Journal of Headache and Pain最新文献

Background: Migraine is a complex neurological disorder with poorly understood molecular mechanisms. Despite advances in genetic and omics research, the shared mechanisms between central and peripheral nervous systems in migraine pathogenesis remain unclear.

Methods: We employed a multi-omics approach, integrating human trigeminal ganglion (TG) single-nucleus RNA sequencing (snRNA-seq) data and expression quantitative trait loci (eQTL) data from eight major cortical cell types. Mendelian randomization (MR) analysis was used to prioritize susceptibility genes, followed by functional enrichment, molecular network mapping, and computational drug screening. Key findings were experimentally validated in the primary sensory cortex hindlimb area brain region and TG, given their established roles in pain processing.

Results: We identified 586 migraine-associated genes in TG and 1,108 in the cortex, with 109 overlapping genes. These overlapping genes converge on pathways including autophagy and neuroinflammation, suggesting shared mechanisms of central and peripheral nervous systems. Five hub genes - HSP90AB1, EGFR, ERBB3, MET and ATG7 - were implicated in both TG and cortical tissues. Experimental validation identified five hub genes strongly linked to migraine, with ATG7 emerging as a key candidate. Immunofluorescence co-localization revealed ATG7's prominent expression in both cortical astrocytes and neurons, suggesting its dual role in glial and neuronal pathways underlying migraine pathophysiology. Western blot analysis revealed that in the S1HL brain region of migraine model mice, the protein level of LC3-II showed an increasing trend, while the expressions of both LC3-I and p62 exhibited decreasing trends compared to the control group. Furthermore, both the LC3-II/LC3-I ratio and the LC3-II/p62 ratio were significantly elevated in the model group, suggesting that the upregulation of ATG7 promotes the activation of autophagic flux in the migraine model, with the autophagic flux remaining unobstructed.

Conclusions: Our study provides novel insights into migraine's central and peripheral mechanisms, highlighting cell-type-specific genetic contributions and potential therapeutic targets. The integrative framework combining snRNA-seq, eQTL, GWAS, and MR enhances the understanding of migraine biology and accelerates drug discovery, offering a pathway toward more effective treatments.

Neuropathic pain (NP), characterized by its complex pathophysiological mechanisms, has long posed a formidable therapeutic challenge. The burden of NP is further exacerbated by the increasing prevalence of chronic diseases. Emerging evidence highlights the pivotal role of gut microbiota in modulating immune responses, offering novel insights into NP pathogenesis. This review explores recent advancements in understanding how gut microbiota-derived metabolites - including short-chain fatty acids (SCFAs), bile acids, and tryptophan derivatives - regulate immune processes that influence neuroinflammation and nociceptive signaling. We focus on key immune mediators, including macrophages, microglia, T cells, and astrocytes, elucidating their involvement in microbiota-driven immune regulation via pathways such as TLR4/NF-κB signaling, histone deacetylase (HDAC) inhibition, and aryl hydrocarbon receptor (AhR) activation. Additionally, we examine emerging evidence of sex-specific immune mechanisms in NP. Despite promising preclinical findings on microbiota-targeted therapies, such as probiotics and fecal microbiota transplantation, translational challenges, such as microbiota heterogeneity and sex-specific responses, necessitate further investigation. This review aims to bridge microbiology, neuroimmunology, and pain research, offering a multidimensional perspective and actionable insights for the future management of NP.

Background: Migraine impacts 15% of the global population, predominantly women. Previous studies have shown a role for prolactin in animal migraine models induced by either stimulation of the dura mater or repeated stress exposure. However, the site of prolactin action is not fully known nor are its downstream mechanisms. This study investigated the potential downstream mechanisms and the cell types involved in prolactin- and repeated stress-induced migraine-like responses.

Methods: Two preclinical migraine models were used in this study, dural stimulation and repeated restraint stress. Dural injections in mice enabled drug delivery to the dura mater through the intersection of the lambdoidal and sagittal sutures. Additionally, a model of repeated stress-induced periorbital hypersensitivity and priming to a subthreshold nitric oxide donor was used. Von Frey filaments were used to measure periorbital mechanical thresholds before and after dural administration of prolactin or stress.

Results: Conditional knockout of prolactin receptors in Nav1.8-expressing sensory neurons partially but significantly blocked the periorbital hypersensitivity caused by dural application of prolactin (0.5 µg) to female mice. Depletion of macrophages using clodronate liposome injections before dural prolactin significantly blocked the prolactin responses. The inducible nitric-oxide synthase (iNOS) inhibitor AR-C102222 (ARC; 15 mg/kg) significantly blocked the dural prolactin-induced responses. To determine whether macrophages and iNOS contribute to repetitive stress-induced periorbital hypersensitivity and priming to SNP, clodronate liposomes or ARC were given before or after repetitive stress exposure. Macrophage depletion prior to or following stress significantly inhibited stress-induced periorbital hypersensitivity in both males and females. However, ARC only blocked stress-induced migraine-like behaviors in females.

Conclusion: This study demonstrates that dural prolactin acts through both neuronal and immune cell mechanisms and is dependent on iNOS activity. In response to repeated stress, macrophages contribute to behavioral responses in both sexes while iNOS is only required in females. These findings suggest that interactions between the immune and nervous systems are important for the effects of prolactin and stress on migraine-relevant mechanisms and demonstrate further sex differences in specific pathways.

Background: Orofacial pain, affecting 10-15% of adults, is a prevalent form of chronic pain that remains a major clinical challenge. The Schwann cell involvement in this pathophysiology is not fully understood. Low-density lipoprotein receptor-related protein 1 (LRP1) in Schwann cells has an unclear role in orofacial pain mechanisms.

Findings: We demonstrate that Schwann cell-specific conditional knockout of Lrp1 (scLrp1^-/^-) in mice leads to pronounced mechanical and thermal hypersensitivity in the orofacial region. RNA-seq of trigeminal ganglia (TG) from scLrp1^-/^- mice revealed broad changes in mitochondrial and metabolic pathways, reactive oxygen species (ROS) signaling, calcium homeostasis, and neurodegeneration-related processes. Altered mitochondrial function and ROS production in the TG were further confirmed with Seahorse metabolic flux analysis and biochemical assays. Additionally, mechano- and thermos-sensitive ion channels TRPV1 and TRPA1 are overexpressed and sensitized in the TG isolated from scLrp1^-/^- mice. Schwann cells isolated from scLrp1^-/^- mice displayed defective oxLDL uptake and excessive H₂O₂ release. Conditioned medium from LRP1 ablated Schwann cells induced orofacial hypersensitivity in vivo and robustly activated TG neurons in vitro in a TRPV1/TRPA1 dependent manner.

Conclusions: Our results demonstrate that Schwann cell LRP1 safeguards mitochondrial function and supports neuron-glia metabolic coupling in the trigeminal system. The finding that LRP1 deficiency in Schwann cells drives orofacial pain in the absence of external insults highlights Schwann cells as active drivers, rather than passive amplifiers of chronic pain and identifies LRP1 as a promising target for orofacial pain management.