiency may be associated in patients with type 2 DM. Research design and methods: This is a cross-sectional study that involved 239 participants with type 2 DM. Neuropathic pain was assessed using PainDETECT questionnaire. Serum 25-hydroxyvitamin D was measured by the electrochemiluminescence immunoassay, fasting blood glucose was measured by the hexokinase method and hemoglobin A1c was measured by the turbidimetric inhibition immunoassay. Results: The prevalence of neuropathic pain among type 2 DM participants was 26.8%. Vitamin D deficiency was reported in 67.8% of type 2 DM participants. The neuropathy score for females was significantly higher than that for males (p<0.01). There was no significant difference in serum vitamin D between type 2 DM participants according to their gender and according to their neuropathy status (p>0.05). Ordinal logistic regression analysis has shown that female gender was the only significant predictor of neuropathic pain among type 2 DM participants (p<0.01 with an OR (95% CI) of 2.45 (1.29 to 4.67)). Conclusions: Neuropathic pain was not associated with serum vitamin D but was associated with female gender in type 2 DM. Because our results were not consistent with other studies that used different neuropathy assessment tools, we suggest that further research should be conducted to check the validity of these tools in identifying subjects with neuropathy.

Frontline Science: Blood-circulating leukocytes fail to infiltrate the spinal cord parenchyma after spared nerve injury.

The development of neuropathic pain after peripheral nerve injury involves neuroimmune-glial interactions in the spinal cord. However, whether the development of neuropathic pain depends on the infiltration of peripheral immune cells, such as monocytes, into the spinal cord parenchyma after peripheral nerve damage remains unclear. Here, we used a combination of different techniques such as transgenic reporter mouse (Cx3cr1GFP/+ and Ccr2RFP/+ mice), bone marrow chimeric mice, and parabiosis to investigate this issue in spared nerve injury (SNI) model. Herein, we provided robust evidence that, although microglial cells are activated/proliferate at the dorsal horn of the spinal cord after SNI, peripheral hematopoietic cells (including monocytes) are not able to infiltrate into the spinal cord parenchyma. Furthermore, there was no evidence of CCR2 expression in intrinsic cells of the spinal cord. However, microglial cells activation/proliferation in the spinal cord and mechanical allodynia after SNI were reduced in Ccr2-deficient mice. These results suggest that blood-circulating leukocytes cells are not able to infiltrate the spinal cord parenchyma after distal peripheral nerve injury. Nevertheless, they indicate that CCR2-expressing cells might be indirectly regulating microglia activation/proliferation in the spinal cord after SNI. In conclusion, our study supports that CCR2 inhibition could be explored as an interventional approach to reduce microglia activation and consequently neuropathic pain development after peripheral nerve injury.