Sigma-1 receptor as an emerging target for painful diabetic neuropathy—a review

Abstract

Neuropathic pain (NP) is a significant global health challenge, affecting an estimated 7–10% of the population. Painful diabetic neuropathy (PDN), a severe complication of diabetes, impacts approximately one in every three diabetic patients. With the rising global prevalence of diabetes, PDN is projected to become an increasingly urgent health concern. Current treatments for PDN often provide inadequate pain relief and are associated with adverse side effects, emphasizing the need for safe and effective therapeutic options. This review examines the limitations of existing pharmacological therapies for PDN and presents the sigma-1 receptor (S1R) as a promising therapeutic target. We explore the biological role of S1R, its implication in NP and PDN, its structural biology, and the expanding preclinical and clinical evidence supporting its potential. Furthermore, we present evidence for various S1R antagonists in addressing NP and PDN, with a particular focus on E-52862 and [¹⁸F]FTC-146. These compounds represent first-in-class ligands for therapeutic and diagnostic applications, respectively, marking significant advances in the development of S1R antagonists. This review underscores the potential of S1R antagonism as a strategy for developing more effective treatments for PDN, with the ability to significantly improve patient outcomes.

Keywords

Neuropathic pain / painful diabetic neuropathy / sigma-1 receptor / sigma-1 receptor antagonist / E-52862 / [¹⁸F]FTC-146 / PW507

References

[1] van Hecke O,Austin SK,Khan RA,Smith BH,Torrance N.Neuropathic pain in the general population: a systematic review of epidemiological studies.Pain.2014;155:654-62Erratum in: Pain. 2014;155:1907.

[2] Scholz J,Finnerup NB,Attal N,Aziz Q,Baron R,Bennett MI,et al.Classification Committee of the Neuropathic Pain Special Interest Group (NeuPSIG).The IASP classification of chronic pain for ICD-11: chronic neuropathic pain.Pain.2019;160:53-9.

[3] Neuropathic Pain Market Size, Share & Industry Analysis, By Drug Class (Anticonvulsants, Tricyclic Antidepressants (TCA), Opioids, Capsaicinoids, and Others), By Application (Diabetic Neuropathy, Chemotherapy Induced Neuropathy, Sciatic Neuropathy, and Others), By Route of Administration (Oral and Parenteral), By Distribution Channel (Hospital Pharmacy, Retail Pharmacy, and Online Pharmacy), and Regional Forecast, 2024-2032 [Internet]Fortune Business Insights; c2025 [cited 2024 Dec 6]. Available from: https://www.fortunebusinessinsights.com/neuropathic-pain-market-110546

[4] Staudt MD,Prabhala T,Sheldon BL,Quaranta N,Zakher M,Bhullar R,et al.Current Strategies for the Management of Painful Diabetic Neuropathy.J Diabetes Sci Technol.2022;16:341-52.

[5] Rugnath R,Orzechowicz C,Newell C,Carullo V,Rugnath A.A Literature Review: The Mechanisms and Treatment of Neuropathic Pain—A Brief Discussion.Biomedicines.2024;12:204.

[6] IDF Diabetes Atlas [Internet]International Diabetes Federation; c2022 [cited 2024 Jun 30]. Available from: https://www.diabetesatlas.org

[7] Abbott CA,Malik RA,van Ross ER,Kulkarni J,Boulton AJM.Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K.Diabetes Care.2011;34:2220-4.

[8] Schmader KE.Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy.Clin J Pain.2002;18:350-4.

[9] Finnerup NB,Kuner R,Jensen TS.Neuropathic Pain: From Mechanisms to Treatment.Physiol Rev.2021;101:259-301.

[10] Gupta M,Knezevic NN,Abd-Elsayed A,Ray M,Patel K,Chowdhury B.Treatment of Painful Diabetic Neuropathy—A Narrative Review of Pharmacological and Interventional Approaches.Biomedicines.2021;9:573.

