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Migraine and headache frequently co-occur with type 2 diabetes (T2D), suggesting a shared aetiology between the two conditions. We used genome-wide association study (GWAS) data to investigate the genetic overlap and causal relationship between migraine and headache with T2D. Using linkage disequilibrium score regression (LDSC), we found a significant genetic correlation between migraine and T2D ( = 0.06, = 1.37 × 10) and between headache and T2D ( = 0.07, = 3.0 × 10). Using pairwise GWAS (GWAS-PW) analysis, we identified 11 pleiotropic regions between migraine and T2D and 5 pleiotropic regions between headache and T2D. Cross-trait SNP meta-analysis identified 23 novel SNP loci ( < 5 × 10) associated with migraine and T2D, and three novel SNP loci associated with headache and T2D. Cross-trait gene-based overlap analysis identified 33 genes significantly associated ( < 3.85 × 10) with migraine and T2D, and 11 genes associated with headache and T2D, with 7 genes (, , , , , , and ) common between them. There was also a significant overlap of genes nominally associated ( < 0.05) with both migraine and T2D ( = 2.83 × 10) and headache and T2D ( = 4.08 × 10). Mendelian randomisation (MR) analyses did not provide consistent evidence for a causal relationship between migraine and T2D. However, we found headache was causally associated (inverse-variance weighted, OR = 0.90, = 7 × 10) with T2D. Our findings robustly confirm the comorbidity of migraine and headache with T2D, with shared genetically controlled biological mechanisms contributing to their co-occurrence, and evidence for a causal relationship between headache and T2D.
Learn More >MRI-based resting-state functional connectivity (rsFC) has been shown to predict response to pharmacological and non-pharmacological treatments for chronic pain, but not yet for motor cortex transcranial magnetic stimulation (M1-rTMS). Twenty-seven fibromyalgia syndrome (FMS) patients participated in this double-blind, crossover, and sham-controlled study. Ten daily treatments of 10 Hz M1-rTMS were given over 2 weeks. Before treatment series, patients underwent resting-state fMRI and clinical pain evaluation. Significant pain reduction occurred following active, but not sham, M1-rTMS. The following rsFC patterns predicted reductions in clinical pain intensity after the active treatment: weaker rsFC of the default-mode network with the middle frontal gyrus (r = 0.76, p < 0.001), the executive control network with the rostro-medial prefrontal cortex (r = 0.80, p < 0.001), the thalamus with the middle frontal gyrus (r = 0.82, p < 0.001), and the pregenual anterior cingulate cortex with the inferior parietal lobule (r = 0.79, p < 0.001); and stronger rsFC of the anterior insula with the angular gyrus (r = - 0.81, p < 0.001). The above regions process the attentional and emotional aspects of pain intensity; serve as components of the resting-state networks; are modulated by rTMS; and are altered in FMS. Therefore, we suggest that in FMS, the weaker pre-existing interplay between pain-related brain regions and networks, the larger the pain relief resulting from M1-rTMS.
Learn More >Neuropathic pain is a condition that impacts a substantial portion of the population and is expected to affect a larger percentage in the future. This type of pain is poorly managed by current therapies, including opioids and NSAIDS, and novel approaches are needed. We used a cisplatin-induced model of neuropathic pain in mice to assess the effects of the cannabinoids THC and CBD alone or in varying ratios as anti-nociceptive agents. In addition to testing pure compounds, we also tested extracts containing high THC or CBD at the same ratios. We found that pure CBD had little impact on mechanical hypersensitivity, whereas THC reduced mechanical hypersensitivity in both male and female mice (as has been reported in the literature). Interestingly, we found that high CBD cannabis extract, at the same CBD dose as pure CBD, was able to reduce mechanical hypersensitivity, although not to the same level as high THC extract. These data suggest that, at least for CBD-dominant cannabis extracts, there is an increase in the anti-nociceptive activity that may be attributed to other constitutes of the plant. We also found that high THC extract or pure THC is the most efficacious treatment for reducing neuropathic pain in this model.
