Molecular Pain最新文献

Background: Diabetic peripheral neuropathy (DPN) and chemotherapy-induced peripheral neuropathy (CIPN) are major clinical challenges with limited therapeutic options. While these conditions arise from different causes, they may share common molecular mechanisms that could be targeted for intervention.

Methods: We performed consensus weighted gene co-expression network analysis (WGCNA) on two publicly available datasets: GSE185011 (DPN vs. healthy controls in peripheral blood mononuclear cells) and GSE173610 (paclitaxel-treated vs. control iPSC-derived sensory neurons). After filtering all but the most variable genes, consensus analysis was used to identify conserved co-expression modules across both conditions.

Results: Consensus analysis identified a 193-gene module (ME3/brown) significantly associated with both DPN (correlation=0.817, p=0.0040) and CIPN (correlation=0.971, p=0.0060). Functional enrichment analysis of this module revealed pathways related to Glycolysis, FoxO signaling, Apoptosis, and Autophagy.

Conclusions: Our analysis reveals a convergent molecular signature underlying both DPN and CIPN, centered on metabolic reprogramming, transcriptional stress, and programmed cell death. These findings provide a systems-level framework for developing therapies targeting shared pathological mechanisms.

Objective: The purpose of this paper is to expound the effect of asiatic acid (AA) on psoriasis via modulating the PI3K/Akt/NF-κB pathway and NLRP3 inflammasome.

Methods: An imiquimod (IMQ)-induced psoriasis model in BALB/c mice was established. Mice were divided into the control, IMQ, and AA treatment groups with different doses. Psoriasis area and severity were scored using the Psoriasis Area Severity Index (PASI). Histological changes, inflammatory factor levels in skin lesions, and expressions of NLRP3 inflammasome-related proteins and pathway proteins were measured. For cellular experiments, HaCaT cells were classified into control, model, AA low and high concentration groups, and AA-H + IGF group. Cells were stimulated with IL-17A, IL-22, TNF-α, IL-1α, and OSM (M5) to induce psoriasis-like conditions, followed by treatment with AA or IGF. Cell viability, oxidative stress levels, inflammatory factors, NLRP3 expression, and PI3K/Akt/NF-κB pathway protein levels were assessed.

Results: In vivo, IMQ-induced mice showed psoriasis-like symptoms, including increased PASI scores, IL-6, TNF-α, IL-17A, and NLRP3-related protein levels. AA treatment alleviated these symptoms, reducing NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and Caspase-1 expression, and restraining the PI3K/Akt/NF-κB pathway phosphorylation. In cellular experiments, M5 induction impeded cell viability and advanced oxidative stress, IL-1β, IL-6, and NLRP3 expression, activating the PI3K/Akt/NF-κB pathway. AA markedly reversed these change.

Conclusion: AA alleviates psoriasis symptoms by blocking the PI3K/Akt/NF-κB pathway and NLRP3 inflammasome.

Damage-associated molecular patterns (DAMPs), including mitochondria-derived molecules, are known to trigger immune responses and produce nociceptor sensitization during tissue inflammation. This animal study investigated whether mitochondrial debris promotes inflammatory hyperalgesia through activation of the stimulator of interferon genes (STING) signaling pathway in dorsal root ganglion (DRG) neurons.The results showed that local administration of mitochondrial debris into the hind paws of rats induced significant mechanical hyperalgesia and increased STING expression in DRG neurons. Pretreatment with H-151, a selective STING inhibitor, attenuated both debris-induced hyperalgesia and neuronal STING upregulation. STING expression in DRG neurons was similarly upregulated in a model of tissue inflammation induced by Complete Freund's Adjuvant (CFA), and administration of H-151 significantly alleviated the inflammatory hyperalgesia and increase in STING expression. These findings suggest that mitochondrial debris released during tissue inflammation activates the STING pathway in primary afferent neurons. Effective suppression of hyperalgesia by pharmacological inhibition of STING in both debris-induced and CFA-induced models in this study highlights the pronociceptive role of STING activation in peripheral sensory neurons.In conclusion, mitochondrial debris-induced STING activation in DRG neurons plays a critical role in the development of inflammatory hyperalgesia, and targeting this pathway might represent a novel therapeutic strategy for inflammatory pain.

