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Cumulative evidence suggests that abnormal differentiation of T lymphocytes influences the pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Thus, understanding the immune activation landscape of CP/CPPS would be helpful for improving therapeutic strategies. Here, we utilized BD™ AbSeq to digitally quantify both the protein and mRNA expression levels in single peripheral blood T cells from two CP/CPPS patients and two healthy controls. We utilized an integrated strategy based on canonical correlation analysis of 10 000+ AbSeq profiles and identified fifteen unique T-cell subpopulations. Notably, we found that the proportion of cluster 0 in the CP/CPPS group (30.35%) was significantly increased compared with the proportion in the healthy control group (9.38%); cluster 0 was defined as effector T cells based on differentially expressed genes/proteins. Flow cytometry assays confirmed that the proportions of effector T-cell subpopulations, particularly central memory T cells, T helper (Th)1, Th17 and Th22 cells, in the peripheral blood mononuclear cell populations of patients with CP/CPPS were significantly increased compared with those of healthy controls (P < 0.05), further confirming that aberration of effector T cells possibly leads to or intensifies CP/CPPS. Our results provide novel insights into the underlying mechanisms of CP/CPPS, which will be beneficial for its treatment.
Learn More >Evidence suggests a bidirectional association between migraine and depression in individuals and in twins. However, whether a bidirectional association between migraine and depression also occurs among siblings (probands and unaffected nontwin siblings) remains unknown.
Learn More >Atopic dermatitis is a common, chronic inflammatory skin disease that is characterized by skin barrier dysfunction, inflammation and intense itch. Although the exact mechanisms behind its pathogenesis remain unclear, it is evident that the complex interplay among barrier dysfunction, inflammation and itch are critical in its development, progression and chronicity. Abnormalities in filaggrin, intercellular lipids and tight junctions induce barrier-disrupted skin, which produces thymic stromal lymphopoietin, interleukin (IL)-25 and IL-33; these in turn promote skin inflammation characterized by type 2 immune deviation. This inflammation then downregulates the expression of filaggrin in keratinocytes and exacerbates epidermal barrier dysfunction. Furthermore, various itch mediators/pruritogens produced during this inflammatory process can act directly on sensory nerves and cause itch. In this review, we summarize the basics and recent advances in our understanding of the pathophysiology of atopic dermatitis focusing on three aspects: barrier dysfunction, skin inflammation and itch.
Learn More >Identifying the optimal fremanezumab treatment strategy is crucial in treating patients with migraines. The optimal strategy was investigated by assessing the cumulative 50% reduction rate (50%CRR), cumulative 75% reduction rate (75%CRR), reduction in the number of migraine days, treatment-related adverse events, and serious adverse events in patients treated with fremanezumab 225 mg monthly (225 mg), 675 mg monthly (675 mg), 900 mg monthly (900 mg), a single high dose of 675 mg (S675mg), 675 mg at baseline with 225 mg monthly (675/225 mg), and placebo. Biomedical databases were searched for randomized controlled trials on this topic, and data were individually extracted. Risk ratios and mean differences were used to present the pooled results. The surface under the cumulative ranking curve (SUCRA) was used to determine the effects of the medication strategies of fremanezumab. Five trials (n = 3404) were used to form a six-node network meta-analysis. All fremanezumab medication strategies displayed significantly higher cumulative 50% reduction rates than the placebo. The SUCRA revealed that treatment with 675 mg yielded the highest 50%CRR value (mean rank = 2.5). S675 mg was the only treatment with significantly higher 75%CRR reduction rate than placebo, whereas the SUCRA for 225 mg displayed the highest mean rank (2.2). Moreover, 225 mg (mean rank = 2.2) and S675 mg (mean rank = 2.2) presented lower probabilities of serious adverse events. Collectively, S675mg and 225 mg exhibited the optimal balance between efficacy and safety within three months. Long-term efficacy and safety remain unclear, and future studies should further evaluate the long-term outcomes.
