Maguire Aislinn D, Lamothe Shawn M, Yousuf Muhammad Saad, Goss Kree, Rao Jayadeep, Tenorio Gustavo, Kaulagari Sridhar R, Hazlehurst Lori, Plemel Jason R, Taylor Anna M W, Kurata Harley T, Simmen Thomas, Kerr Bradley J
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
Anesthesiology. 2025 Jul 1;143(1):168-190. doi: 10.1097/ALN.0000000000005453. Epub 2025 Mar 19.
In the peripheral nervous system, nociceptors become hyperexcitable in both acute and chronic pain conditions. This phenotype can be mediated by dysregulated calcium, which occurs if the endoplasmic reticulum and mitochondria fail to buffer it appropriately. The redox enzyme endoplasmic reticulum oxidoreductin 1 (ERO1) regulates calcium transfer at endoplasmic reticulum-mitochondria contact sites (ERMCSs). This study hypothesized that inhibiting ERO1 and thereby dampening ERMCS calcium transfer might lower nociceptor hyperexcitability in sensory neurons and pain-like behaviors in mice.
C57BL/6 mice were used for histology, behavior, and cell culture experiments. Behavior included thermal tail flick, the formalin hind paw injection model of acute inflammatory pain, and hind paw incision postsurgical pain. Postmortem human dorsal root ganglia (DRGs) were used for immunohistochemistry and in vitro calcium imaging.
This study demonstrates that the α isoform of ERO1 is expressed in mouse DRGs across multiple subtypes of mouse sensory neurons. This led us to peripherally administer an ERO1 inhibitor in mice, which acutely reversed nociception in acute inflammatory and postsurgical pain models. The hypothesis was that this may be due to reduced excitability of DRG neurons and tested ERO1 inhibition in vitro. In cultured DRGs, ERO1 inhibition dampened nociceptor excitability and mitochondrial function, suggesting that reduced calcium transfer through ERMCS could be responsible for the behavior observed in vivo . ERO1α expression was also found in human DRGs using immunohistochemistry and previously published single-cell RNA-sequencing data. Finally, the study showed that ERO1 inhibition modulates human sensory neuronal excitability in cultured post-mortem DRGs.
This study found that ERO1 inhibition dampens mitochondrial function, sensory neuron excitability, and acute pain-like behavior in mice. Additionally, ERO1 inhibition decreases sensory neuron excitability in post-mortem human sensory neurons in vitro. The results indicate that targeting ERO1 may be a viable strategy for non-narcotic acute pain relief.
在外周神经系统中，伤害感受器在急性和慢性疼痛状态下都会变得过度兴奋。这种表型可能由钙调节失调介导，如果内质网和线粒体不能适当缓冲钙就会出现这种情况。氧化还原酶内质网氧化还原酶1（ERO1）在内质网-线粒体接触位点（ERMCSs）调节钙转运。本研究假设，抑制ERO1从而减弱ERMCS钙转运可能会降低感觉神经元中伤害感受器的过度兴奋性以及小鼠的疼痛样行为。
C57BL/6小鼠用于组织学、行为学和细胞培养实验。行为学实验包括热尾甩实验、急性炎性疼痛的福尔马林后爪注射模型和后爪切开术后疼痛模型。死后的人背根神经节（DRG）用于免疫组织化学和体外钙成像。
本研究表明，ERO1的α亚型在小鼠感觉神经元的多个亚型的小鼠DRG中表达。这促使我们在小鼠外周给予ERO1抑制剂，其可在急性炎性和术后疼痛模型中急性逆转伤害感受。假设这可能是由于DRG神经元兴奋性降低，并在体外测试了ERO1抑制作用。在培养的DRG中，ERO1抑制减弱了伤害感受器的兴奋性和线粒体功能，表明通过ERMCS的钙转运减少可能是体内观察到的行为的原因。使用免疫组织化学和先前发表的单细胞RNA测序数据，在人DRG中也发现了ERO1α表达。最后，该研究表明，ERO1抑制可调节培养的死后DRG中的人感觉神经元兴奋性。
本研究发现，ERO1抑制可减弱小鼠的线粒体功能、感觉神经元兴奋性和急性疼痛样行为。此外，ERO1抑制可降低体外死后人类感觉神经元的感觉神经元兴奋性。结果表明，靶向ERO1可能是一种可行的非麻醉性急性疼痛缓解策略。
