Eukaryotic initiation factor 3d Regulates Context-Dependent Pain Hypersensitivity Through the Integrated Stress Response

Eukaryotic translation initiation factor 3 subunit D (eIF3d) is a noncanonical cap binding protein implicated in selective mRNA translation under stress conditions. Here, we investigate the contribution of eIF3d to pain processing using a heterozygous eIF3d knockout (eIF3d +/− ) mouse model. We first validated this model, confirming substantial reductions in eIF3d mRNA and protein levels in dorsal root ganglia. Baseline assessments revealed no differences in mechanical, thermal, cold, or spontaneous pain behaviors between eIF3d +/− (HET) and eIF3d +/+ (WT) mice, indicating intact basal nociceptive function. In pain models involving peripheral inflammation and metabolic stress, including methylglyoxal injection, IL-6 administration and paw incision, HET mice displayed significantly reduced mechanical and cold hypersensitivity. In contrast, HET mice exhibited increased second phase nocifensive behavior in the formalin test, possibly indicating enhanced central sensitization. Hyperalgesic priming was comparable between HET and WT mice following IL-6 exposure. Experimental autoimmune encephalomyelitis (EAE) induced mice were unaffected by eIF3d reduction. These findings demonstrate that eIF3d selectively modulates nociceptive plasticity under defined stress conditions and suggests a context dependent role in the regulation of inflammatory and central pain sensitization. Highlights Baseline mechanical, thermal, cold and spontaneous pain are intact in eIF3d +/– mice Methylglyoxal-evoked ISR activation and mechanical pain is blunted in eIF3d +/– mice IL-6-evoked mechanical and cold pain are reduced without altered priming Mechanical hypersensitivity is reduced in eIF3d +/– mice with paw incision EAE pain is unaltered but increased pain in phase II formalin pain in eIF3d +/– mice Graphical Abstract