[11] Mallick-Searle T,Adler JA.Update on Treating Painful Diabetic Peripheral Neuropathy: A Review of Current US Guidelines with a Focus on the Most Recently Approved Management Options.J Pain Res.2024;17:1005-28.

[12] Jang HN,Oh TJ.Pharmacological and Nonpharmacological Treatments for Painful Diabetic Peripheral Neuropathy.Diabetes Metab J.2023;47:743-56.

[13] Calandre EP,Rico-Villademoros F,Slim M.Alpha₂delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use.Expert Rev Neurother.2016;16:1263-77Erratum in: Expert Rev Neurother. 2016;16:iii.

[14] Derry S,Bell RF,Straube S,Wiffen PJ,Aldington D,Moore RA.Pregabalin for neuropathic pain in adults.Cochrane Database Syst Rev.2019;1:CD007076.

[15] Chalabianloo F,Schjøtt J.Pregabalin and its potential for abuse.Tidsskr Nor Laegeforen.2009;129:186-7.

[16] Zajączkowska R,Mika J,Leppert W,Kocot-Kępska M,Malec-Milewska M,Wordliczek J.Mirogabalin—A Novel Selective Ligand for the α2δ Calcium Channel Subunit.Pharmaceuticals (Basel).2021;14:112.

[17] Bauduceau B,Bordier L.Painful forms of diabetic neuropathy.Presse Med.2024;53:104236.

[18] Yasaei R,Katta S,Patel P,Saadabadi A.GabapentinIn: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025.

[19] Schifano F.Misuse and abuse of pregabalin and gabapentin: cause for concern?CNS Drugs.2014;28:491-6.

[20] Peselow ED,Clevenger S,IsHak WW.Prophylactic efficacy of lithium, valproic acid, and carbamazepine in the maintenance phase of bipolar disorder: a naturalistic study.Int Clin Psychopharmacol.2016;31:218-23.

[21] Grant SM,Faulds D.Oxcarbazepine. A review of its pharmacology and therapeutic potential in epilepsy, trigeminal neuralgia and affective disorders.Drugs.1992;43:873-88.

[22] Dogra S,Beydoun S,Mazzola J,Hopwood M,Wan Y.Oxcarbazepine in painful diabetic neuropathy: a randomized, placebo-controlled study.Eur J Pain.2005;9:543-54.

[23] Fricke-Galindo I,LLerena A,Jung-Cook H,López-López M.Carbamazepine adverse drug reactions.Expert Rev Clin Pharmacol.2018;11:705-18.

[24] Fang S,Gong Z.Adverse effects of oxcarbazepine.Zhongguo Dang Dai Er Ke Za Zhi.2015;17:414-9.

[25] Wu C,Huang Y,Ko Y,Lee C.Efficacy and safety of duloxetine in painful diabetic peripheral neuropathy: a systematic review and meta-analysis of randomized controlled trials.Syst Rev.2023;12:53.

[26] Goldstein DJ,Lu Y,Detke MJ,Lee TC,Iyengar S.Duloxetine vs. placebo in patients with painful diabetic neuropathy.Pain.2005;116:109-18.

[27] Pergolizzi JV Jr,Raffa RB,Taylor R Jr,Rodriguez G,Nalamachu S,Langley P.A review of duloxetine 60 mg once-daily dosing for the management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic osteoarthritis pain and low back pain.Pain Pract.2013;13:239-52.

[28] Dugan SE,Fuller MA.Duloxetine: a dual reuptake inhibitor.Ann Pharmacother.2004;38:2078-85.

[29] Bymaster FP,Dreshfield-Ahmad LJ,Threlkeld PG,Shaw JL,Thompson L,Nelson DL,et al.Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors.Neuropsychopharmacology.2001;25:871-80.

[30] Rowbotham MC,Goli V,Kunz NR,Lei D.Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study.Pain.2004;110:697-706Erratum in: Pain. 2005;113:248.

[31] Aiyer R,Barkin RL,Bhatia A.Treatment of Neuropathic Pain with Venlafaxine: A Systematic Review.Pain Med.2017;18:1999-2012.