Learn More >The newly designed fentanyl derivative [( ±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide] (NFEPP) was recently shown to produce analgesia selectively via peripheral mu-opioid receptors (MOR) at acidic pH in rat inflamed tissues. Here, we examined the pH-dependency of NFEPP binding to brain MOR and its effects on bone cancer-induced pain in mice. The IC of NFEPP to displace bound [H]-DAMGO was significantly higher compared to fentanyl at pH 7.4, but no differences were observed at pH 5.5 or 6.5. Intravenous NFEPP (30-100 nmol/kg) or fentanyl (17-30 nmol/kg) inhibited heat hyperalgesia in mice inoculated with B16-F10 melanoma cells. The peripherally-restricted opioid receptor antagonist naloxone-methiodide reversed the effect of NFEPP (100 nmol/kg), but not of fentanyl (30 nmol/kg). The antihyperalgesic effect of NFEPP was abolished by a selective MOR- (cyprodime), but not delta- (naltrindole) or kappa- (nor-binaltorphimine) receptor antagonists. Ten-fold higher doses of NFEPP than fentanyl induced maximal antinociception in mice without tumors, which was reversed by the non-restricted antagonist naloxone, but not by naloxone-methiodide. NFEPP also reduced heat hyperalgesia produced by fibrosarcoma- (NCTC 2472) or prostate cancer-derived (RM1) cells. These data demonstrate the increased affinity of NFEPP for murine MOR at low pH, and its ability to inhibit bone cancer-induced hyperalgesia through peripheral MOR. In mice, central opioid receptors may be activated by ten-fold higher doses of NFEPP.
Learn More >TRPM3 channels play important roles in the detection of noxious heat and in inflammatory thermal hyperalgesia. The activity of these ion channels in somatosensory neurons is tightly regulated by µ-opioid receptors through the signaling of Gβγ proteins, thereby reducing TRPM3-mediated pain. We show here that Gβγ directly binds to a domain of 10 amino acids in TRPM3 and solve a cocrystal structure of this domain together with Gβγ. Using these data and mutational analysis of full-length proteins, we pinpoint three amino acids in TRPM3 and their interacting partners in Gβ that are individually necessary for TRPM3 inhibition by Gβγ. The 10-amino-acid Gβγ-interacting domain in TRPM3 is subject to alternative splicing. Its inclusion in or exclusion from TRPM3 channel proteins therefore provides a mechanism for switching on or off the inhibitory action that Gβγ proteins exert on TRPM3 channels.
Learn More >Published assays for mechanical nociception in Drosophila have led to variable assessments of behavior. Here, we fabricated, for use with Drosophila larvae, customized metal nickel-titanium alloy (nitinol) filaments. These mechanical probes are similar to the von Frey filaments used in vertebrates to measure mechanical nociception. Here, we demonstrate how to make and calibrate these mechanical probes and how to generate a full behavioral dose-response from subthreshold (innocuous or non-noxious range) to suprathreshold (low to high noxious range) stimuli. To demonstrate the utility of the probes, we investigated tissue damage-induced hypersensitivity in Drosophila larvae. Mechanical allodynia (hypersensitivity to a normally innocuous mechanical stimulus) and hyperalgesia (exaggerated responsiveness to a noxious mechanical stimulus) have not yet been established in Drosophila larvae. Using mechanical probes that are normally innocuous or probes that typically elicit an aversive behavior, we found that Drosophila larvae develop mechanical hypersensitization (both allodynia and hyperalgesia) after tissue damage. Thus, the mechanical probes and assay that we illustrate here will likely be important tools to dissect the fundamental molecular/genetic mechanisms of mechanical hypersensitivity.