Learn More >Measuring outcomes in clinical practice can aid patient care, quality improvement, and real-world evidence generation. The Harmonising Outcome Measures for Eczema (HOME) Clinical Practice initiative is developing a list of validated, feasible instruments to measure atopic eczema in clinical care. Prior work identified symptoms and long-term control as the most important domains to measure in clinical practice. The Patient-Oriented Eczema Measure (POEM) and the Patient-Oriented Scoring Atopic Dermatitis Index (PO-SCORAD) were recommended by consensus to measure symptoms in clinical practice, but a need for instruments to measure itch intensity specifically was recognized. The HOME group also previously decided that long-term control should be captured by repeated measurements of eczema control. Recommended instruments to measure eczema control in clinical practice have not been defined.
Learn More >Brain-derived neurotrophic factor (BDNF) is a neurotrophin regulating synaptic plasticity, neuronal excitability, and nociception. It seems to be one of the key molecules in interactions between the central nervous system and immune-related diseases, i.e., diseases with an inflammatory background of unknown etiology, such as inflammatory bowel diseases or rheumatoid arthritis. Studies show that BDNF levels might change in the tissues and serum of patients during the course of these conditions, e.g., affecting cell survival and modulating pain severity and signaling pathways involving different neurotransmitters. Immune-related conditions often feature psychiatric comorbidities, such as sleep disorders (e.g., insomnia) and symptoms of depression/anxiety; BDNF may be related as well to them as it seems to exert an influence on sleep structure; studies also show that patients with psychiatric disorders have decreased BDNF levels, which increase after treatment. BDNF also has a vital role in nociception, particularly in chronic pain, hyperalgesia, and allodynia, participating in the formation of central hypersensitization. In this review, we summarize the current knowledge on BDNF's function in immune-related diseases, sleep, and pain. We also discuss how BDNF is affected by treatment and what consequences these changes might have beyond the nervous system.
Learn More >Fibroblast Growth Factor Homologous Factors (FHFs) are cytosolic members of the of the FGF proteins. Four members of this subfamily (FHF1-4) are differentially expressed in multiple tissues in an isoform-dependent manner. Mutations in FHF proteins have been associated with multiple neurological disorders. FHF proteins bind to the C-terminus of voltage-gated sodium (Nav) channels and regulate current amplitude and gating properties of these channels. FHF2, which is expressed in DRG neurons, has two main splicing isoforms, FHF2A and FHF2B, which differ in the length and sequence of their N-termini, have been shown to differentially regulate gating properties of Nav1.7, a channel that is a major driver of DRG neuron firing. FHF2 expression levels are downregulated following peripheral nerve axotomy, which suggests that they may regulate neuronal excitability via an action on Nav channels after injury. We have previously shown that knockdown of FHF2 leads to gain-of-function changes in Nav1.7 gating properties: enhanced repriming, increased current density and hyperpolarized activation. From this we posited that knockdown of FHF2 might also lead to DRG hyperexcitability. Here we show that knockdown of either FHF2A alone or all isoforms of FHF2 results in increased DRG neuron excitability. In addition, we demonstrate that supplementation of FHF2A and FHF2B reduces DRG neuron excitability. Overexpression of FHF2A or FHF2B also reduced excitability of DRG neurons treated with a cocktail of inflammatory mediators, a model of inflammatory pain. Our data suggest that increased neuronal excitability after nerve injury might be triggered, in part, via a loss of FHF2-Nav1.7 interaction.
