Molecular Pain最新文献

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.

Background: Primary headache and psychiatric diseases are bidirectional correlated. The real-world data of depression and anxiety in Chinese patients hospitalized for primary headache, considering all subtypes, remain unclear.

Methods: This study enrolled patients attending eight Chinese headache centers from October 2022 to September 2023. A WeChat mini-program was designed to collect data. Headache was diagnosed and confirmed by two headache specialists. The Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 were used to assess depression and anxiety.

Results: Overall, 1963 patients with primary headache were analyzed; the prevalence of depression and anxiety was 20.1% (396/1963) and 14.8% (290/1963), respectively. Of the 1963 patients, 217 (11.1%) had history of anxiety or depression and 184 (9.4%) had undergone assessments. Patients with both primary headache and depression were more likely to be women (77.8% vs 71.9%), experience more severe headache (numerical rating scale; 6.2 ± 1.9 vs 5.7 ± 1.9) and greater impacts on quality of life (Headache Impact Test-6; 65.3± 8.5 vs 58.1 ± 11.5). Those with both primary headache and anxiety exhibited similar results and were less educated. Depression and anxiety were more prevalent in chronic migraineurs (CM) than in episodic migraineurs (36.8% vs 16.9% and 28.9% vs 12.3%, respectively) and in those with chronic (CTTH) than in those with episodic tension-type headache (30.6% vs 15.1% and 20.1% vs 12.8%, respectively).

Conclusion: Depression and anxiety are inadequately diagnosed and strongly associated with sex, severe headache, chronification and disability in patients with primary headache in China. To improve the health of patients with primary headaches, early screening for depression and anxiety is important.

Depression is a common comorbidity of chronic pain. The comorbidity of pain and depression causes longer symptoms and poorer patient prognosis. Periaqueductal gray (PAG) is the key region for the regulation of pain and depression. Puerarin (Pue) is a natural isoflavone compound that has a neuroprotective effect, but the mechanisms on the comorbidity of chronic pain and depression remain unclear. In this study, the spared nerve injury (SNI) produced mechanical allodynia and depressive-like behaviors and elevated the neurological damage in ventrolateral (vl) PAG. Meanwhile, at the 8 weeks following injury, mitochondrial dysfunctions including the dysregulated protein levels, the decreased Mn-SOD activity and the reduced ATP contents were observed in vlPAG of SNI model mice. Pue administration improved mechanical pain, motor coordination, and depression-like behaviors, decreased the neuronal activity and neuroinflammation, and elevated the mitochondrial function in vlPAG. Database analysis and experimental assay showed that Pue bound with Bax at the affinity of 2.4 ± 0.1 μM via D102 residue, and decreased Bax level in vlPAG of mice and in primary astrocytic cells. In addition, Pue also recovered levels of mitochondrial membrane potential and reactive oxygen species, and decreased inflammation in primary astrocytic cells. These results suggest that Pue improves the comorbidity of chronic pain and depression by targeting Bax and reducing mitochondrial dysfunction in vlPAG. This study may provide a theoretical basis for Pue application in improving the comorbidity of chronic pain and depression.

Neuropathic pain affects approximately 10% of the adult population and is commonly treated with gabapentin (GBP), a repurposed anticonvulsant drug. Despite its widespread use, GBP's effectiveness varies significantly among patients, highlighting the need to better understand its functional and molecular impacts on human nociceptors. Here we characterized the electrophysiological and transcriptomic effects of GBP on primary neurons derived from the dorsal root ganglia (DRGs) of ethically consented human donors. Using patch-clamp electrophysiology, we demonstrated that GBP treatment reduced neuronal excitability, with more pronounced effects in multi-firing vs. single-firing neurons. Notably, significant donor-specific variability was observed in electrophysiological responsiveness to GBP treatment in vitro. RNA sequencing of DRG tissue from the donor that was more responsive to GBP revealed differences in transcriptome-wide expression of genes associated with ion transport, synaptic transmission, inflammation, and immune response. Cross-transcriptomic analyses further showed that GBP treatment counteracted these alterations, rescuing aberrant gene expression at the pathway level and for several key genes. This study provides a comprehensive electrophysiological and transcriptomic profile of the effects of GBP on human DRG neurons. These findings enhance our understanding of GBP's mechanistic actions on peripheral sensory neurons and could help optimize its use for managing neuropathic pain.

Mitochondria, known as the powerhouses of cells, are considered a key source of reactive oxygen species (ROS) production in various cell types. In the context of neuropathic and inflammatory pain, both mitochondrial dysfunction and hyperfunction can lead to aberrant production of mitochondrial reactive oxygen species (mtROS), which has been implicated in the development and persistence of pain hyperalgesia. This comprehensive review delves into the compelling correlation between mitochondrial functional activity and diverse pain conditions, with a special emphasis on inflammatory pain and chemotherapy-induced peripheral neuropathy (CIPN). Furthermore, it explores the therapeutic potential of targeting mitochondrial protection and mtROS scavenging to maintain mitochondrial redox homeostasis, offering a novel approach for pain management. The findings presented here provide valuable insights into the multifaceted role of mitochondria in pain modulation, laying a solid foundation for future research and the development of innovative analgesic strategies.

Background: Diabetic neuropathic pain (DNP) is a common complication of diabetes with significant impact on patients' quality of life. Current treatments have limitations, and exploring new mechanisms and targets is crucial.ObjectiveOur study aims to explore the role and mechanism of circRNA_19601 (circ19601) in regulating miR-324-5p in DNP within the dorsal root ganglion (DRG).

Methods: This study used streptozotocin (STZ) and high-fat diet-induced diabetic rat models, as well as high-sugar treated DRG neurons to construct cell models. The STZ and high-fat diet induced a diabetic neuropathic pain model in rats, and high-glucose conditions were used to extract DRG neurons. The effects of the positive control drug pregabalin on STZ rats were monitored under different dosing conditions by measuring body weight, blood glucose, mechanical paw withdrawal threshold, and thermal paw withdrawal latency. The study also analyzed the expression of circular RNA in DRG neurons affected by diabetic neuropathic pain. Next, we also examined the effects of knocking down circ19601 with or without the miR-324-5p inhibitor on DNP. The expression of pain-related membrane proteins was analyzed using Western blot.

Results: STZ treatment in diabetic rats led to reduced body weight, elevated blood glucose, and decreased pain sensitivity. Pregabalin effectively improved mechanical hyperalgesia but mainly influenced mechanical sensitivity long-term. Transcriptomic analysis revealed upregulation of circ19601 in diabetic rats, which was reversed by pregabalin. Knockdown of circ19601 improved body weight, reduced blood glucose, and alleviated pain sensitivity by increasing miR-324-5p levels and decreasing neurotransmitter and pain-related protein levels. MiR-324-5p inhibition reversed these effects, highlighting its role in regulating pain pathways in diabetic neuropathy.

Conclusion: Pregabalin mitigates mechanical and thermal pain in diabetic rats. It does so by reversing decreased pain thresholds and modifying the expression of circ19601. This, in turn, impacts miR-324-5p and pain-related proteins, leading to improvements in body weight and blood glucose levels.