[32] Frank C.Recognition and treatment of serotonin syndrome.Can Fam Physician.2008;54:988-92.

[33] Benbouzid M,Gavériaux-Ruff C,Yalcin I,Waltisperger E,Tessier L,Muller A,et al.Delta-opioid receptors are critical for tricyclic antidepressant treatment of neuropathic allodynia.Biol Psychiatry.2008;63:633-6.

[34] de Gandarias JM,Echevarria E,Acebes I,Silio M,Casis L.Effects of imipramine administration on mu-opioid receptor immunostaining in the rat forebrain.Arzneimittelforschung.1998;48:717-9.

[35] Hussein A,Digges M,Chang S,Hunt J,Doogue M,Rowett D,et al.Pharmacovigilance in hospice/palliative care: Net effect of amitriptyline or nortriptyline on neuropathic pain: UTS/IMPACCT Rapid programme international consecutive cohort.Palliat Med.2022;36:938-44.

[36] Fayez R,Gupta V.ImipramineIn: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025.

[37] Maan JS,Rosani A,Saadabadi A.Desipramine. 2023 Aug 14In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025.

[38] Toth C.Pregabalin: latest safety evidence and clinical implications for the management of neuropathic pain.Ther Adv Drug Saf.2014;5:38-56.

[39] Schwartz S,Etropolski M,Shapiro DY,Okamoto A,Lange R,Haeussler J,et al.Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial.Curr Med Res Opin.2011;27:151-62.

[40] Volpe DA,Tobin GAM,Mellon RD,Katki AG,Parker RJ,Colatsky T,et al.Uniform assessment and ranking of opioid Mu receptor binding constants for selected opioid drugs.Regul Toxicol Pharmacol.2011;59:385-90.

[41] Lalovic B,Kharasch E,Hoffer C,Risler L,Liu-Chen L,Shen DD.Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites.Clin Pharmacol Ther.2006;79:461-79.

[42] Vadivelu N,Kai A,Maslin B,Kodumudi G,Legler A,Berger JM.Tapentadol extended release in the management of peripheral diabetic neuropathic pain.Ther Clin Risk Manag.2015;11:95-105.

[43] Smit JW,Oh C,Rengelshausen J,Terlinden R,Ravenstijn PGM,Wang S,et al.Effects of acetaminophen, naproxen, and acetylsalicylic acid on tapentadol pharmacokinetics: results of two randomized, open-label, crossover, drug-drug interaction studies.Pharmacotherapy.2010;30:25-34.

[44] Wong M,Chung JWY,Wong TKS.Effects of treatments for symptoms of painful diabetic neuropathy: systematic review.BMJ.2007;335:87.

[45] Keating GM.Tramadol sustained-release capsules.Drugs.2006;66:223-30.

[46] Gilron I,Bailey JM,Tu D,Holden RR,Weaver DF,Houlden RL.Morphine, gabapentin, or their combination for neuropathic pain.N Engl J Med.2005;352:1324-34.

[47] Benyamin R,Trescot AM,Datta S,Buenaventura R,Adlaka R,Sehgal N,et al.Opioid complications and side effects.Pain Physician.2008;11:S105-20.

[48] Barrett JE,Shekarabi A,Inan S.Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments.Pharmacol Rev.2023;75:1062-118Erratum in: Pharmacol Rev. 2023;76:195.

[49] Cortright DN,Szallasi A.Biochemical pharmacology of the vanilloid receptor TRPV1. An update.Eur J Biochem.2004;271:1814-9.

[50] Simpson DM,Robinson-Papp J,Van J,Stoker M,Jacobs H,Snijder RJ,et al.Capsaicin 8% Patch in Painful Diabetic Peripheral Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Study.J Pain.2017;18:42-53.

[51] Ziegler D,Hanefeld M,Ruhnau KJ,Meissner HP,Lobisch M,Schütte K,et al.Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant α-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study).Diabetologia.1995;38:1425-33.