Learn More >Understanding of the basis of osteoarthritis (OA) has seen some interesting advancements in recent years. It has been observed that cartilage degeneration is preceded by subchondral bone lesions, suggesting a key role of this mechanism within the pathogenesis and progression of OA, as well as the formation of ectopic bone and osteophytes. Moreover, low-grade, chronic inflammation of the synovial lining has gained a central role in the definition of OA physiopathology, and central immunological mechanisms, innate but also adaptive, are now considered crucial in driving inflammation and tissue destruction. In addition, the role of neuroinflammation and central sensitization mechanisms as underlying causes of pain chronicity has been characterized. This has led to a renewed definition of OA, which is now intended as a complex multifactorial joint pathology caused by inflammatory and metabolic factors underlying joint damage. Since this evidence can directly affect the definition of the correct therapeutic approach to OA, an improved understanding of these pathophysiological mechanisms is fundamental. To this aim, this review provides an overview of the most updated evidence on OA pathogenesis; it presents the most recent insights on the pathophysiology of OA, describing the interplay between immunological and biochemical mechanisms proposed to drive inflammation and tissue destruction, as well as central sensitization mechanisms. Moreover, although the therapeutic implications consequent to the renewed definition of OA are beyond this review scope, some suggestions for intervention have been addressed.
Learn More >The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field.
Learn More >Low back and radicular pain syndromes, usually caused by local inflammation and irritation to the nerve root and dorsal root ganglion (DRG), are common throughout medical practice, but sufficient pain relief is scarce. In this study, we employed a chronic compression of DRG (CCD)-induced radicular pain model in rats to explore whether lysine-specific demethylase 1 (LSD1), a histone demethylase and transcriptional co-repressor, is involved in the pathological process of radicular pain. We found that LSD1 was expressed in various-sized DRG neurons by immunohistochemistry. CCD induced the upregulation of LSD1 in compressed L-L DRGs. Moreover, either LSD1 small interfering RNAs or LSD1 inhibitor attenuated CCD-induced pain hypersensitivities. LSD1 was also upregulated in the injured lumbar 4 (L) DRG in a spinal nerve ligation (SNL)-induced neuropathic pain mouse model. Nevertheless, LSD1 was not altered in L-L DRGs in complete Freund's adjuvant-induced inflammatory pain mouse model, paclitaxel- or streptozotocin-induced neuropathic pain models. Furthermore, knockdown of LSD1 in the injured L DRG reversed SNL-induced pain hypersensitivities in mice. Therefore, we speculate that nerve injury induced the upregulation of LSD1 in the injured DRGs, which contributes to neuropathic pain hypersensitivities; thus, LSD1 may serve as a potential target for the treatment of radicular pain and neuropathic pain.
Learn More >Patients with chronic pain exhibit anxiety and deficits in memory. Additionally, α-adrenoceptors that are wildly expressed in the brain have an important role in modulating both pain and memory formation. In the present study, we investigated the interaction effects of crocin with central α-adrenoceptors on pain comorbidity and hippocampal synaptic plasticity changes following chronic constriction injury (CCI) of the sciatic nerve in rats. All the drugs (crocin, an antagonist (yohimbine) and agonist (clonidine) of α-adrenergic receptors) were injected (via intracerebroventricular injection) from the day of CCI operation (day 0) and continued daily (once per day) until the 14 day post-CCI. The effects of drugs on the cold allodynia (using acetone test) and anxiety-like behaviors (using elevated plus maze, EPM and open field tests) were assessed. Spatial memory (using Barnes maze) was assessed on day 14 post-CCI operation. Hippocampal synaptic plasticity (using in-vivo extracellular field potential recording) was performed on day 14 post-CCI operation. We observed that crocin induced analgesic, anxiolytic and memory enhancer action following CCI surgery. Furthermore, crocin significantly increased long-term potentiation (LTP) (increased fEPSP slope and population spike amplitude). Furthermore, the co-injection of yohimbine effectively decreased analgesic, anxiolytic and enhancer action of crocin on the LTP parameters (fEPSP slope and population spike amplitude). Our study provided information that protective effects of crocin on pain/anxiety responses and synaptic plasticity were possibly mediated by central α-adrenoceptor in the rats with chronic pain.
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