Molecular Pain最新文献

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.

Purpose: Migraine is a neurological disorder, affecting approximately 1.16 billion individuals globally. Zinc finger HIT-type containing 1 (Znhit1), a chromatin remodeler, has exhibited a neuroprotective role. This study aims to investigate the role of Znhit1 in migraine.

Methods: A migraine mouse model was established by repeated intraperitoneal injection of nitroglycerin (NTG). The Znhit1 expression in trigeminal nucleus caudalis (TNC) was detected using reverse transcription quantitative polymerase chain reaction and western blot assays. Behavioral phenotype caused by central sensitization was assessed by Von Frey monofilaments and hot plate assays. Inflammatory response was evaluated through enzyme-linked immunosorbent assay and western blot analysis. Gene set enrichment analysis, western blot, cell counting kit-8 (CCK-8), and flow cytometry were utilized to explore potential molecular mechanisms in vitro.

Results: Repeated injection of NTG reduced Znhit1 expression in the TNC. Overexpression of Znhit1 alleviated hyperalgesia, upregulated 5-hydroxytryptamine (5-HT) level, and inhibited FBJ osteosarcoma oncogene (c-Fos) and calcitonin gene-related peptide (CGRP) expression. Moreover, overexpression of Znhit1 downregulated the expression of inflammatory markers [interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS)] and inhibited the activation of NOD-like receptor protein 3 (NLRP3) inflammasome. CCK-8 assay found that cell viability was enhanced in lipopolysaccharide (LPS)-induced BV2 cells treated with Znhit1 overexpression, while silencing of Znhit1 resulted in decreased cell viability. In LPS-induced BV2 cells, silencing of Znhit1 enhanced inflammatory response, promoted cell apoptosis, and activated NLRP3 inflammasome, whereas MCC950, a specific inhibitor of NLRP3, reversed these effects induced by silencing of Znhit1.

Conclusion: Our results demonstrated that Znhit1 ameliorated hyperalgesia and inhibited inflammatory response by suppressing the activation of NLRP3 inflammasome.

Cerulein is an orthologue of cholecystokinin, which is often used to induce acute pancreatitis in pre-clinical studies. In these models, animals show signs of pain, and this is the most common complaint of patients with acute pancreatitis. However, little is known about how this pain is mediated, the role of cerulein murine pain responses, or its relevance to human pancreatitis pain. We injected 25 or 50 µg/kg cerulein intraperitoneally into male and female mice and assessed pain behaviors using the von Frey test of mechanical hypersensitivity. The excitability of mouse and human visceral dorsal root ganglia (DRG) neurons was assessed using whole-cell patch-clamp electrophysiology. Pharmacology was performed using commercial antagonists of cholecystokinin (CCK) A or B receptors. We show that pain behaviors developed similarly in male and female cerulein-injected mice and that visceral DRG from these mice exhibited increased excitability compared to controls. Direct application of cerulein to T8-L2 mouse and human DRG showed increased excitability compared to controls consistent with DRG from cerulein-injected mice. The actions of cerulein on visceral DRG neurons were attributed to CCK-A, but not CCK-B receptor. A similar response to cerulein was observed in human thoracic DRG neurons. These findings highlight the importance of the cholecystokinin system, particularly the CCK-A receptor, to visceral pain including pancreatitis through direct sensitization of visceral DRG neurons from mice or humans.

Purpose: To investigate evodiamine's analgesic effects and molecular mechanisms on chemotherapy-induced peripheral neuropathy (CIPN), focusing on the p38/MAPK-TRPV1 signaling axis and macrophage polarization in dorsal root ganglia (DRG).

Methods: A paclitaxel-induced CIPN rat model was established with behavioral assessments via von Frey and thermal hyperalgesia tests. TRPV1, TRPV4, and inflammatory cytokine expression were analyzed using qRT-PCR, ELISA, and Western blot. Macrophage infiltration and polarization were evaluated by flow cytometry and immunofluorescence. Mechanistic studies utilized macrophage-conditioned media from RAW264.7 cells and clodronate liposome-mediated macrophage depletion to establish causal relationships between macrophage polarization and nociceptive behavior.

