Eukaryotic initiation factor 3d regulates context-dependent pain hypersensitivity through the integrated stress response

• Baseline mechanical, thermal, cold and spontaneous pain are intact in HET mice. • Methylglyoxal evoked ISR activation and mechanical pain is blunted in HET mice. • IL-6 evoked ISR is blunted in HET mice with reduced pain and no altered priming. • Inflammatory pain induced mechanical hypersensitivity is reduced in HET mice. • EAE pain is unaltered but increased pain in phase II formalin pain in eIF3d +/– mice. 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 +/− , HET) mouse model. We first validated this model, confirming significant 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 HET and eIF3d +/+ (wildtype, WT) mice, indicating intact basal nociceptive function. In pain models involving peripheral inflammation and metabolic stress, including methylglyoxal injection, IL-6 administration, carrageenan injection, and paw incision, HET mice displayed significantly reduced mechanical and cold hypersensitivity. In contrast, HET mice exhibited increased second phase nocifensive behaviors in the formalin test, possibly indicating enhanced central sensitization. Hyperalgesic priming, induced by prostaglandin E2, was comparable between HET and WT mice following IL-6 administration. We further demonstrated that IL-6 administration increased phosphorylation of eIF2α in DRG tissue, which was attenuated in HET mice, consistent with reduced ISR activation and correlating with nocifensive behaviors. Experimental autoimmune encephalomyelitis (EAE)-induced motor signs and pain hypersensitivity were unaffected in eIF3d HETs. 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.