Visceral hypersensitivity is a hallmark feature of irritable bowel syndrome (IBS), yet its underlying mechanisms remain incompletely understood. In the present study, we found that miRNA-let7b5p was downregulated in the spinal cord of IBS model rats induced by neonatal colorectal distension. Concurrently, microglia exhibited a shift toward a pro-inflammatory M1 phenotype and selectively engulfed inhibitory synapses, resulting in impaired GABAergic neuronal function and disruption of the excitatory/inhibitory balance. Intrathecal administration of a miRNA-let7b5p agomir suppressed M1-type microglial activation in the spinal cord, reduced pro-inflammatory cytokine levels, and alleviated visceral hypersensitivity, whereas antagomir treatment induced visceral hypersensitivity in control rats. Mechanistically, MAP3K3 was identified as a direct target of miRNA-let7b5p, and its knockdown recapitulated the protective effects conferred by miRNA upregulation. Collectively, these findings demonstrate that miRNA-let7b5p attenuates IBS-associated visceral hypersensitivity by downregulating MAP3K3, thereby inhibiting spinal microglial activation and restoring GABAergic neuronal function. This study provides novel insights into the pathogenesis of IBS-related visceral hypersensitivity and highlights a potential therapeutic target for drug development.

Purpose: To investigate the analgesic effects and mechanisms of IL-10-modified BMSCs administered via intrathecal injection in CCD rats.

Patients and methods: After CCD surgery, rats were administered intrathecal injections of PBS, BMSCs, BMSCs-IL-10+, BMSCs-IL-10++Anti-IL-10, LV-IRF-8, and LV-IRF-8+IL-10. Pain was assessed by measuring the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL). Glial cell activation and M2 microglial polarization were evaluated by immunofluorescence staining of Iba-1, GFAP, and Arg-1, and by WB for Iba-1 and Arg-1. Spinal cord inflammation was assessed by PCR analysis of TGF-β, TNF-α, and IL-1β expression.

Results: Compared with the CCD+PBS group, intrathecal injection of both BMSCs and BMSCs-IL-10+ significantly alleviated CCD-induced mechanical and thermal pain. However, the analgesic effect of the BMSCs group markedly decreased after 4 days, while the BMSCs-IL-10+ group lasted at least 14 days. The BMSCs-IL-10+ group significantly upregulated the expression of TGF-β while downregulating TNF-α and IL-1β, inhibiting glial cell activation and promoting M2 microglia polarization. These effects were superior to the BMSCs group and could be abolished by anti-IL-10 antibody. IRF-8 overexpression exacerbated pain and inflammation in CCD rats, but the combined application of IL-10 protein reversed this impact.

Conclusion: IL-10 is a key cytokine mediating the analgesic effects of BMSCs. Transplantation of BMSCs-IL-10+ cells reduces glial activation, alleviates neuroinflammation, and relieves neuropathic pain by enhancing IL-10 expression and suppressing IRF-8.

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and dose-limiting side effect of oxaliplatin treatment, yet its molecular mechanisms remain incompletely understood. Calcitonin gene-related peptide alpha (CGRPα, encoded by Calca) is a neuropeptide implicated in several chronic pain conditions and has been proposed to mediate CIPN-related hypersensitivity. Here, we investigated the role of CGRPα in a mouse model of chronic oxaliplatin-induced neuropathy. Mice treated with oxaliplatin over eight weeks developed cold allodynia and reduced sensory nerve conduction velocity, recapitulating hallmark clinical symptoms of chronic CIPN. However, contrary to expectations, we observed no increase in Calca mRNA expression or protein levels in the dorsal root ganglia (DRG) of male mice and a significant decrease in female mice. The proportion of CGRP-expressing neurons remained unchanged. RNA-seq revealed a two-fold upregulation of Ramp1, a subunit of the CGRP receptor complex. These results suggest that CGRPα signaling may be enhanced not by increased peptide expression, but rather by increased calcium-dependent release from existing neurons and increased CGRP receptor sensitization. This is consistent with known effects of oxaliplatin-induced oxidative stress, which can activate TRPA1 channels and promote calcium-dependent vesicular release of neuropeptides. Although additional validation of this model is needed, our data support a revised rationale of CGRP involvement in CIPN based on sensitization and neuropeptide release, rather than upregulation, and point to TRPA1-CGRP interactions as a potential therapeutic target in oxaliplatin-induced neuropathic pain.

