Neuropathic pain is a common symptom of multiple sclerosis (MS) and current treatment options are ineffective. In this study, we investigated whether endoplasmic reticulum (ER) stress in dorsal root ganglia (DRG) contributes to the pain hypersensitivity in the experimental autoimmune encephalomyelitis (EAE) mouse model and by extension in MS. Firstly, we demonstrate inflammation and increased levels of ER stress markers in post-mortem DRGs from MS patients. Similarly, we observed ER stress in the DRG of EAE animals and relieving ER stress with a chemical chaperone, 4-phenylbutyric acid (4-PBA), reduced pain hypersensitivity. In vitro, 4-PBA and the selective PERK inhibitor, AMG44, normalize cytosolic Ca2+ transients in putative DRG nociceptors. In contrast, gene knockdown of CHOP and XBP1 mRNA had no effect on Ca2+ transients in EAE neurons suggesting that PERK signalling, independent of CHOP, may contribute to neuronal hyperexcitability in EAE. To investigate how aberrant Ca2+ dynamics affects neuronal excitability, we assessed disease-mediated changes in functional properties of Ca2+-sensitive BK-type K+ channels in IB4+ non-peptidergic DRG neurons. We found that the conductance-voltage (GV) relationship of BK channels was shifted to a more positive voltage, together with a more depolarized resting membrane potential in EAE cells. Changes in BK channel physiology correlated with reduced 4 and 1 subunit expression. 4- PBA and AMG44 normalized subunit levels and reversed BK channel pathophysiology. Our results suggest that ER stress in sensory neurons of MS patients and mice with EAE is a source of pain and that ER stress modulators can effectively counteract this phenotype.