Omics · study · 2026
Hippocampal CA3 Nex+ neuronal TNFR2 alleviates chronic neuropathic pain by sex-dependently engaging opioid and endocannabinoid pathways
Listed in NCBI GEO
Chronic neuropathic pain develops due to persistant neuroinflammation and maladaptive synaptic plasticity in the central nervous system following nerve injury.
Description
While TNFR2 signaling has been extensively studied in pain resolution, its expression on specific neuronal populations and the molecular pathways involved in spontaneous pain recovery remain unknown. In this, study, we investigated the role of TNFR2 within hippocampal Nex/Neurod6+ pyramidal neurons in promoting recovery from chronic constriction injury (CCI).
To achieve neuron-specific deletion of TNFR2, we generated tamoxifen-inducible conditional knockout mice (NexCreERT2:TNFR2F/F). We demonstrate that TNFR2 deletion from Nex/Neurod6+ neurons prevents spontaneous pain recovery in both sexes. Exogenous administration of a TNFR2 agonist significantly improved mechanial withdrawal thresholds in both sexes of wld-type mice but did not alleviate pain in NexCreERT2:TNFR2F/F, indicating that Nex-TNFR2 expression is required for TNFR2-mediated analgesia.
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Bulk RNA sequencing of hippocampal (Hc) tissue collected six weeks after CCI revealed that TNFR2 activation upregulates genes Pomc and oleoyl-ACP-hydrolase (Olah). Immunostaining also showed that TNFR2 agonism restored cornu ammonis 3 (CA3) region POMC and β-Endorphin protein levels that were suppresed after CCI. A behavioral experiment demonstrated that systemic blockade of the u-opioid receptor with naltrexone prevented TNFR2-mediated pain recovery in males but only partially in females.
In contrast, inhibition of cannabinoid 1 receptor (CB1R) signaling abolished TNFR2-driven analgesia in both sexes. Together, these data reveal that Hc TNFR2 signaling in Nex+ neurons is critical for CNP recovery and TNFR2 acivation promotes analgesia by engaging endogenous u-opioid and endocannabinoid pathways in a sex-dependent manner
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE333nnn/GSE333494 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE333494 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1471192 ncbi.nlm.nih.gov/bioproject/PRJNA1471192 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Mus musculus
- From keywords
- Life Sciences
- Inferred from text
- RNA sequencing 75% · Sequencing 75%
Provenance · 1 source records, 9 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE333494 | 14 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[modality].local:modality:sequencing | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[organism].NCBITaxon:10090 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |