Molecular Pain最新文献

The primary and secondary somatosensory cortices (S1 and S2) play crucial roles in processing sensory inputs from various body regions, encompassing tactile, pressure, thermal, and nociceptive stimuli. These cortices are anatomically distinct, with S1 primarily involved in mechanical and cold stimulus discrimination and S2 in the interpretation of mechanical and thermal inputs, particularly in pain perception. However, the upstream innervation patterns of the somatosensory system remain less explored. In this study, we employed a modified rabies virus (RV)-mediated transsynaptic retrograde tracing system to map and compare the whole-brain input patterns of S1 and S2 in mice. Our results revealed that both S1 and S2 receive inputs from diverse brain regions, including the cortical plate, thalamus, cortical subplate, striatum, and pallidum. Notably, the cortical plate emerged as the primary source of input neurons for both S1 and S2, while the thalamus demonstrated preferential projections to S1. Through quantitative analysis, we identified distinct input distribution patterns across 64 brain subregions, revealing that S1 and S2 exhibit complex internal circuitry, including abundant local projections. Furthermore, we observed notable variations in the proportional contributions of inputs from diverse subregions to S1 and S2. This comprehensive anatomical framework provides new insights into the neural circuits underlying somatosensory perception and modulation, with potential implications for the development of targeted therapeutic strategies for pain and other somatosensory disorders.

Migraine is a chronic episodic neurological disorder. However, its diagnosis and management remain unclear. The pathogenesis of migraine is intricately linked to the dysfunction of mitochondria and aberrant trigeminal neuronal activity. Here, we established a murine migraine model via intraperitoneal administration of nitroglycerin (NTG) to examine alterations in mitochondria-associated proteins and calcium signaling patterns within trigeminal neurons, while also investigating the underlying mechanisms. NTG-treated mice exhibited marked periorbital allodynia, decreased crossing of the central area, and decreased time spent in the central area in the open field test compared to Veh treated animals. Furthermore, increased calcium signaling in response to adenosine triphosphate (ATP) stimulation was observed in the trigeminal ganglion (TG) of mice with migraine. Meanwhile, mRNA levels of genes including nuclear respiratory factor-1 (Nrf1), nuclear respiratory factor-2 (Nrf2) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1) were decreased in the TG. Pharmacological regulation of the mitochondrial function affected NTG-induced migraine chronic pain symptoms. TG mitochondria dysfunctions is implicated in the regulation of mechanical hyperalgesia through the modulation of calcium signaling in an NTG-induced migraine animal model.

Pain, particularly chronic pain, is a major reason patients seek physical therapy. Inflammation plays a crucial role in both the development and persistence of chronic pain. Neuronal PAS domain protein 2 (NPAS2), a core circadian transcriptional regulator, has been implicated in modulating pain-related stress responses. In this study, we first examined NPAS2 expression in nociceptive-sensitized mice following complete Freund's adjuvant (CFA) administration. We then systematically investigated the effects of CFA on astrocyte activation and inflammatory factor release in NPAS2 knockout (KO) mice. Our results demonstrated that NPAS2 deletion did not alter baseline pain thresholds under normal physiological conditions. However, in CFA-injected mice, NPAS2 KO significantly lowered mechanical and thermal pain thresholds in 50% of subjects, leading to enhanced nociceptive sensitization. This effect may be attributed to the promotion of astrocyte activation and the upregulation of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α, and NF-κB. These findings highlight NPAS2 as a potential prognostic biomarker for pain chronification and a promising therapeutic target for biologically tailored pain interventions.

Background: Acupuncture effectively reduces chronic neck pain and plasma Substance P (SP) levels, but upstream molecular mechanisms remain unknown.

Objectives: We aimed to identify circulating microRNAs (miRNAs) associated with acupuncture-induced SP reduction and explore potential neuroplasticity mechanisms.

Methods: We performed longitudinal plasma miRNA profiling (Affymetrix miRNA 4.0 Array, ~4600 miRNAs) in chronic neck pain patients: Acupuncture group (n = 3; 0, 4, 8 weeks) and Control group (n = 3; 0, 4 weeks). Linear Mixed-Effects Models (LMMs) tested associations between each miRNA and SP dynamics (miRNA × Time × Group interaction). Statistical significance was validated using permutation testing (2000 iterations).

Results: Screening identified 53 miRNAs significantly associated with SP, validated by permutation testing (p < 0.001). Fourteen high-confidence miRNAs showed significant three-way interactions, indicating treatment-specific SP relationships. The most significant was miR-1302-6 (p = 7.65 × 10^-6), followed by miR-181b-2. These miRNAs displayed diverse temporal patterns: some (miR-196b, miR-6788) increased during treatment, while others (let-7d, miR-1302-6) decreased parallel to SP. Functional enrichment revealed striking convergence on neuroplasticity pathways: axon guidance (p = 2.61 × 10^-6), MAPK signaling (p = 4.18 × 10^-5), neuron projection development (p = 7.52 × 10^-10), and synaptic structures (p = 9.52 × 10^-12).