[52] Haupt E,Ledermann H,Köpcke W.Benfotiamine in the treatment of diabetic polyneuropathy—a three-week randomized, controlled pilot study (BEDIP study).Int J Clin Pharmacol Ther.2005;43:71-7Erratum in: Int J Clin Pharmacol Ther. 2005;43:304.

[53] Theodosis-Nobelos P,Papagiouvannis G,Tziona P,Rekka EA.Lipoic acid. Kinetics and pluripotent biological properties and derivatives.Mol Biol Rep.2021;48:6539-50.

[54] Martin WR,Eades CG,Thompson JA,Huppler RE,Gilbert PE.The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog.J Pharmacol Exp Ther.1976;197:517-32.

[55] Su TP.Evidence for sigma opioid receptor: binding of [3H]SKF-10047 to etorphine-inaccessible sites in guinea-pig brain.J Pharmacol Exp Ther.1982;223:284-90.

[56] Bowen WD,de Costa BR,Hellewell SB,Walker JM,Rice KC.[³H]-(+)-Pentazocine: a potent and highly selective benzomorphan-based probe for sigma-1 receptors.Mol Neuropharmacol.1993;3:117-26.

[57] Hanner M,Moebius FF,Flandorfer A,Knaus HG,Striessnig J,Kempner E,et al.Purification, molecular cloning, and expression of the mammalian sigma1-binding site.Proc Natl Acad Sci U S A.1996;93:8072-7.

[58] Harrison OJ,Brasch J,Lasso G,Katsamba PS,Ahlsen G,Honig B,et al.Structural basis of adhesive binding by desmocollins and desmogleins.Proc Natl Acad Sci U S A.2016;113:7160-5.

[59] Fu C,Xiao Y,Zhou X,Sun Z.Insight into binding of endogenous neurosteroid ligands to the sigma-1 receptor.Nat Commun.2024;15:5619.

[60] Meng F,Xiao Y,Ji Y,Sun Z,Zhou X.An open-like conformation of the sigma-1 receptor reveals its ligand entry pathway.Nat Commun.2022;13:1267.

[61] Schmidt HR,Betz RM,Dror RO,Kruse AC.Structural basis for σ₁ receptor ligand recognition.Nat Struct Mol Biol.2018;25:981-7.

[62] Alon A,Lyu J,Braz JM,Tummino TA,Craik V,O’Meara MJ,et al.Structures of the σ₂ receptor enable docking for bioactive ligand discovery.Nature.2021;600:759-64.

[63] Schmidt HR,Zheng S,Gurpinar E,Koehl A,Manglik A,Kruse AC.Crystal structure of the human σ₁ receptor.Nature.2016;532:527-30.

[64] Ruiz-Cantero MC,González-Cano R,Tejada MÁ,Santos-Caballero M,Perazzoli G,Nieto FR,et al.Sigma-1 receptor: A drug target for the modulation of neuroimmune and neuroglial interactions during chronic pain.Pharmacol Res.2021;163:105339.

[65] Mei J,Pasternak GW.Molecular cloning and pharmacological characterization of the rat sigma₁ receptor.Biochem Pharmacol.2001;62:349-55.

[66] Su TP,London ED,Jaffe JH.Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems.Science.1988;240:219-21.

[67] Fontanilla D,Johannessen M,Hajipour AR,Cozzi NV,Jackson MB,Ruoho AE.The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator.Science.2009;323:934-7.

[68] Ramachandran S,Chu UB,Mavlyutov TA,Pal A,Pyne S,Ruoho AE.The sigma1 receptor interacts with N-alkyl amines and endogenous sphingolipids.Eur J Pharmacol.2009;609:19-26.

[69] Brailoiu E,Chakraborty S,Brailoiu GC,Zhao P,Barr JL,Ilies MA,et al.Choline Is an Intracellular Messenger Linking Extracellular Stimuli to IP₃-Evoked Ca²⁺ Signals through Sigma-1 Receptors.Cell Rep.2019;26:330-7.e4.

