{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T02:03:49Z","timestamp":1774922629734,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T00:00:00Z","timestamp":1736121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["31771190"],"award-info":[{"award-number":["31771190"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The sigma-1 receptor (Sig-1R) has emerged as a significant target in the realm of pain management and has been the subject of extensive research. Nonetheless, its specific function in inflammatory pain within dorsal root ganglion (DRG) neurons remains inadequately elucidated. This study utilized whole-cell patch clamp techniques, single-cell real-time PCR, and immunohistochemistry to examine the influence of Sig-1R on inflammatory pain induced by complete Freund\u2019s adjuvant (CFA) in a rat model. Our results revealed several key findings: (1) The expression of Sig-1R was found to be upregulated during the progression of inflammatory pain, with a notable translocation from the cytoplasm to the membrane; (2) Inhibition of peripheral Sig-1R using S1RA resulted in a reduction of CFA-induced allodynia; (3) Activation of Sig-1R through PRE-084 led to a decrease in the fast sodium current in isolated DRG neurons from CFA-treated rats, which was associated with a diminished action potential (AP) peak and maximum depolarizing rate (MDR), as well as an increased rheobase; (4) Furthermore, PRE-084 was observed to enhance the slow component of the sodium current, resulting in hyperpolarization of the threshold potential and an increase in AP firing frequency, alongside an elevation in the mRNA expression of the slow sodium channel Nav1.9 in CFA-treated rats. In conclusion, our findings suggest that the modulation of sodium channels by Sig-1R in DRG neurons plays a significant role in the mechanisms underlying inflammatory pain.<\/jats:p>","DOI":"10.3390\/biom15010073","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T10:40:52Z","timestamp":1736160052000},"page":"73","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Sigma-1 Receptor Modulates CFA-Induced Inflammatory Pain via Sodium Channels in Small DRG Neurons"],"prefix":"10.3390","volume":"15","author":[{"given":"Yuanlong","family":"Song","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan 430030, China"},{"name":"Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan 430030, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zifen","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan 430030, China"},{"name":"College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liangpin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan 430030, China"},{"name":"Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan 430030, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0642-1960","authenticated-orcid":false,"given":"Linlin","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan 430030, China"},{"name":"Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan 430030, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.tins.2012.09.007","article-title":"The sigma-1 receptor: Roles in neuronal plasticity and disease","volume":"35","author":"Kourrich","year":"2012","journal-title":"Trends Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.tips.2019.07.006","article-title":"The Molecular Function of \u03c3 Receptors: Past, Present, and Future","volume":"40","author":"Schmidt","year":"2019","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/jnc.14149","article-title":"Sigma-1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors","volume":"143","author":"Brindley","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Zhang, K., Zhao, Z., Lan, L., Wei, X., Wang, L., Liu, X., Yan, H., and Zheng, J. (2017). Sigma-1 Receptor Plays a Negative Modulation on N-type Calcium Channel. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00302"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Bangaru, M.L., Weihrauch, D., Tang, Q.B., Zoga, V., Hogan, Q., and Wu, H.E. (2013). Sigma-1 receptor expression in sensory neurons and the effect of painful peripheral nerve injury. Mol. Pain, 9.","DOI":"10.1186\/1744-8069-9-47"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.neuroscience.2016.06.030","article-title":"Sigma-1 receptor expression in the dorsal root ganglion: Reexamination using a highly specific antibody","volume":"331","author":"Mavlyutov","year":"2016","journal-title":"Neuroscience"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.pain.2009.05.013","article-title":"Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury","volume":"145","author":"Puente","year":"2009","journal-title":"Pain"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Gris, G., Portillo-Salido, E., Aubel, B., Darbaky, Y., Deseure, K., Vela, J.M., Merlos, M., and Zamanillo, D. (2016). The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats. Sci. Rep., 