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

Abstract

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. HighlightsO_LIBaseline mechanical, thermal, cold and spontaneous pain are intact in eIF3d+/-mice C_LIO_LIMethylglyoxal-evoked ISR activation and mechanical pain is blunted in eIF3d+/-mice C_LIO_LIIL-6-evoked mechanical and cold pain are reduced without altered priming C_LIO_LIMechanical hypersensitivity is reduced in eIF3d+/- mice with paw incision C_LIO_LIEAE pain is unaltered but increased pain in phase II formalin pain in eIF3d+/-mice C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=164 HEIGHT=200 SRC="FIGDIR/small/695844v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@26d9aforg.highwire.dtl.DTLVardef@9d7350org.highwire.dtl.DTLVardef@fdbabeorg.highwire.dtl.DTLVardef@1ef1074_HPS_FORMAT_FIGEXP M_FIG C_FIG