[70] Langa F,Codony X,Tovar V,Lavado A,Giménez E,Cozar P,et al.Generation and phenotypic analysis of sigma receptor type I (σ1) knockout mice.Eur J Neurosci.2003;18:2188-96.

[71] Hayashi T,Su T.Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca²⁺ signaling and cell survival.Cell.2007;131:596-610.

[72] Su T,Su T,Nakamura Y,Tsai S.The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems.Trends Pharmacol Sci.2016;37:262-78.

[73] Alonso G,Phan V,Guillemain I,Saunier M,Legrand A,Anoal M,et al.Immunocytochemical localization of the sigma₁ receptor in the adult rat central nervous system.Neuroscience.2000;97:155-70.

[74] Bangaru ML,Weihrauch D,Tang Q,Zoga V,Hogan Q,Wu H.Sigma-1 receptor expression in sensory neurons and the effect of painful peripheral nerve injury.Mol Pain.2013;9:47.

[75] Maurice T,Su T.The pharmacology of sigma-1 receptors.Pharmacol Ther.2009;124:195-206.

[76] Schröder M,Kaufman RJ.The mammalian unfolded protein response.Annu Rev Biochem.2005;74:739-89.

[77] Weng T,Tsai SA,Su T.Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases.J Biomed Sci.2017;24:74.

[78] Merlos M,Burgueño J,Portillo-Salido E,Plata-Salamán CR,Vela JM.Pharmacological Modulation of the Sigma 1 Receptor and the Treatment of Pain.Adv Exp Med Biol.2017;964:85-107.

[79] Rodríguez-Muñoz M,Sánchez-Blázquez P,Herrero-Labrador R,Martínez-Murillo R,Merlos M,Vela JM,et al.The σ1 receptor engages the redox-regulated HINT1 protein to bring opioid analgesia under NMDA receptor negative control.Antioxid Redox Signal.2015;22:799-818.

[80] Sánchez-Blázquez P,Rodríguez-Muñoz M,Herrero-Labrador R,Burgueño J,Zamanillo D,Garzón J.The calcium-sensitive Sigma-1 receptor prevents cannabinoids from provoking glutamate NMDA receptor hypofunction: implications in antinociception and psychotic diseases.Int J Neuropsychopharmacol.2014;17:1943-55.

[81] Zhang H,Cuevas J.Sigma receptors inhibit high-voltage-activated calcium channels in rat sympathetic and parasympathetic neurons.J Neurophysiol.2002;87:2867-79.

[82] Balasuriya D,Stewart AP,Edwardson JM.The σ-1 receptor interacts directly with GluN1 but not GluN2A in the GluN1/GluN2A NMDA receptor.J Neurosci.2013;33:18219-24.

[83] Kim FJ,Kovalyshyn I,Burgman M,Neilan C,Chien C,Pasternak GW.σ₁ receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding.Mol Pharmacol.2010;77:695-703.

[84] Sánchez-Fernández C,Entrena JM,Baeyens JM,Cobos EJ.Sigma-1 Receptor Antagonists: A New Class of Neuromodulatory Analgesics.Adv Exp Med Biol.2017;964:109-32.

[85] Kourrich S,Su T,Fujimoto M,Bonci A.The sigma-1 receptor: roles in neuronal plasticity and disease.Trends Neurosci.2012;35:762-71.

[86] Schmidt HR,Kruse AC.The Molecular Function of σ Receptors: Past, Present, and Future.Trends Pharmacol Sci.2019;40:636-54.

[87] Malar DS,Thitilertdecha P,Ruckvongacheep KS,Brimson S,Tencomnao T,Brimson JM.Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders.CNS Drugs.2023;37:399-440.

[88] Pergolizzi J Jr,Varrassi G.The Emerging Role of Sigma Receptors in Pain Medicine.Cureus.2023;15:e42626.

[89] Mishra AK,Mavlyutov T,Singh DR,Biener G,Yang J,Oliver JA,et al.The sigma-1 receptors are present in monomeric and oligomeric forms in living cells in the presence and absence of ligands.Biochem J.2015;466:263-71.