6.","DOI":"10.1038\/srep24591"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/j.jpain.2012.08.006","article-title":"Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice","volume":"13","author":"Nieto","year":"2012","journal-title":"J. Pain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1111\/j.1476-5381.2012.01942.x","article-title":"Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization","volume":"166","author":"Romero","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1111\/j.1476-5381.2009.00197.x","article-title":"Intrathecal injection of the neurosteroid, DHEAS, produces mechanical allodynia in mice: Involvement of spinal sigma-1 and GABA receptors","volume":"157","author":"Yoon","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.phrs.2018.02.008","article-title":"Targeting immune-driven opioid analgesia by sigma-1 receptors: Opening the door to novel perspectives for the analgesic use of sigma-1 antagonists","volume":"131","author":"Tejada","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1007\/s13311-017-0572-5","article-title":"Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial","volume":"15","author":"Bruna","year":"2018","journal-title":"Neurotherapeutics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1111\/bph.16003","article-title":"The sigma-1 receptor curtails endogenous opioid analgesia during sensitization of TRPV1 nociceptors","volume":"180","author":"Jain","year":"2023","journal-title":"Br. J. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ruiz-Cantero, M.C., Gonz\u00e1lez-Cano, R., Tejada, M.\u00c1., Santos-Caballero, M., Perazzoli, G., Nieto, F.R., and Cobos, E.J. (2021). Sigma-1 receptor: A drug target for the modulation of neuroimmune and neuroglial interactions during chronic pain. Pharmacol. Res., 163.","DOI":"10.1016\/j.phrs.2020.105339"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Xiong, J., Zhuang, T., Ma, Y., Xu, J., Ye, J., Ma, R., Zhang, S., Liu, X., Liu, B.F., and Hao, C. (2021). Optimization of bifunctional piperidinamide derivatives as \u03c3(1)R Antagonists\/MOR agonists for treating neuropathic pain. Eur. J. Med. Chem., 226.","DOI":"10.1016\/j.ejmech.2021.113879"},{"key":"ref_17","first-page":"E1657","article-title":"TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain","volume":"115","author":"Islas","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1093\/brain\/awac273","article-title":"TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy","volume":"146","author":"Marcotti","year":"2023","journal-title":"Brain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3855","DOI":"10.1007\/s00213-014-3524-3","article-title":"Sigma-1 receptor inhibition reverses acute inflammatory hyperalgesia in mice: Role of peripheral sigma-1 receptors","volume":"231","author":"Tejada","year":"2014","journal-title":"Psychopharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8396","DOI":"10.1073\/pnas.1620068114","article-title":"Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice","volume":"114","author":"Tejada","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1113\/jphysiol.2002.026559","article-title":"Sensory and electrophysiological properties of guinea-pig sensory neurones expressing Nav 1.7 (PN1) Na+ channel alpha subunit protein","volume":"546 Pt 2","author":"Djouhri","year":"2003","journal-title":"J. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1113\/jphysiol.2003.042127","article-title":"The TTX-resistant sodium channel Nav1.8 (SNS\/PN3): Expression and correlation with membrane properties in rat nociceptive primary afferent neurons","volume":"550 Pt 3","author":"Djouhri","year":"2003","journal-title":"J. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7425","DOI":"10.1523\/JNEUROSCI.22-17-07425.2002","article-title":"The presence and role of the tetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptive primary afferent neurons","volume":"22","author":"Fang","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1111\/j.1469-7793.1998.857ba.x","article-title":"Association of somatic action potential shape with sensory receptive properties in guinea-pig dorsal root ganglion neurones","volume":"513 Pt 3","author":"Djouhri","year":"1998","journal-title":"J. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/S0166-2236(02)02150-1","article-title":"NaN\/Nav1.9: A sodium channel with unique properties","volume":"25","author":"Black","year":"2002","journal-title":"Trends Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1097\/j.pain.0000000000001807","article-title":"Pharmacological characterization of a rat Nav1.7 loss-of-function model with insensitivity to pain","volume":"161","author":"Chen","year":"2020","journal-title":"Pain"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nrn3977","article-title":"NaV1.9: A sodium channel linked to human pain","volume":"16","author":"Black","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3157","DOI":"10.1093\/brain\/awae071","article-title":"Nav1.8 in small dorsal root ganglion neurons contributes to vincristine-induced mechanical allodynia","volume":"147","author":"Nascimento","year":"2024","journal-title":"Brain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1097\/j.pain.0000000000001774","article-title":"Dexpramipexole blocks Nav1.8 sodium channels and provides analgesia in multiple nociceptive and neuropathic pain models","volume":"161","author":"Urru","year":"2020","journal-title":"Pain"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1111\/j.1469-7793.1999.t01-1-00565.x","article-title":"Changes in somatic action potential shape in guinea-pig nociceptive primary afferent neurones during inflammation in vivo","volume":"520","author":"Djouhri","year":"1999","journal-title":"J. