Molecular Pain最新文献

Neuropathic pain (NP), a specific subtype of chronic pain, can induce depression-like behavior, presenting significant challenges for clinical treatment. Ascorbic acid (AA) is a free radical scavenger; however, its regulatory effects on NP, particularly within the spinal cord, remain ambiguous. In this research, we examined the impact of AA on NP and associated depression-like behavior by establishing a spinal nerve injury (SNI) NP model. Behavioral tests showed that mice in the SNI group exhibited hyperalgesia and depression-like behavior. Compared with the control group, the SNI group showed attenuated antioxidant responses (impaired Nrf2 signaling), excessive NLRP3 inflammasome activation, and elevated AMPK activity in spinal cord tissues. However, treatment with AA alleviated NP and depression-like behavior in mice with SNI by suppressing NLRP3-mediated inflammation and enhancing Nrf2-driven antioxidant responses. In vivo electrophysiology demonstrated that AA reversed the increase in theta, alpha, and beta band energies in mice with SNI. The results suggest that AA mitigates NP and comorbid depression-like behavior by inhibiting the activity of NLRP3 inflammasome and activating the Nrf2 pathway. Its ability to normalize neurophysiological rhythms further supports its therapeutic potential for NP. These findings imply that AA is a novel therapeutic agent for NP.

This study aimed to evaluate the effects of electroacupuncture (EA) on cancer-induced bone pain (CIBP) and investigate its interaction with the STING/IFN-I pathway. A CIBP model was established in female rats. EA was administered for six consecutive days at bilateral L3-L5 Jia Ji points (EX-B2). EA-induced antinociception was evaluated through mechanical, thermal, and cold sensitivity assessments. EA significantly increased the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in rats with CIBP (p < 0.01). In the spinal cord of CIBP model rats, western blot analysis demonstrated that the application of EA upregulated the expression of STING, IRF3, and IFNAR (p < 0.05). The ELISA results indicated that EA significantly increased the expression of IFN-α (p < 0.005) and IFN-β (p < 0.01) and reduced the expression of TNF-α and IL-1β (p < 0.05). Immunofluorescence analysis revealed that STING was predominantly localized in microglia, with a minimal presence in neuronal cells. Furthermore, intrathecal administration of the STING antagonist C-176 attenuated the analgesic effects of EA in CIBP (p < 0.05). Both EA and STING agonist were effective in alleviating pain in rats with CIBP, possibly through the activation of the STING/IFN-I pathway. Notably, EA treatment reduced pro-inflammatory cytokines and increased anti-inflammatory cytokines. In contrast, while the STING agonist exhibited analgesic effects, it was associated with elevated levels of pro-inflammatory cytokines. These finding underscore the therapeutic potential of EA in the management of CIBP.

Background: Acute postoperative pain (APP) are key factors in the recovery of surgical patients after surgery. This study used the machine learning eXtreme Gradient Boosting (XGBoost) algorithm for the prediction of acute postoperative pain after major noncardiac surgery in older patients.

Methods: This was a secondary analysis of data from a randomized controlled trial containing 1720 older patients undergoing general anesthesia. The training and test sets were divided according to the timeline. The Boruta function was made to screen for relevant characteristic variables. The XGBoost model was built on the training set using 10-fold cross-validation and hyperparameter optimization, and the tuned optimal model plotted the importance ranking diagram of feature variables, partial dependence profile (PDP) and Break down profile (BDP). The optimal model was used to calculate the confusion matrices and their parameters for the training and validation sets, and to plot the receiver operating characteristic curve (ROC), precision recall curve (PRC), calibration curve and Clinical decision curve (CDC) on the validation set.

Results: The Boruta function was used to screen the relevant characteristic variables, and the screened postoperative acute pain characteristic variables were CHARLSON score, Mini-Mental State Examination (MMSE), duration of surgery, preoperative depression score, smoking or not, duration of anesthesia, intraoperative mean heart rate, lidocaine dosage, age, intraoperative morphine dosage, grouping, preoperative anxiety score, loperamide dosage, intraoperative colloid amount, APACHE -II score, postoperative ICU or not, surgical site and postoperative tracheal intubation or not. Test set and validation set accuracy (ACC) for acute postoperative pain: 0.921 and 0.871; AUC-ROC: 0.964 and 0.920; AUC-PRC: 0.983 and 0.959; Brier: 0.067 and 0.098; Matthews Correlation Coefficient (MCC): 0.847 and 0.746.