[90] Gromek KA,Suchy FP,Meddaugh HR,Wrobel RL,LaPointe LM,Chu UB,et al.The oligomeric states of the purified sigma-1 receptor are stabilized by ligands.J Biol Chem.2014;289:20333-44.

[91] Sánchez-Fernández C,Montilla-García Á,González-Cano R,Nieto FR,Romero L,Artacho-Cordón A,et al.Modulation of peripheral μ-opioid analgesia by σ₁ receptors.J Pharmacol Exp Ther.2014;348:32-45.

[92] Sánchez-Fernández C,Nieto FR,González-Cano R,Artacho-Cordón A,Romero L,Montilla-García Á,et al.Potentiation of morphine-induced mechanical antinociception by σ₁ receptor inhibition: role of peripheral σ₁ receptors.Neuropharmacology.2013;70:348-58.

[93] Vidal-Torres A,de la Puente B,Rocasalbas M,Touriño C,Bura SA,Fernández-Pastor B,et al.Sigma-1 receptor antagonism as opioid adjuvant strategy: enhancement of opioid antinociception without increasing adverse effects.Eur J Pharmacol.2013;711:63-72.

[94] Cendán CM,Pujalte JM,Portillo-Salido E,Montoliu L,Baeyens JM.Formalin-induced pain is reduced in σ₁ receptor knockout mice.Eur J Pharmacol.2005;511:73-4.

[95] Entrena JM,Cobos EJ,Nieto FR,Cendán CM,Gris G,Pozo ED,et al.Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: studies with selective sigma-1 ligands and sigma-1 knockout mice.Pain.2009;143:252-61.

[96] Bravo-Caparrós I,Perazzoli G,Yeste S,Cikes D,Baeyens JM,Cobos EJ,et al.Sigma-1 Receptor Inhibition Reduces Neuropathic Pain Induced by Partial Sciatic Nerve Transection in Mice by Opioid-Dependent and -Independent Mechanisms.Front Pharmacol.2019;10:613.

[97] Gris G,Portillo-Salido E,Aubel B,Darbaky Y,Deseure K,Vela JM,et al.The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats.Sci Rep.2016;6:24591.

[98] Castany S,Codony X,Zamanillo D,Merlos M,Verdú E,Boadas-Vaello P.Repeated Sigma-1 Receptor Antagonist MR309 Administration Modulates Central Neuropathic Pain Development After Spinal Cord Injury in Mice.Front Pharmacol.2019;10:222.

[99] Zhu S,Wang C,Han Y,Song C,Hu X,Liu Y.Sigma-1 Receptor Antagonist BD1047 Reduces Mechanical Allodynia in a Rat Model of Bone Cancer Pain through the Inhibition of Spinal NR1 Phosphorylation and Microglia Activation.Mediators Inflamm.2015;2015:265056.

[100] Castany S,Gris G,Vela JM,Verdú E,Boadas-Vaello P.Critical role of sigma-1 receptors in central neuropathic pain-related behaviours after mild spinal cord injury in mice.Sci Rep.2018;8:3873.

[101] Nieto FR,Cendán CM,Sánchez-Fernández C,Cobos EJ,Entrena JM,Tejada MA,et al.Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice.J Pain.2012;13:1107-21.

[102] de la Puente B,Nadal X,Portillo-Salido E,Sánchez-Arroyos R,Ovalle S,Palacios G,et al.Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury.Pain.2009;145:294-303.

[103] Peng Y,Zhang Q,Welsh WJ.Novel Sigma 1 Receptor Antagonists as Potential Therapeutics for Pain Management.J Med Chem.2021;64:890-904.

[104] Romero L,Zamanillo D,Nadal X,Sánchez-Arroyos R,Rivera-Arconada I,Dordal A,et al.Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization.Br J Pharmacol.2012;166:2289-306.

[105] Bura AS,Guegan T,Zamanillo D,Vela JM,Maldonado R.Operant self-administration of a sigma ligand improves nociceptive and emotional manifestations of neuropathic pain.Eur J Pain.2013;17:832-43.

