49: Loss of Mecp2 in mice alters CFA-evoked hypersensitivity and leads to endocannabinoid dysregulation

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Genetics and Epigenetics

Background and Aims: Pain is a major yet under-recognised burden in Rett syndrome and related MECP2 disorders, but the underlying neurobiological mechanisms remain poorly defined. The endocannabinoid system (ECS) is a key nociceptive modulator potentially regulated by MeCP2 (1,2).

Methods: Here, we subjected Mecp2-null male mice and wild-type littermates to an inflammatory pain model via hindpaw injection of complete Freund’s adjuvant (CFA) and followed for up to 3 days post-injection. Mechanical allodynia and thermal hyperalgesia were quantified longitudinally using von Frey filaments and the Hargreaves assay, respectively. At the endpoint, blood was collected to isolate serum for mass spectrometry-based profiling of ECS-related lipid mediators, and brains harvested for immunohistochemistry. We performed region- and layer-resolved analyses on CB1 and CB2 immunoreactivity within pain-relevant areas.

Results: Following CFA, Mecp2-null males did not develop hypersensitivity relative to WTs, showing higher mechanical withdrawal thresholds and reduced thermal hyperalgesia. Serum mass spectrometry revealed genotype-dependent differences that were selective for NAPE-PLD-associated lipid mediators. Immunohistochemistry further indicated remodelling of cannabinoid receptor signalling substrates in pain-relevant brain networks, with altered CB1-positive fibre distribution and emerging CB2-associated signals.

Conclusions: Together, these findings indicate that Mecp2 loss-of-function blunts inflammatory pain behaviours and is accompanied by a pathway-specific ECS lipid signature. The observed CB1 redistribution, alongside CB2, supports the view that cannabinoid-modulated components are remodelled in Mecp2 deficiency, highlighting ECS dysregulation as a mechanistic driver and therapeutic entry point for pain in MECP2-related disorders. Funding: Generalitat Valenciana (CIGE/2024/73); Spanish Ministry of Science, Innovation and Universities (MCIN/AEI/10.13039/501100011033) and the European Union “NextGenerationEU”/PRTR (RYC2021–034012-I).

References: (1) Cuitavi J, Martínez-Rodríguez E, Abellán-Álvaro M, Rodríguez-Agut M, García-Arencibia M, Santos M, Hipólito L, Forte A, Agustín-Pavón C, Torres-Pérez JV. Longitudinal analysis in Mecp2-het female mice reveals atypical nociceptive behaviours. J Mol Med (Berl). 2026 Jan 13;104(1):28. doi: 10.1007/s00109-025-02628-8. PMID: 41526543.
(2) Abellán-Álvaro M, Primo-Hernando L, Martínez-Rodríguez E, Lanuza E, Santos M, Agustín-Pavón C, Torres-Pérez JV. Altered Microglial Plasticity in the Periaqueductal Grey of Pre-Symptomatic Mecp2-Heterozygous Mice Following Early-Life Stress. Neuromolecular Med. 2025 Jun 17;27(1):46. doi: 10.1007/s12017-025-08867-9. PMID: 40526341; PMCID: PMC12174278.

Presenting Author: Jose Vicente Torres-Pérez
Submitting Author: Jose Vicente Torres Perez

Senior Author: Maria Abellán-Álvaro

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Jose Vicente Torres-Pérez: PhD - Universitat de València, Departament de Biologia Cel·lular i Biologia Funcional; Av. Vicent Andrés Estellés, 19; 46100 Burjassot, València
• Maria Gil-Navarro: MRes - Universitat de València, Departament de Biologia Cel·lular i Biologia Funcional; Av. Vicent Andrés Estellés, 19; 46100 Burjassot, València
• Sebastián Bascuas-Véntola: BSc - Universitat de València, Departament de Biologia Cel·lular i Biologia Funcional; Av. Vicent Andrés Estellés, 19; 46100 Burjassot, València
• Maria Abellán-Álvaro: PhD - Universitat de València, Departament de Biologia Cel·lular i Biologia Funcional; Av. Vicent Andrés Estellés, 19; 46100 Burjassot, València