Conclusions: A high-performance algorithm was developed and validated to predict the degree of change in postoperative pain; controlling important characterizing variables may be helpful for postoperative analgesia.

Objectives: Widespread pain is a hallmark characteristic of fibromyalgia, commonly affecting older individuals. This study aimed to identify novel genetic variants associated with widespread pain by utilizing the extensive UK Biobank dataset.

Methods: We conducted a primary genome-wide association study (GWAS) using a novel definition of widespread pain, defined as pain experienced all over the body during the past month. Sex-stratified GWAS analysis approach was also performed to analyze the impact of sex on widespread pain.

Results: The primary GWAS identified one novel significant genetic locus (rs34691025, p = 1.76 × 10^-8) on chromosome 5q13.2 within the ARHGEF28 gene and several loci that approached genome-wide significance. The sex-stratified GWAS outputs revealed biological difference widespread pain between males and females, with a novel locus identified in the female-specific analysis within the LRMDA gene on chromosome 10. Genetic Correlation analysis demonstrated significant genetic correlations between widespread pain and other phenotypes, including joint disorders and spondylosis. The PheWAS revealed associations between the significant genetic variants with hearing disorders and cardiovascular diseases. A two-sample Mendelian randomization analysis found no significant causal association between hearing loss and widespread pain.

Conclusions: Our study advances the understanding of the genetic factors contributing to widespread pain, highlighting notable differences between males and females and identifying a novel genetic locus associated with this condition.

The retrosplenial cortex (RSC) plays an important role in navigation, memory and pain. However, there are few studies on excitatory synaptic transmission in the RSC. Here, we used a multi-electrode array recording system (MED64) to study the characteristics of excitatory synaptic transmission in the RSC and the contribution of different types of voltage-gated Ca²⁺ channels (VGCCs) in excitatory synaptic transmission. We found that glutamate is the major excitatory transmitter for RSC, and postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors contribute to excitatory synaptic transmission. We also found that the N-type calcium channel blocker ω-conotoxin GVIA (ω-Ctx GVIA) had an inhibitory effect on basal synaptic transmission. The inhibitory effect was not consistent across channels, suggesting the actions effect of N-type VGCCs in RSC was inhomogeneous in spatial distribution. Our findings provide strong evidence that excitatory synaptic transmission in the RSC is mainly mediated by AMPA receptors and that N-type VGCCs mediate fast synaptic transmission in the RSC of adult mice.

Background: Cancer-induced bone pain (CIBP) is a debilitating complication with few effective treatments. Microglial activation contributes to the progression of CIBP. 2-deoxy-D-glucose (2-DG), a glycolytic inhibitor, could inhibit microglial activation. Its effect on CIBP remains unclear. This study aims to investigate the role of 2-DG in CIBP mice and underlying mechanisms.

Methods: In this research, we established a CIBP mouse model by injecting Lewis lung cancer (LLC) cells into the bone marrow of the femur. Relevant pain behaviors were assessed by measuring the paw withdrawal threshold and spontaneous hind limb lifting. Additionally, the glycolysis inhibitor 2-DG was intrathecally administered to treat CIBP in mice. Western blotting and immunofluorescence techniques were employed to analyze microglial activation and M1/M2 phenotype markers in the spinal cord.

Results: Our findings demonstrated significant microglial activation and polarization toward the M1 phenotype in the spinal cord of CIBP mice. Intrathecal administration of 2-DG effectively alleviated pain-related behaviors in CIBP mice. Furthermore, this treatment suppressed microglial activation and M1 polarization, while significantly restoring levels of the M2 phenotype. Additionally, 2-DG attenuated the production of pro-inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), while boosting the secretion of the anti-inflammatory factor (IL-10) in the spinal cord of CIBP mice. Notably, 2-DG effectively suppresses microglia activation and M1 polarization in LPS + IFN-γ-induced BV-2 cells by downregulating CD86, iNOS expression, TNF-α, IL-1β, IL-6 levels while upregulating Arg-1, CD206 expression and IL-10 level.

Conclusion: These results suggest that 2-DG ameliorates mechanical allodynia, spontaneous pain and neuroinflammation in the spinal cord of CIBP mice by promoting the transition from the M1 phenotype to the M2 phenotype. This study may provide a novel strategy for the treatment of CIBP.

