Patients with systemic lupus erythematosus (SLE) frequently experience chronic pain due to the limited effectiveness and safety profiles of current analgesics. Understanding the molecular and ...synaptic mechanisms underlying abnormal neuronal activation along the pain signaling pathway is essential for developing new analgesics to address SLE-induced chronic pain. Recent studies, including those conducted by our team and others using the SLE animal model (
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lupus-prone mice), have unveiled heightened excitability in nociceptive primary sensory neurons within the dorsal root ganglia and increased glutamatergic synaptic activity in spinal dorsal horn neurons, contributing to the development of chronic pain in mice with SLE. Nociceptive primary sensory neurons in lupus animals exhibit elevated resting membrane potentials, and reduced thresholds and rheobases of action potentials. These changes coincide with the elevated production of TNFα and IL-1β, as well as increased ERK activity in the dorsal root ganglion, coupled with decreased AMPK activity in the same region. Dysregulated AMPK activity is linked to heightened excitability in nociceptive sensory neurons in lupus animals. Additionally, the increased glutamatergic synaptic activity in the spinal dorsal horn in lupus mice with chronic pain is characterized by enhanced presynaptic glutamate release and postsynaptic AMPA receptor activation, alongside the reduced activity of glial glutamate transporters. These alterations are caused by the elevated activities of IL-1β, IL-18, CSF-1, and thrombin, and reduced AMPK activities in the dorsal horn. Furthermore, the pharmacological activation of spinal GPR109A receptors in microglia in lupus mice suppresses chronic pain by inhibiting p38 MAPK activity and the production of both IL-1β and IL-18, as well as reducing glutamatergic synaptic activity in the spinal dorsal horn. These findings collectively unveil crucial signaling molecular and synaptic targets for modulating abnormal neuronal activation in both the periphery and spinal dorsal horn, offering insights into the development of analgesics for managing SLE-induced chronic pain.
Patients with systemic lupus erythematosus (SLE) often suffer from chronic pain. Little is known about the peripheral mechanisms underlying the genesis of chronic pain induced by SLE. The aim of this ...study was to investigate whether and how membrane properties in nociceptive neurons in the dorsal root ganglions (DRGs) are altered by SLE. We found elevation of resting membrane potentials, smaller capacitances, lower action potential thresholds and rheobases in nociceptive neurons in the DRGs from MRL/lpr mice (an SLE mouse model) with thermal hyperalgesia. DRGs from MRL/lpr mice had increased protein expressions in TNFα, IL-1β, and phosphorylated ERK but suppressed AMPK activity, and no changes in sodium channel 1.7 protein expression. We showed that intraplantar injection of Compound C (an AMPK inhibitor) induced thermal hyperalgesia in normal mice while intraplantar injection of AICAR (an AMPK activator) reduced thermal hyperalgesia in MRL/Lpr mice. Upon inhibition of AMPK membrane properties in nociceptive neurons from normal control mice could be rapidly switched to those found in SLE mice with thermal hyperalgesia. Our study indicates that increased excitability in peripheral nociceptive sensory neurons contributes to the genesis of thermal hyperalgesia in mice with SLE, and AMPK regulates membrane properties in nociceptive sensory neurons as well as thermal hyperalgesia in mice with SLE. Our study provides a basis for targeting signaling pathways regulating membrane properties of peripheral nociceptive neurons as a means for conquering chronic pain caused by SLE.
Many patients with systemic lupus erythematosus (SLE) live with chronic pain despite advances in medical management in reducing mortality related to SLE. Few animal studies have addressed mechanisms ...and treatment for chronic pain caused by SLE. In this study, we provide the first evidence for the analgesic effects of a GPR109A specific agonist (MK1903) and its action mechanisms in thermal hyperalgesia in female MRL/lpr mice, an SLE mouse model. Specifically, we show that MRL/lpr mice had a higher sensitivity to thermal stimuli at age 11–16 weeks, which was accompanied with significantly microglial and astrocytic activation, increases in p38 MAPK and glutamatergic synaptic activities in the spinal dorsal horn. We demonstrate that thermal hyperalgesia in MRL/lpr mice was significantly attenuated by intrathecal injection of MK1903. GPR109A was expressed in spinal microglia but not astrocytes or neurons. Its expression was significantly increased in MRL/lpr mice with thermal hyperalgesia. Activation of GPR109A receptors in microglia attenuated glutamatergic synaptic activity via suppressing production of interleukin‐18 (IL‐18). We provide evidence that activation of GPR109A attenuated thermal hyperalgesia in the SLE animal model via suppressing p38 MAPK activity and production of IL‐18. Our study suggests that targeting the microglial GPR109A is a potent approach for reversing spinal neuroinflammation, abnormal excitatory synaptic activity, and management of thermal hyperalgesia caused by SLE.