Conclusions: This exploratory study provides first molecular evidence for an acupuncture-miRNA-SP axis in chronic pain. The enrichment of neuroplasticity pathways suggests acupuncture may induce structural remodeling of nociceptive circuits rather than simply suppressing inflammation, offering novel mechanistic insights and potential biomarkers for personalized acupuncture therapy. The trial was registered with the Korean Clinical Trial Registry (KCT0005363).

Background: Chronic pain and cancer interact bidirectionally, with pain enhancing sensory peptides and potentially promoting tumor growth. Despite this, most chemotherapy-induced neuropathic pain (CIPN) studies overlook the contribution of cancer itself to neuropathy, focusing instead on chemotherapy-induced mechanisms. Animal models of chemotherapy-induced neuropathic pain (CINP) have been developed by injecting chemotherapeutic drugs such as paclitaxel into normal animals without cancer. This study aimed to develop a new model in mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mice, a widely used breast cancer model with normal immune function.

Results: The percentage of positive response (PPR) of paclitaxel-injected MMTV-PyMT mice increased (about 20%; baseline, 10%) on day 4, reached the highest levels (50%-60%) on days 6-9, and then plateaued by day 29. In comparison, the PPR of paclitaxel-injected C57BL/6 was less than 10% on days 0-6, was about 40% on day 9, and then plateaued by day 29. Breast tumor-bearing mice exhibited an earlier onset and greater severity of paclitaxel-induced pain behaviors than tumor-free C57BL/6 mice. Systemic LGK-974 ameliorated paclitaxel-induced pain behaviors in MMTV-PyMT mice. Active β-catenin was detected in neurons and satellite cells of the dorsal root ganglia.

Conclusions: Paclitaxel-induced neuropathic pain model in breast tumor-bearing female MMTV-PyMT mice may be a useful animal model for investigating the analgesic effects and underlying mechanisms for CINP in breast cancer patients as well as the interplay between CINP development and cancer progression.

Background: Inflammation affects labor by influencing contractions and dilation. Pain, often linked to tissue ischemia, involves mediators like nitric oxide (NO), TNF-α, and substance P (SP). Neuraxial analgesia, including combined spinal epidural analgesia (SEA) with levobupivacaine, is preferred for its effectiveness and minimal side effects in painless labor. Understanding the impact of painless labor techniques on biomolecular processes such as NO, TNF-α, and substance P levels is crucial for improving pain management strategies. This study investigates these effects in parturients undergoing SEA with levobupivacaine, contributing to the development of novel pain medications and enhancing obstetric care.

Methods: This experimental study, conducted at a General Hospital in Indonesia, involved 60 expectant mothers in labor or in the third trimester, expected to give birth vaginally at Permata Hati Metro Hospital. Blood serum was used for analysis, and serum NO, TNF-α, and SP levels were assessed using ELISA kit.

Results: There's a significant decrease in NO levels before and post-treatment in the SEA group compared to the control group (p < 0.05). However, no significant difference in TNF-α levels was observed between groups before and after treatment (p > 0.05). Additionally, there was no significant difference in SP levels between groups before treatment, but a significant difference was seen after treatment (p < 0.05). SEA significantly reduced labor pain compared to the control group (P < 0.05), with notable improvements in vital signs and APGAR scores, while also shortening labor duration (P < 0.001).

Conclusion: In conclusion, SEA with levobupivacaine during painless labor reduces NO levels significantly and shows a trend of decreasing TNF-α and substance P levels, although not statistically significant, with clinical benefits for both patients and babies.

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disease characterized by chronic visceral pain with a complex etiology and challenging treatment. Although accumulating evidence supports the involvement of central nervous system sensitization in the development of visceral pain, the precise molecular mechanisms remain incompletely understood. In this study, we highlight the critical regulatory role of lysine-specific demethylase 6B (KDM6B) in the anterior cingulate cortex (ACC) in chronic visceral pain. To simulate clinical IBS conditions, we utilized the neonatal maternal deprivation (NMD) mouse model. Our results demonstrated that NMD induced chronic visceral pain and anxiety-like behaviors in mice. Notably, the protein expression level of KDM6B significantly increased in the ACC of NMD mice, leading to a reduction in the expression level of H32K7me3. Immunofluorescence staining revealed that KDM6B primarily co-localizes with neurons in the ACC, with minimal presence in microglia and astrocytes. Injecting GSK-J4 (a KDM6B-specific inhibitor) into ACC of NMD mice, resulted in a significant alleviation in chronic visceral pain and anxiety-like behaviors, as well as a remarkable reduction in NR2B expression level. ChIP assay further indicated that KDM6B regulates NR2B expression by influencing the demethylation of H3K27me3. In summary, our findings underscore the critical role of KDM6B in regulating chronic visceral pain and anxiety-like behaviors in NMD mice. These insights provide a basis for further understanding the molecular pathways involved in IBS and may pave the way for targeted therapeutic interventions.