Background: Bone cancer metastases are the third most common site of cancer spread after lungs and liver. This condition often causes severe pain that impairs patients' physical, psychological, and social well-being. We aimed to explore the potential therapeutic benefits of magnesium hydride (MgH₂) on bone cancer pain (BCP).

Methods: A BCP model was established in Wistar rats. Daily oral dosing of 0.5% w/w MgH₂ was administered. Assessment included pain sensitivity, motor coordination, and emotional behaviors. Hippocampal samples underwent RNA sequencing, Western blotting, immunofluorescence, and quantitative RT-PCR.

Results: MgH₂ markedly reduced mechanical hypersensitivity and depressive behaviors in rats with BCP. These effects were linked to suppression of the TRPM2-NLRP3 signaling axis in hippocampal microglia. Additionally, MgH₂ served as an adjuvant to reduce opioid tolerance during fentanyl co-treatment, enabling lower opioid dosages. Collectively, MgH₂ inhibited TRPM2 activation, microglial activation, oxidative stress, and NLRP3 inflammasome formation, which together reduced neuroinflammation and improved therapeutic outcomes.

Conclusion: MgH₂ nanoparticles may relieve BCP and comorbid depressive symptoms by inhibiting TRPM2-mediated NLRP3 inflammasome activation in hippocampal microglia.

Anterolateral system (ALS) projection neurons underlie perception of pain, itch and skin temperature. These cells are heterogeneous, and there have therefore been many attempts to define functional populations. A recent study identified two classes of ALS neuron in mouse superficial dorsal horn (SDH) based on expression of the G protein-coupled receptors Tacr1 or Gpr83. It was reported that cells expressing these receptors formed largely non-overlapping populations, and that ~60% of ALS cells in SDH expressed Tacr1. An additional finding was that while Tacr1- and Gpr83-expressing ALS cells projected to several brain nuclei, their axons did not reach the ventral posterolateral (VPL) thalamic nucleus, which is reciprocally connected to the primary somatosensory cortex. These results were surprising, because we had reported that ~90% of SDH ALS neurons in the mouse possess the neurokinin 1 receptor (NK1r), which is encoded by Tacr1, and in addition the VPL is thought to receive input from lamina I ALS cells. Here we use retrograde and anterograde labelling in Tacr1^CreERT2 and Gpr83^CreERT2 mice to reinvestigate the expression of the receptors by ALS neurons and to reassess their projection patterns. We find that ~90% of ALS neurons in SDH express Tacr1, with 40%-50% expressing Gpr83. We also show that axons of both Tacr1- and Gpr83-expressing ALS neurons reach the VPL. These results suggest that ALS neurons in the SDH that express these GPCRs show considerable overlap, and that they are likely to contribute to the sensory-discriminative dimension of pain through their projections to VPL.

Bone cancer pain (BCP), one of the most intractable symptoms in patients with cancer, remains poorly understood and lacks effective therapeutic interventions. In this study, we employed an established rat model of BCP induced by intratibial injection of MRMT-1 mammary carcinoma cells. Transcriptomic profiling of the L4-L6 dorsal root ganglia (DRGs) revealed an upregulation of the amino acid transporter SLC38A3. This finding was further confirmed by time-dependent increases in both its mRNA and protein levels. Immunofluorescence co-localization indicated that SLC38A3 was expressed in NF200-, CGRP-, and IB4-positive neurons within the L4-L6 DRGs, and its expression was upregulated in the BCP model. Concomitantly, the transient receptor potential vanilloid 1 (TRPV1) expression in BCP rat DRGs was dynamically upregulated at both the mRNA and protein levels, aligning temporally with pain hypersensitivity. Lentivirus-mediated overexpression or knockdown of SLC38A3 in the DRGs led to a corresponding upregulation or downregulation of TRPV1-expression. Activation of the PI3K/AKT signaling pathway corresponds with BCP-related pain behaviors and expression patterns of SLC38A3 and TRPV1. Bexarotene alleviates BCP in rats by suppressing the aberrant overexpression of SLC38A3, thereby blocking the PI3K/AKT signaling pathway-mediated upregulation of TRPV1. These findings indicate that SLC38A3, through its downstream PI3K/AKT-TRPV1 axis, may serve as a potential molecular mechanism for analgesia in BCP.