Main Points
In this study, we found that activation of spinal microglial GPR109A alleviates chronic pain in a female mouse model of systemic lupus erythematosus by suppressing IL‐18 production and glutamatergic synaptic activity.
Aims
This study aims to examine the prevalence of anxiety symptoms and identify predictors of anxiety among pregnant women with gestational diabetes mellitus and their partners and explore the ...mediating role of marital satisfaction between maternal and paternal anxiety.
Design
A cross‐sectional study was conducted in Guangzhou, China, from July 2021 to May 2022.
Methods
A total of 306 dyads of pregnant women with gestational diabetes mellitus and their partners completed the State–Trait Anxiety Inventory, Locke–Wallace Marital Adjustment Test and the socio‐demographic and clinical data sheet.
Results
The prevalence of anxiety symptoms was 32.4% and 36.6% in pregnant women with gestational diabetes mellitus and their partners, respectively. The predictors of maternal anxiety were paternal anxiety, maternal marital satisfaction, maternal monthly salary, fasting glucose value and 1‐h glucose value. By contrast, the predictors of paternal anxiety were maternal anxiety, paternal marital satisfaction and paternal monthly salary. Moreover, the relationship between maternal and paternal anxiety was mediated by marital satisfaction.
Conclusions
The anxiety symptoms of pregnant women with gestational diabetes mellitus and their partners influence each other, and this relationship was mediated by marital satisfaction. Every couple should be screened for anxiety symptoms and treated as a team rather than focusing solely on the pregnant woman.
Summary statement
What is already known about this topic?
Gestational diabetes mellitus is strongly associated with various short‐ and long‐term adverse maternal and neonatal outcomes.
The diagnosis of gestational diabetes mellitus is stressful for pregnant women and their partners.
No studies have been conducted to examine and compare the anxiety symptoms among pregnant women with GDM and their partners in mainland China.
What this paper adds?
The anxiety symptoms of pregnant women with gestational diabetes mellitus and their partners influence each other.
The prevalence of anxiety symptoms was high in both pregnant women with gestational diabetes mellitus and their partners.
Marital satisfaction played a mediating role between maternal and paternal anxiety.
The implications of this paper:
Study findings provide important information to guide future practice for nurses and other health‐care professionals.
For the future, routine screening for anxiety symptoms is necessary for both pregnant women with gestational diabetes mellitus and their partners; mental health support should be delivered in a timely fashion for couples.
Pregnant women with gestational diabetes mellitus and their partners should be treated as a team rather than focusing solely on pregnant women, with couples given training on enhancing marital satisfaction skills to prevent and reduce their anxiety symptoms.
Excessive activation of glutamate receptors in spinal dorsal horn neurons is a key mechanism leading to abnormal neuronal activation in pathological pain conditions. Previous studies have shown that ...activation of glutamate receptors in the spinal dorsal horn is enhanced by impaired glial glutamate transporter functions and proinflammatory cytokines including interleukin‐1 beta (IL‐1β). In this study, we for the first time revealed that spinal glial glutamate transporter activities in the neuropathic animals are attenuated by endogenous IL‐1β. Specifically, we demonstrated that nerve injury results in an increased expression of IL‐1β and activation of PKC in the spinal dorsal horn as well as suppression of glial glutamate uptake activities. We provided evidence that the nerve‐injury induced suppression of glial glutamate uptake is at least in part ascribed to endogenous IL‐1β and activation of PKC in the spinal dorsal horn. IL‐1β reduces glial glutamate transporter activities through enhancing the endocytosis of both GLT‐1 and GLAST glial glutamate transporters. The IL‐1β induced trafficking of glial glutamate transporters is through the calcium/PKC signaling pathway, and the dynamin‐dependent endocytosis, which is dependent on the integrity of actin filaments. The signaling pathway regulating glial glutamate transporters revealed in this study provides novel targets to attenuate aberrant activation of glutamate receptors in the spinal dorsal horn, which could ultimately help the development of analgesics. GLIA 2014;62:1093–1109
Main points
Impaired glutamate uptake enhances glutamate receptor activation in pathological pain. We found that IL‐1β reduces glial glutamate transporter activities through the calcium/PKC signaling, and the dynamin‐ and actin filament‐dependent endocytosis.