Learn More >Inhibiting the activity of fatty-acid amide hydrolase (FAAH), the enzyme that deactivates the endocannabinoid anandamide, enhances anandamide-mediated signaling and holds promise as a molecular target for the treatment of human pathologies such as anxiety and pain. We have previously shown that the peripherally restricted FAAH inhibitor, URB937, prevents nitroglycerin-induced hyperalgesia – an animal model of migraine – and attenuates the activation of brain areas that are relevant for migraine pain, e.g. trigeminal nucleus caudalis and locus coeruleus. The current study is aimed at profiling the behavioral and biochemical effects of URB937 in animal models of acute and chronic migraine. We evaluated the effects of URB937 in two rat models that capture aspects of acute and chronic migraine, and are based on single or repeated administration of the vasodilating drug, nitroglycerin (NTG). In addition to nocifensive behavior, in trigeminal ganglia and medulla, we measured mRNA levels of neuropeptides and pro-inflammatory cytokines along with tissue levels of anandamide and palmitoylethanolamide (PEA), an endogenous agonist of peroxisome proliferator-activated receptor type-a (PPAR-a), which is also a FAAH substrate. In the acute migraine model, we also investigated the effect of subtype-selective antagonist for cannabinoid receptors 1 and 2 (AM251 and AM630, respectively) on nocifensive behavior and on levels of neuropeptides and pro-inflammatory cytokines. In the acute migraine paradigm, URB937 significantly reduced hyperalgesia in the orofacial formalin test when administered either before or after NTG. This effect was accompanied by an increase in anandamide and PEA levels in target neural tissue, depended upon CB1 receptor activation, and was associated with a decrease in calcitonin gene-related peptide (CGRP), substance P and cytokines TNF-alpha and IL-6 mRNA. Similar effects were observed in the chronic migraine paradigm, where URB937 counteracted NTG-induced trigeminal hyperalgesia and prevented the increase in neuropeptide and cytokine transcription. The results show that peripheral FAAH inhibition by URB937 effectively reduces both acute and chronic NTG-induced trigeminal hyperalgesia, likely via augmented anandamide-mediated CB1 receptor activation. These effects are associated with inhibition of neuropeptidergic and inflammatory pathways.
Learn More >Mechanism-based classification of pain has been advocated widely to aid tailoring of interventions for individuals experiencing persistent musculoskeletal pain. Three pain mechanism categories are defined by the International Association for the Study of Pain: nociceptive, neuropathic, and nociplastic pain. Discrimination between them remains challenging. This study aimed to: build on a framework developed to converge the diverse literature of pain mechanism categories to systematically review methods purported to discriminate between them; synthesise and thematically analyse these methods to identify convergence and divergence of opinion; and report validation, psychometric properties and strengths/weaknesses of these methods. The search strategy identified papers discussing methods to discriminate between mechanism-based categories of pain experienced in the musculoskeletal system. Studies that assessed validity of methods to discriminate between categories were assessed for quality. Extraction and thematic analysis were undertaken on 184 papers. Data synthesis identified 200 methods in five themes: clinical examination, quantitative sensory testing, imaging, diagnostic and laboratory testing, and pain-type questionnaires. Few methods have been validated for discrimination between pain mechanism categories. There was general convergence but some disagreement regarding findings that discriminate between pain mechanism categories. A combination of features and methods, rather than a single method, was generally recommended to discriminate between pain mechanism categories. Two major limitations were identified: overlap of findings of methods between categories due to mixed presentations, and many methods considered discrimination between two pain mechanism categories but not others. The results of this review provide a foundation to refine methods to differentiate mechanisms for musculoskeletal pain.
Learn More >The personalization of neuropathic pain treatment could be improved by identifying specific sensory phenotypes (i.e. specific combinations of symptoms and signs) predictive of the response to different classes of drugs. A simple and reliable phenotyping method is required for such a strategy. We investigated the utility of an algorithm for stratifying patients into clusters corresponding to specific combinations of neuropathic symptoms assessed with the Neuropathic Pain Symptom Inventory (NPSI). Consistent with previous results, we first confirmed, in a cohort of 628 patients, the existence of a structure consisting of three clusters of patients characterized by higher NPSI scores for: pinpointed pain (cluster 1), evoked pain (cluster 2) or deep pain (cluster 3). From these analyses, we derived a specific algorithm for assigning each patient to one of these three clusters. We then assessed the clinical relevance of this algorithm for predicting treatment response, through post hoc analyses of two previous controlled trials of the effects of subcutaneous injections of botulinum toxin A (BTX-A). Each of the 97 patients with neuropathic pain included in these studies was individually allocated to one cluster, by applying the algorithm to their baseline NPSI responses. We found significant effects of BTX-A relative to placebo in clusters 2 and 3, but not in cluster 1, suggesting that this approach was, indeed, relevant. Finally, we developed and performed a preliminary validation of a web-based version of the NPSI and algorithm for the stratification of patients in both research and daily practice.
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