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1097\/00000542-199908000-00025","article-title":"Different Actions of General Anesthetics on the Firing Patterns of Neocortical Neurons Mediated by the GABAA Receptor","volume":"91","author":"Antkowiak","year":"1999","journal-title":"Anesthesiology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s13105-017-0606-9","article-title":"Difference of acute dissociation and 1-day culture on the electrophysiological properties of rat dorsal root ganglion neurons","volume":"74","author":"Song","year":"2018","journal-title":"J. Physiol. Biochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1006\/abio.2001.5530","article-title":"A new quantitative method of real time reverse transcription polymerase chain reaction assay based on simulation of polymerase chain reaction kinetics","volume":"302","author":"Liu","year":"2002","journal-title":"Anal. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Bravo-Caparros, I., Perazzoli, G., Yeste, S., Cikes, D., Baeyens, J.M., Cobos, E.J., and Nieto, F.R. (2019). Sigma-1 Receptor Inhibition Reduces Neuropathic Pain Induced by Partial Sciatic Nerve Transection in Mice by Opioid-Dependent and -Independent Mechanisms. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.00613"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5951","DOI":"10.1096\/fj.201901921R","article-title":"Sigma-1 receptors control neuropathic pain and macrophage infiltration into the dorsal root ganglion after peripheral nerve injury","volume":"34","author":"Perazzoli","year":"2020","journal-title":"FASEB J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41434-020-0157-5","article-title":"Sigma-1 receptor activity in primary sensory neurons is a critical driver of neuropathic pain","volume":"29","author":"Shin","year":"2022","journal-title":"Gene Ther."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lachance, V., Belanger, S., Hay, C., Le Corvec, V., Banouvong, V., Lapalme, M., Tarmoun, K., Beaucaire, G., Lussier, M.P., and Kourrich, S. (2023). Overview of Sigma-1R Subcellular Specific Biological Functions and Role in Neuroprotection. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24031971"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1111\/neup.12080","article-title":"Accumulation of the sigma-1 receptor is common to neuronal nuclear inclusions in various neurodegenerative diseases","volume":"34","author":"Miki","year":"2014","journal-title":"Neuropathology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0165-6147(00)01585-6","article-title":"Involvement of Na+ channels in pain pathways","volume":"22","author":"Baker","year":"2001","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"37021","DOI":"10.1074\/jbc.M112.382077","article-title":"The sigma-1 receptor binds to the Nav1.5 voltage-gated Na+ channel with 4-fold symmetry","volume":"287","author":"Balasuriya","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Docherty, R.J., and Farmer, C.E. (2009). The pharmacology of voltage-gated sodium channels in sensory neurones. Handbook of Experimental Pharmacology, Springer.","DOI":"10.1007\/978-3-540-79090-7_15"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1016\/j.biocel.2006.06.008","article-title":"Neuronal voltage-gated sodium channel subtypes: Key roles in inflammatory and neuropathic pain","volume":"38","author":"Ekberg","year":"2006","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Gao, X., Yao, J., He, Y., Hu, C., and Mei, Y. (2012). Sigma-1 receptor agonists directly inhibit Nav1.2\/1.4 channels. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049384"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1038\/s41594-018-0137-2","article-title":"Structural basis for sigma(1) receptor ligand recognition","volume":"25","author":"Schmidt","year":"2018","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4868","DOI":"10.1523\/JNEUROSCI.0249-05.2005","article-title":"trkA is expressed in nociceptive neurons and influences electrophysiological properties via Nav1.8 expression in rapidly conducting nociceptors","volume":"25","author":"Fang","year":"2005","journal-title":"J. Neurosci."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/1\/73\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:23:39Z","timestamp":1759919019000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/1\/73"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,6]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["biom15010073"],"URL":"https:\/\/doi.org\/10.3390\/biom15010073","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,6]]}}}