Spinal cord injury (SCI) triggers a cascade of secondary insults-including vascular disruption, excitotoxicity, oxidative stress, inflammation, and apoptosis-that worsen neurological outcomes. Among the molecular mediators, transient receptor potential (TRP) channels have emerged as pivotal regulators of SCI pathology. Distinct subtypes contribute to diverse processes: TRPV1 and TRPA1 drive pain hypersensitivity and inflammation, TRPM2 and TRPM7 amplify oxidative injury and barrier breakdown, TRPC6 shapes astrocyte reactivity, while TRPML1 may confer neuroprotection via autophagy. Although these insights highlight TRPs as attractive therapeutic targets, clinical translation is hampered by widespread channel distribution, poor selectivity of available modulators, and systemic toxicity. Advancing SCI treatment will require innovative strategies to selectively modulate TRP signaling, exploit targeted delivery systems, and integrate TRP modulation into multimodal therapeutic approaches.

This study aimed to evaluate the therapeutic impact of Onabotulinumtoxin A (botulinum toxin) injections in patients suffering from chronic migraine and chronic tension-type headache, while assessing changes in salivary pain biomarkers-calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP). A total of 45 subjects were recruited: 25 diagnosed with chronic migraine and 20 with chronic tension-type headache, based on criteria from the International Classification of Headache Disorders (ICHD-3 and ICHD-2 revisions, respectively). Diagnosis confirmation was supported by MRI or CT imaging to exclude other etiologies. Salivary CGRP and PACAP levels were measured before and after botulinum toxin administration using enzyme-linked immunosorbent assay (ELISA). In this open-label, uncontrolled design, results showed a statistically significant reduction (p < 0.05) in both biomarkers post-treatment across both patient groups. Onabotulinumtoxin A demonstrated apparent effectiveness as a prophylactic therapy, contributing to notable improvement in headache symptoms. Among all clinical parameters evaluated, orofacial pain showed the highest responsiveness to treatment.

Most basic and clinical research on chronic pain has traditionally focused on the mechanisms and treatment of physical pain resulting from peripheral injuries in individual animals or humans. However, growing evidence highlights the importance of emotional pain, a form of distress that extends beyond the individual to include family members, partners, and friends affected by another's suffering. In this review, I summarize recent advances in animal models of empathic pain and explore cortical synaptic mechanisms underlying this form of social or emotional pain. I compare the cortical processes mediating physical pain and emotional pain, drawing on evidence from both human brain imaging and animal studies. Converging findings suggest that the anterior cingulate cortex (ACC) and insular cortex (IC) play central roles in the perception and persistence of emotional pain. Cortical potentiation appears to be a key synaptic mechanism driving long-term emotional pain, and cortical top-down modulation of spinal nociceptive transmission may help explain how emotional distress leads to abnormal somatosensory perception. Finally, the calcium-stimulated adenylyl cyclase subtype 1 (AC1) is discussed as a potential therapeutic target for the treatment of chronic pain and its associated emotional disorders.

Background: Chronic Back Pain (CBP) may lead to a reorganization of brain function, which can be observed through the indicator of degree centrality (DC). Traditional pain research has predominantly focused on static measurements of brain function within classical frequency bands, which may not fully capture the complexities of chronic pain. This study not only employed static frequency division but also incorporated dynamic analyses to capture the evolving nature of brain activity in chronic pain conditions.

Methods: This study included a total of 31 patients with CBP and 33 age- and gender-matched healthy controls. Spontaneous brain activity was investigated by traditional DC, DC in subfrequency bands (slow-5, slow-4) and dynamic DC (dDC). Differences in brain regions between the two groups were obtained using two-sample t-tests. The association of abnormal brain regions with pain intensity and psychological tests were analyzed in parallel.

Results: Compared to classical frequency band, the number of brain regions with changes in DC values in the slow-5 frequency band is greater. The right angular gyrus was found in both the slow-5 frequency band and the classical frequency band, while the left putamen was only found in the slow-5 frequency band. The dDC values were changed in left hippocampus, and right putamen, which were all different from the brain regions that the static DC (sDC) value altered.

Conclusion: This study demonstrates that incorporating frequency and dynamic analysis in addition to traditional DC metrics can better understand the functional characteristics of the brain in CBP.