[106] Roh D,Kim H,Yoon S,Seo H,Kwon Y,Kim K,et al.Intrathecal injection of the ς¹ receptor antagonist BD1047 blocks both mechanical allodynia and increases in spinal NR1 expression during the induction phase of rodent neuropathic pain.Anesthesiology.2008;109:879-89.

[107] Son JS,Kwon YB.Sigma-1 Receptor Antagonist BD1047 Reduces Allodynia and Spinal ERK Phosphorylation Following Chronic Compression of Dorsal Root Ganglion in Rats.Korean J Physiol Pharmacol.2010;14:359-64.

[108] Moon J,Choi S,Roh D,Yoon S,Kwon S,Choi H,et al.Spinal sigma-1 receptor activation increases the production of D-serine in astrocytes which contributes to the development of mechanical allodynia in a mouse model of neuropathic pain.Pharmacol Res.2015;100:353-64.

[109] Gálvez R,Mayoral V,Cebrecos J,Medel FJ,Morte A,Sust M,et al.E-52862—A selective sigma-1 receptor antagonist, in peripheral neuropathic pain: Two randomized, double-blind, phase 2 studies in patients with chronic postsurgical pain and painful diabetic neuropathy.Eur J Pain.2025;29:e4755.

[110] Bruna J,Videla S,Argyriou AA,Velasco R,Villoria J,Santos C,et al.Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial.Neurotherapeutics.2018;15:178-89.

[111] Peng Y,Zhang AH,Wei L,Welsh WJ.Preclinical Evaluation of Sigma 1 Receptor Antagonists as a Novel Treatment for Painful Diabetic Neuropathy.ACS Pharmacol Transl Sci.2024;7:2358-68.

[112] Wang X,Feng C,Qiao Y,Zhao X.Sigma 1 receptor mediated HMGB1 expression in spinal cord is involved in the development of diabetic neuropathic pain.Neurosci Lett.2018;668:164-8.

[113] Ventura-Martínez R,Ángeles-López GE,González-Ugalde D,Domínguez-Páez T,Navarrete-Vázquez G,Jaimez R,et al.Antinociceptive effect of LMH-2, a new sigma-1 receptor antagonist analog of haloperidol, on the neuropathic pain of diabetic mice.Biomed Pharmacother.2024;174:116524.

[114] Paniagua N,Girón R,Goicoechea C,López-Miranda V,Vela JM,Merlos M,et al.Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats.Eur J Pain.2017;21:61-72.

[115] Song T,Zhao J,Ma X,Zhang Z,Jiang B,Yang Y.Role of sigma 1 receptor in high fat diet-induced peripheral neuropathy.Biol Chem.2017;398:1141-9.

[116] Cirino TJ,Eans SO,Medina JM,Wilson LL,Mottinelli M,Intagliata S,et al.Characterization of Sigma 1 Receptor Antagonist CM-304 and Its Analog, AZ-66: Novel Therapeutics Against Allodynia and Induced Pain.Front Pharmacol.2019;10:678.

[117] Junod A,Lambert AE,Stauffacher W,Renold AE.Diabetogenic action of streptozotocin: relationship of dose to metabolic response.J Clin Invest.1969;48:2129-39.

[118] Kolb H.Mouse models of insulin dependent diabetes: low-dose streptozocin-induced diabetes and nonobese diabetic (NOD) mice.Diabetes Metab Rev.1987;3:751-78.

[119] Furman BL.Streptozotocin-Induced Diabetic Models in Mice and Rats.Curr Protoc.2021;1:e78.

[120] Herrero JF,Laird JM,López-García JA.Wind-up of spinal cord neurones and pain sensation: much ado about something?Prog Neurobiol.2000;61:169-203.

[121] Woolf CJ,Thompson SWN.The induction and maintenance of central sensitization is dependent on N-methyl-d-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states.Pain.1991;44:293-9.

