Browse by Audience
Voltage-gated sodium channels (VGSCs), formed by 24 transmembrane segments arranged into four domains, have a key role in the initiation and propagation of electrical signaling in excitable cells. VGSCs are involved in a variety of diseases, including epilepsy, cardiac arrhythmias, and neuropathic pain, and, therefore, have been regarded as appealing therapeutic targets for the development of anticonvulsant, antiarrhythmic, and local anesthetic drugs. In this review, we discuss recent advances in understanding the structures and biological functions of VGSCs. In addition, we systematically summarize eight pharmacologically distinct ligand-binding sites in VGSCs and representative isoform-selective VGSC modulators in clinical trials. Finally, we review studies on molecular modeling and computer-aided drug design (CADD) for VGSCs to help understanding of biological processes involving VGSCs.
Learn More >The molecular mechanisms underlying neuropathic pain (NP) remain poorly understood. Emerging evidence has suggested the role of microRNAs (miRNAs) in the initiation and development of NP, but the specific effects of miRNAs in NP are largely unknown. Here, we use network- and pathway-based methods to investigate NP-induced miRNA changes and their biological functions by conducting a systematic search through multiple electronic databases. Thirty-seven articles meet the inclusion criteria. Venn analysis and target gene forecasting are performed and the results indicate that 167 overlapping target genes are co-regulated by five down-regulated miRNAs (rno-miR-183, rno-miR-96, rno-miR-30b, rno-miR-150 and rno-miR-206). Protein-protein interaction network analysis shows that 77 genes exhibit interactions, with cyclic adenosine monophosphate (cAMP)-dependent protein kinase catalytic subunit beta (degree = 11) and cAMP-response element binding protein 1 (degree = 10) having the highest connectivity degree. Gene ontology analysis shows that these target genes are enriched in neuron part, neuron projection, somatodendritic compartment and nervous system development. Moreover, analysis of Kyoto Encyclopedia of Genes and Genomes reveals that three pathways, namely, axon guidance, circadian entrainment and insulin secretion, are significantly enriched. In addition, rno-miR-183, rno-miR-96, rno-miR-30b, rno-miR-150 and rno-miR-206 are consistently down-regulated in the NP models, thus constituting the potential biomarkers of this disease. Characterizing these miRNAs and their target genes paves way for their future use in clinical practice.
Learn More >Trigeminal neuralgia (TN) is a type of chronic neuropathic pain that is caused by peripheral nerve lesions that result from various conditions, including the compression of vessels, tumors and viral infections. MicroRNAs (miRs) are increasingly recognized as potential regulators of neuropathic pain. Previous evidence has demonstrated that miR-195 is involved in neuropathic pain, but the mechanism remains unclear. To investigate the pathophysiological role of miR-195 and Shh signaling in TN, persistent facial pain was induced by infraorbital nerve chronic constriction injury (CCI-IoN), and facial pain responses were evaluated by Von Frey hairs. qPCR and Western blotting were used to determine the relative expression of miR-195 and Patched1, the major receptor of the Sonic Hedgehog (Shh) signaling pathway, in the caudal brain stem at distinct time points after CCI-IoN. Here, we found that the expression of miR-195 was increased in a rat model of CCI-IoN. In contrast, the expression of Patched1 decreased significantly. Luciferase assays confirmed the binding of miR-195 to Patched1. In addition, the overexpression of miR-195 by an intracerebroventricular (i.c.v) administration of LV-miR-195 aggravated facial pain development, and this was reversed by upregulating the expression of Patched1. These results suggest that miR-195 is involved in the development of TN by targeting Patched1 in the Shh signaling pathway, thus regulating extracellular glutamate.
Learn More >Persistent postsurgical pain (PPP) is defined as the discomfort that lasts >3 months postoperatively. The primary aim of this retrospective study was to estimate the risk of developing moderate-to-severe PPP after primary total knee arthroplasty (TKA). The secondary goal was to explore potential predictors of this outcome.Data were collected via hospital arthroplasty registry and chart review. The risk of moderate-to-severe PPP, defined as ≥4 on the numerical rating scale (NRS) at minimum of 3 months post-surgery, was calculated. Multivariable logistic regression was used to estimate the association of patient demographics, diagnoses, length of hospital stay, and preoperative NRS with the odds of developing PPP. Exploratory, simple logistic regression was used to estimate the association of perioperative factors with the odds of developing PPP on a subset of patients (n = 72).The risk of PPP after TKA was 31.3% (95% confidence interval [CI]: 27.5-35.0) (n = 578). Every 2-point increase in baseline NRS was associated with 1.66 (95% CI: 1.37-2.03) times the odds of developing PPP (P < .001). African-Americans (vs whites) had 1.82 (95% CI: 1.03-3.22) times the odds of developing PPP (P = .040). Exploratory analysis suggested that the adductor canal saphenous nerve (vs femoral nerve) blocks were associated with 2.87 (95% CI: 1.00-8.26) times the odds of developing PPP (P = .049).This study estimated a high risk (31.3%) of moderate-to-severe PPP after primary TKA. This study suggested that higher preoperative pain scores might be associated with greater odds of developing PPP. Moreover, this study suggested the possibility that racial differences and types of peripheral nerve blocks might be associated with greater odds of developing moderate-to-severe PPP after TKA surgery. However, the evidence obtained from our exploratory analysis of limited data certainly requires further exploration in large-scale studies.