Results: Evodiamine dose-dependently alleviated paclitaxel-induced mechanical and thermal allodynia both acutely and preventively. It selectively inhibited upregulation of TRPV1 without affecting TRPV4 and reduced pro-inflammatory cytokine levels (TNF-α, IL-1β, IL-6, MCP-1) in the DRG. Evodiamine significantly reduced F4/80+ macrophage infiltration and shifted macrophage polarization from a pro-inflammatory M1 phenotype (decreased MCP1, CD86) to an anti-inflammatory M2 phenotype (increased CD163, CD206). Notably, macrophage-conditioned medium experiments revealed that evodiamine indirectly modulates neuronal TRPV1 expression through macrophage-derived factors. Furthermore, evodiamine attenuated paclitaxel-induced p38 MAPK phosphorylation in DRG neurons, with selective p38 MAPK inhibition by SB203580 confirming this pathway's critical involvement in TRPV1 regulation and pain modulation.

Conclusion: Evodiamine alleviates CIPN through a novel neuroimmune mechanism involving M2 macrophage polarization and inhibition of the p38/MAPK-TRPV1 axis in DRG neurons. These findings establish macrophage polarization as a key therapeutic target and highlight evodiamine's potential as a natural therapeutic agent for CIPN management.

Aims: The precise mechanisms underlying the pathogenesis of opioid-induced thermal hyperalgesia and tolerance are not yet fully understood.

Methods: In adult CD-1 mice, repeated morphine treatment was used to examine the expression of the non-canonical pathway of sonic hedgehog signaling, behavioral changes, and neurochemical alterations induced by morphine in the spinal cord and DRG. Additionally, to delve into the underlying mechanisms of the non-canonical pathway of Shh signaling in morphine-induced thermal hyperalgesia (MITH) and tolerance, we utilize the brain-derived neurotrophic factor (BDNF) inhibitor.

Results: Morphine administration repeatedly resulted in apparent thermal hyperalgesia and tolerance. The initiation and maintenance of MITH and tolerance, as well as related neurochemical alterations, were greatly inhibited by pharmacological and genetic suppression of the mTOR. By blocking the mTOR/p70 ribosomal S6 protein kinase 1 (S6K1)/Gli1 signaling, the morphine-induced increase in BDNF was considerably inhibited. Moreover, mTOR activator injection in naive mice resulted in significant heat hyperalgesia and BDNF upregulation. Suppression of BDNF effectively mitigated the development of thermal hyperalgesia induced by the mTOR activator.

Conclusion: These findings indicate that the non-canonical pathway of Shh signaling might serve as a crucial mediator in the development of MITH and tolerance through the regulation of BDNF expression.

Dysmenorrhea (period pain) affects over 40% of women and is a leading cause of missed school and workdays. However, the molecular mechanisms underlying this pain are not fully understood. We conducted a systematic review (Prospero registration: CRD42024535081) to identify and evaluate the biomolecules in menstrual effluent that may contribute to dysmenorrhea and assess how non-hormonal medications (e.g. NSAIDs) impact these biomarkers. Fifteen studies involving two hundred twenty-three participants met the inclusion criteria. We used the Newcastle-Ottawa Scale (for observational studies) and the Cochrane RoB2 tool (for randomized controlled trials) to evaluate the risk of bias and the quality of studies. Eight studies consistently reported elevated prostaglandin levels in the menstrual effluent of women with dysmenorrhea, though sample sizes were generally small, and methodological issues were noted. Seven studies demonstrated that NSAIDs reduce prostaglandin concentrations; however, these trials utilized multiple-day dosing protocols instead of single-dose regimens, leaving questions about acute treatment effects. Two studies highlighted alternative molecular targets, such as 12-HETE and platelet-activating factor (PAF), that may also play key roles in menstrual pain. Overall, elevated prostaglandins are a recurring finding, but the limited scope and design of existing studies indicate a need for larger, methodologically rigorous investigations. Nevertheless, the few studies that identified molecules other than prostaglandins suggest there are viable druggable targets for clinical trials to reduce menstrual pain.