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Spinal microglia are crucial to neuronal hyper-excitability and pain hypersensitivity. The local anesthetic bupivacaine is commonly used for both peripheral and spinal anesthesia. The pain-relief effects resulting from the peripheral and systemic administration of bupivacaine have been previously reported. In this study, the preventive effects of intrathecal bupivacaine administration against neuropathic pain were revealed in a rat model of sciatic nerve chronic constriction injury (CCI). Using a CCI rat model, pain hypersensitivity, characterized by mechanical allodynia and thermal hyperalgesia, correlated well with microglia M1 polarization, activation and pro-inflammatory cytokine expression in both spinal cord dorsal horns and sciatic nerves. Bupivacaine attenuated pain behaviors and inflammatory alternations. We further identified that the Interferon Regulatory Factor 5 (IRF5)/P2X Purinoceptor 4 (P2X4R) and High Mobility Group Box 1 (HMGB1)/Toll-Like Receptor 4 (TLR4)/NF-κB inflammatory axes may each play pivotal roles in the acquisition of microglia M1 polarization and pro-inflammatory cytokine expression under CCI insult. The relief of pain paralleled with the suppression of microglia M1 polarization, elevation of microglia M2 polarization, and inhibition of IRF5/P2X4R and HMGB1/TLR4/NF-κB in both the spinal cord dorsal horns and sciatic nerve. Our findings provide molecular and biochemical evidence for the anti-neuropathic effect of preventive bupivacaine.
Learn More >This study described patient characteristics and utilization of recently approved novel acute medication and calcitonin gene-related peptide (CGRP) monoclonal antibodies.
Learn More >Neuropathic pain is common in diabetic peripheral neuropathy (DN), probably caused by pathogenic ion channel gene variants. Therefore, we performed molecular inversion probes-next generation sequencing of 5 transient receptor potential cation channels, 8 potassium channels and 2 calcium-activated chloride channel genes in 222 painful- and 304 painless-DN patients. Twelve painful-DN (5.4%) patients showed potentially pathogenic variants (five nonsense/frameshift, seven missense, one out-of-frame deletion) in ANO3 ( = 3), HCN1 ( = 1), KCNK18 ( = 2), TRPA1 ( = 3), TRPM8 ( = 3) and TRPV4 ( = 1) and fourteen painless-DN patients (4.6%-three nonsense/frameshift, nine missense, one out-of-frame deletion) in ANO1 ( = 1), KCNK18 ( = 3), KCNQ3 ( = 1), TRPA1 ( = 2), TRPM8 ( = 1), TRPV1 ( = 3) and TRPV4 ( = 3). Missense variants were present in both conditions, presumably with loss- or gain-of-functions. KCNK18 nonsense/frameshift variants were found in painless/painful-DN, making a causal role in pain less likely. Surprisingly, premature stop-codons with likely nonsense-mediated RNA-decay were more frequent in painful-DN. Although limited in number, painful-DN patients with ion channel gene variants reported higher maximal pain during the night and day. Moreover, painful-DN patients with TRP variants had abnormal thermal thresholds and more severe pain during the night and day. Our results suggest a role of ion channel gene variants in neuropathic pain, but functional validation is required.
Learn More >Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway.
The neuroimmune mechanism underlying neuropathic pain has been extensively studied. Tumor necrosis factor-alpha (TNF-α), a key pro-inflammatory cytokine that drives cytokine storm and stimulates a cascade of other cytokines in pain-related pathways, induces and modulates neuropathic pain by facilitating peripheral (primary afferents) and central (spinal cord) sensitization. Functionally, TNF-α controls the balance between cell survival and death by inducing an inflammatory response and two programmed cell death mechanisms (apoptosis and necroptosis). Necroptosis, a novel form of programmed cell death, is receiving increasing attraction and may trigger neuroinflammation to promote neuropathic pain. Chronic pain is often accompanied by adverse pain-associated emotional reactions and cognitive disorders. Overproduction of TNF-α in supraspinal structures such as the anterior cingulate cortex (ACC) and hippocampus plays an important role in pain-associated emotional disorders and memory deficits and also participates in the modulation of pain transduction. At present, studies reporting on the role of the TNF-α-necroptosis pathway in pain-related disorders are lacking. This review indicates the important research prospects of this pathway in pain modulation based on its role in anxiety, depression and memory deficits associated with other neurodegenerative diseases. In addition, we have summarized studies related to the underlying mechanisms of neuropathic pain mediated by TNF-α and discussed the role of the TNF-α-necroptosis pathway in detail, which may represent an avenue for future therapeutic intervention.
Learn More >The epidemiology of persistent postoperative opioid use at least 3 months after cardiac surgery is poorly characterised despite its potential public health importance.
Learn More >Paclitaxel-induced neuropathic pain (PINP) is a progressive and refractory side effect of chemotherapy with few effective treatments at present. It is well-established that astrocytes activation contributes to the development of PINP. Recent reports showed astrocytes can be divided into A1 and A2 phenotypes. However, whether the transformation of astrocytes participates in PINP and the underlying mechanisms remain unknown. As Notch signaling pathways have shown to be involved in neuropathic pain, we aimed to investigate the relationship between Notch signaling pathway and A1 astrocytes in PINP. Herein we found that both A1 astrocytes and Notch signaling were markedly activated in the spinal cord of PINP rats and the downstream molecules of Notch signaling were colocalized with A1 astrocytes. DAPT (an inhibitor of Notch signaling) not only suppressed the mechanical allodynia of PINP rats, but also inhibited the activation of Notch signaling pathway and A1 astrocytes. Furthermore, Jagged1 (a ligand of Notch1 receptors) dose-dependently induced mechanical hyperalgesia in naïve rats and simultaneously led to Notch signaling activation and A1 astrocytes transformation, all of which were inhibited by DAPT. Taken together, these results demonstrate Notch signaling activation contributes to PINP via A1 astrocytes activation, which provides a promising therapeutic target for PINP.
Learn More >As a brief, noninvasive, cost-effective, and technology-driven therapy, biofeedback is a promising and welcomed clinical intervention for children and adolescents with pediatric chronic pain conditions. The aim of this pilot study was to explore the application of a brief Heart Rate Variability (HRV) biofeedback intervention supplemented by at-home breathing practice as a tool for reducing symptomatology associated with chronic pain in a pediatric urban hospital setting.
Learn More >Attentional deficits in patients with chronic pain are common and well-studied. Yet, few studies have examined the effects of chronic pain on more complex cognitive abilities that rely on well-functioning attentional systems. With the current study, we aimed to investigate whether the impact of chronic pain on attention affects creative ideation as measured with an adaptation of the alternate uses task (AUT).
Learn More >Dementia is a progressive condition that leads to reduced cognition, deteriorating communication and is a risk factor for other acute and chronic health problems. The rise in the prevalence of dementia means untreated pain is becoming increasingly common with healthcare staff being challenged to provide optimal pain management. This negatively impacts the person living with dementia and their carers. There is minimal evidence that explores the pain management experience of patients as they move through acute care settings.
Learn More >Nucleus accumbens (NAcc) played an important role in pain mediation, and presents changes of neuronal plasticity and functional connectivity. However, less is known about altered perfusion of NAcc in chronic migraine (CM). The aim of this study is to investigate the altered perfusion of the NAcc in CM using a MR three-dimensional pseudo-continuous arterial spin labeling (3D PCASL) imaging.
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