Learn More >Diffuse noxious inhibitory controls (DNIC) is a pain inhibits pain phenomenon demonstrated in humans and animals. DNIC is diminished in many chronic pain states, including neuropathic pain. The efficiency of DNIC has been suggested to prospectively predict both the likelihood of pain chronification and treatment response. Little is known as to why DNIC is dysfunctional in neuropathic pain. Here, we evaluated DNIC in the rat L5/L6 spinal nerve ligation (SNL) model of chronic pain using both behavioral and electrophysiological outcomes. For behavior, nociceptive thresholds were determined using response to noxious paw pressure on both hindpaws as the test stimulus before, and after, injection of a conditioning stimulus of capsaicin into the left forepaw. Functionally, the spike firing of spinal wide dynamic range (WDR) neuronal activity was evaluated before and during noxious ear pinch, whilst stimulating the ipsilateral paw with von Frey hairs of increased bending force. In both assays, the DNIC response was significantly diminished in the ipsilateral (i.e., injured) paw of SNL animals. However, behavioral loss of DNIC was not observed on the contralateral (i.e., uninjured) paw. Systemic application of nor-Binaltorphimine (nor-BNI), a kappa opioid antagonist, did not ameliorate SNL-induced hyperalgesia but reversed loss of the behavioral DNIC response. Microinjection of nor-BNI into the right central amygdala (RCeA) of SNL rats did not affect baseline thresholds but restored DNIC both behaviorally and electrophysiologically. Cumulatively, these data suggest that net enhanced descending facilitations may be mediated by kappa opioid receptor signaling from the RCeA to promote diminished DNIC following neuropathy.
Learn More >Multimodal neuroimaging studies provide support for a role of alterations in sensory processing circuits and endogenous pain modulatory systems in provoked vestibulodynia (PVD). In this study we tested the hypotheses that PVD compared to healthy controls (HCs) would demonstrate gray matter volume (GMV) alterations in regions associated with sensorimotor, corticothalamic, and basal ganglia circuits. We also tested the replicability of previously reported gray matter increases in basal ganglia and hippocampal volumes in PVD versus HCs. Additionally, disease-specificity of GMV alterations were examined by comparing PVD to another chronic pain disorder. Finally we examine whether GMV alterations are correlated with symptom measures. Structural magnetic resonance imaging was obtained in 119 premenopausal women (45 PVD, 45 HCs, 29 irritable bowel syndrome (IBS)). A voxel-based morphometry analysis was applied to determine group differences in the hypothesized regions of interest. Compared to HCs, PVD women exhibited greater GMV in the basal ganglia, hippocampus, and sensorimotor cortices. Compared to IBS patients, women with PVD had greater GMV in the hippocampus, and sensorimotor network, but lower GMV in the thalamus and precentral gyrus. Regional gray matter volume alterations were associated with patient reports of pain during intercourse and muscles tenderness. The current findings provide further evidence that GMV is increased in PVD compared to HCs in several regions of the sensorimotor network and the hippocampus in PVD patients. In addition, GMV distinct alterations in the sensorimotor network were identified between two pelvic pain disorders, PVD compared to irritable bowel syndrome.
Learn More >The aim of this study was to evaluate the possibility that migraine patients exhibit specific age-related metabolic changes in the brain, which occur regardless of disease duration or the frequency of attacks.
Learn More >Perception of sensory stimulation is influenced by numerous psychological variables. One example is placebo analgesia, where expecting low pain causes a painful stimulus to feel less painful. Yet, because pain evolved to signal threats to survival, it should be maladaptive for highly-erroneous expectations to yield unrealistic pain experiences. Therefore, we hypothesised that a cue followed by a highly discrepant stimulus intensity, which generates a large prediction error, will have a weaker influence on the perception of that stimulus. To test this hypothesis we collected two independent pain-cueing datasets. The second dataset and the analysis plan were preregistered ( https://osf.io/5r6z7/ ). Regression modelling revealed that reported pain intensities were best explained by a quartic polynomial model of the prediction error. The results indicated that the influence of cues on perceived pain decreased when stimulus intensity was very different from expectations, suggesting that prediction error size has an immediate functional role in pain perception.
Learn More >The Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials demonstrated efficacy/tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. This post hoc analysis assessed time of onset of onabotulinumtoxinA after the first treatment in total and responder populations and consistency weekly through five treatment cycles.
Learn More >Osteoarthritis (OA), characterized by cartilage damage, synovitis inflammation and chronic pain, is a common degenerative joint disease that may lead to physical disability. In the present study, we first explored the association between N-Acylethanolamine acid amidase (NAAA) and OA progression, and then examined the capability of the NAAA inhibitor F215 to attenuate osteoarthritis. Increased NAAA expressions and decreased PEA levels in synovial membrane and lumbar spinal cord were observed in MIA induced osteoarthritic rats. F215 (i.a., and i.p.) significantly protected against cartilage damage and synovial inflammation by directly increasing PEA levels in joints, or normalization of PEA levels and resolution of inflammation in spinal cord. Moreover, F215 also markedly alleviated osteoarthritic pain in rats, and the therapeutic effects of F215 were blocked by the PPAR-α antagonist MK886. The results revealed that NAAA may has been implicated in OA progression, and treatment with NAAA inhibitor F215 alleviated OA development by preventing cartilage damage, reducing inflammation, and alleviating pain. Our study suggested that NAAA inhibitor might be a novel therapeutic agent for OA treatment.
Learn More >