Neuroinflammation plays a critical role in the pathological process of multiple neurological disorders and pathological pain conditions. GPR109A, a Gi protein-coupled receptor, has emerged as an ...important therapeutic target for controlling inflammation in various tissues and organs. In this review, we summarized current data about the role of GPR109A in neuroinflammation. Specifically, we focused on the pharmacological features of GPR109A and signaling pathways used by GPR109A to ameliorate neuroinflammation and symptoms in Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, and pathological pain conditions.
Patients receiving paclitaxel for cancer treatment often develop an acute pain syndrome (paclitaxel‐associated acute pain syndrome, P‐APS), which occurs immediately after paclitaxel treatment. ...Mechanisms underlying P‐APS remain largely unknown. We recently reported that rodents receiving paclitaxel develop acute pain and activation of spinal microglial toll like receptor 4 (TLR4) by paclitaxel penetrating into the spinal cord is a critical event in the genesis of P‐APS. Our current study dissected cellular and molecular mechanisms underlying the P‐APS. We demonstrated that bath‐perfusion of paclitaxel, at a concentration similar to that found in the cerebral spinal fluid in animals receiving i.v. paclitaxel (2 mg/kg), resulted in increased calcium activity in microglia instantly, and in astrocytes with 6 min delay. TLR4 activation in microglia by paclitaxel caused microglia to rapidly release interleukin‐1β (IL‐1β) but not tumor necrosis factor α, IL‐6, or interferon‐γ. IL‐1β release from microglia depended on capthepsin B. IL‐1β acted on astrocytes, leading to elevated calcium activity and suppressed glutamate uptake. IL‐1β also acted on neurons to increase presynaptic glutamate release and postsynaptic AMPA receptor activity in the spinal dorsal horn. Knockout of IL‐1 receptors prevented the development of acute pain induced by paclitaxel in mice. Our study indicates that IL‐1β is a crucial molecule used by microglia to alter functions in astrocytes and neurons upon activation of TLR4 in the genesis of P‐APS, and targeting the signaling pathways regulating the production and function of IL‐1β from microglia is a potential avenue for the development of analgesics for the treatment of P‐APS.
Main Points
Systemic administration of taxol causes rapid release of IL‐1β from spinal microglia via activating TLR4.
IL‐1β enhances glutamatergic synaptic activity pre‐ and postsynaptically, and by reducing astrocytic glutamate uptake, leading to acute pain.
A broadband circularly-polarised monopole antenna is proposed. The broadband property of the antenna is basically achieved not only by the chifre-shaped monopole radiator, but also its asymmetric ...feed. The circular-polarisation characteristics are greatly enhanced by adjusting the location of the monopole microstrip-feed. The antenna delivers good performance on impedance matching and circular polarisation. The measured results demonstrate that the impedance bandwidth is 72% and the 3-dB axial-ratio bandwidth reaches 41.6% with a central frequency of 2.5 GHz.
•pH and biochar dosage are key factors for adsorption by sludge-derived biochar.•Equilibrium temperature has weak adsorption effect.•The mechanism of adsorption by biochar involves surface ...precipitation and ion exchange.
Static equilibrium experiments were carried out to investigate the impact factors and the mechanism of cadmium adsorption on biochar derived from municipal sewage sludge. An appropriate dosage of biochar is sufficient; in the experiment, 0.2% is the optimal dosage for the largest removal capacity, while the removal capacity of biochar reduces with the increasing dosage. pH is another dominant factor of the adsorption process. The removal capacity of biochar is lower than 20mg·g−1 when the solution initial pH is lower than 2 pH units, comparatively retaining more than 40mg·g−1 at the solution initial pH higher than 3 pH units. Temperature has weak influence on the adsorptive performance. The main mechanism of the adsorption process of biochar for cadmium mainly involves (1) surface precipitation by forming insoluble cadmium compounds in alkaline condition, and (2) ion exchange for cadmium with exchangeable cations in the biochar, such as calcium ions.
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