Inhibition of Endoplasmic Reticulum Oxidoreductin 1 Modulates Neuronal Excitability and Nociceptive Sensitivity in Mice.

Summary

In mice, peripheral ERO1 inhibition reduced acute inflammatory and postsurgical pain behaviors and decreased dorsal root ganglion neuron excitability, likely by dampening ER–mitochondria calcium transfer and mitochondrial function. ERO1α is expressed in human DRG, and ERO1 inhibition modulated human sensory neuron excitability in vitro, nominating ERO1 as a non-opioid analgesic target.

Key Findings

• ERO1α is expressed across mouse DRG sensory neuron subtypes and in human DRG.
• Peripheral ERO1 inhibition acutely reversed pain-like behaviors in mouse inflammatory and postsurgical pain models.
• In cultured DRG, ERO1 inhibition reduced nociceptor excitability and mitochondrial function, consistent with dampened ER–mitochondria calcium transfer.
• ERO1 inhibition modulated excitability of post-mortem human sensory neurons in vitro.

Clinical Implications

Potential to develop peripherally acting ERO1 inhibitors for acute pain (e.g., postsurgical) as opioid-sparing strategies; safety profiling must consider mitochondrial function effects.

Limitations

• Predominantly acute pain models; chronic pain efficacy not established
• Specificity and safety of ERO1 inhibitors in vivo require further clarification

Future Directions

Define pharmacology, selectivity, and safety of ERO1 inhibitors; test efficacy in chronic pain models and dosing strategies optimized for peripheral action with minimal mitochondrial compromise.