2. Academic Validation
  3. Spinal microglial membrane glucocorticoid receptors regulate anti-hypersensitivity by stimulating dynorphin A expression

Spinal microglial membrane glucocorticoid receptors regulate anti-hypersensitivity by stimulating dynorphin A expression

  • Eur J Pharmacol. 2026 Jan 10:1010:178362. doi: 10.1016/j.ejphar.2025.178362.
Le Ma 1,  Jinbao Wei 2,  Meng-Yan Deng 3,  Khalil Ali Ahmad 3,  Jinlu Huang 3,  Meng-Jing Zhao 3,  Xinyan Li 3,  Yemeng Mao 4,  Yong-Xiang Wang 5,  Jinghong Chen 6
Affiliations

Affiliations

  • 1 Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, China; King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China.
  • 2 Department of Pharmacy, Xiamen Haicang Hospital, Xiamen, China.
  • 3 King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China.
  • 4 Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, China.
  • 5 King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China. Electronic address: [email protected].
  • 6 Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, China. Electronic address: [email protected].
PMID: 41276104 DOI: 10.1016/j.ejphar.2025.178362
Abstract

Previous studies have speculated the existence of a specific expression of the Glucocorticoid Receptor (GR) that is independent of the nuclear transcription mechanism, this type of receptor may play a decisive role in analgesic effects. The effects were determined by behavioral assessment, whole-cell recording, immunofluorescence staining, and quantitative PCR. A single intrathecal agonism of dexamethasone (DEX) and membrane-impermeable DEX-BSA exerted time-dependent anti-hypersensitivity effects and regulated spinal functional connectivities in formalin and neuropathic rats, respectively. Both DEX and DEX-BSA significantly reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) in a dosage-dependent manner. Pharmacological inhibition of GRs, dynorphin A, kappa-opioid receptors (KORs), and microglia effectively reversed the inhibitory effects of DEX and DEX-BSA on mEPSCs. Protopanaxadiol (PPD), an analogue of DEX, exhibited similar inhibitory effects on mEPSCs, without affecting the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Molecular docking analysis indicated an effective binding of DEX and PPD to GRs. GRs were mainly colocalized with the nuclear biomarker DAPI in the spinal cord. Importantly, scatter GRs, particularly in the substantia gelatinosa, were colocalized with microglia. Pharmacological stimulation of GR expression in neuronal nuclei did not alter the frequency and amplitude of mEPSCs in neuropathic rats. In addition, intrathecal DEX, DEX-BSA, and PPD also suppressed pain in female rats. DEX exerts antinociceptive effects by activating spinal microglial membrane GRs and dynorphin A release, thereby stimulating KORs-mediated inhibition of glutamatergic transmission.

Keywords

Anti-hypersensitivity; Dexamethasone (DEX); Dynorphin A; Glucocorticoid receptors; Glutamatergic transmission; Microglia.

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