[122] Latremoliere A,Woolf CJ.Central sensitization: a generator of pain hypersensitivity by central neural plasticity.J Pain.2009;10:895-926.

[123] Andersson U,Tracey KJ.HMGB1 is a therapeutic target for sterile inflammation and infection.Annu Rev Immunol.2011;29:139-62.

[124] Leysen JE,Janssen PM,Gommeren W,Wynants J,Pauwels PJ,Janssen PA.In vitro and in vivo receptor binding and effects on monoamine turnover in rat brain regions of the novel antipsychotics risperidone and ocaperidone.Mol Pharmacol.1992;41:494-508.

[125] Chaki S,Tanaka M,Muramatsu M,Otomo S.NE-100, a novel potent σ ligand, preferentially binds to σ₁ binding sites in guinea pig brain.Eur J Pharmacol.1994;251:R1-2.

[126] Matsumoto RR,Bowen WD,Tom MA,Vo VN,Truong DD,Costa BRD.Characterization of two novel σ receptor ligands: antidystonic effects in rats suggest σ receptor antagonism.Eur J Pharmacol.1995;280:301-10.

[127] Seminerio MJ,Robson MJ,Abdelazeem AH,Mesangeau C,Jamalapuram S,Avery BA,et al.Synthesis and pharmacological characterization of a novel sigma receptor ligand with improved metabolic stability and antagonistic effects against methamphetamine.AAPS J.2012;14:43-51.

[128] Bedürftig S,Wünsch B.1,4-Diazepanes derived from (S)-serine--homopiperazines with improved σ₁ (sigma) receptor affinity and selectivity.Eur J Med Chem.2009;44:519-25.

[129] Fallica AN,Pittalà V,Modica MN,Salerno L,Romeo G,Marrazzo A,et al.Recent Advances in the Development of Sigma Receptor Ligands as Cytotoxic Agents: A Medicinal Chemistry Perspective.J Med Chem.2021;64:7926-62.

[130] James ML,Shen B,Zavaleta CL,Nielsen CH,Mesangeau C,Vuppala PK,et al.New positron emission tomography (PET) radioligand for imaging σ-1 receptors in living subjects.J Med Chem.2012;55:8272-82.

[131] Meyer C,Schepmann D,Yanagisawa S,Yamaguchi J,Col VD,Laurini E,et al.Pd-catalyzed direct C-H bond functionalization of spirocyclic σ₁ ligands: generation of a pharmacophore model and analysis of the reverse binding mode by docking into a 3D homology model of the σ₁ receptor.J Med Chem.2012;55:8047-65.

[132] Takahashi S,Sonehara K,Takagi K,Miwa T,Horikomi K,Mita N,et al.Pharmacological profile of MS-377, a novel antipsychotic agent with selective affinity for σ receptors.Psychopharmacology (Berl).1999;145:295-302.

[133] Tejada MA,Montilla-García A,Cronin SJ,Cikes D,Sánchez-Fernández C,González-Cano R,et al.Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice.Proc Natl Acad Sci U S A.2017;114:8396-401.

[134] Abadias M,Escriche M,Vaqué A,Sust M,Encina G.Safety, tolerability and pharmacokinetics of single and multiple doses of a novel sigma-1 receptor antagonist in three randomized phase I studies.Br J Clin Pharmacol.2013;75:103-17.

[135] Rabiner EA,Smith K,Bennett C,Rizzo G,Lewis Y,Mundin G,et al.Pharmacokinetics and brain σ1 receptor occupancy of MR309, a selective σ1 receptor antagonist.Br J Clin Pharmacol.2022;88:1644-54.

[136] Hjørnevik T,Cipriano PW,Shen B,Park JH,Gulaka P,Holley D,et al.Biodistribution and Radiation Dosimetry of ¹⁸F-FTC-146 in Humans.J Nucl Med.2017;58:2004-9.

[137] Avery BA,Vuppala PK,Jamalapuram S,Sharma A,Mesangeau C,Chin FT,et al.Quantification of highly selective sigma-1 receptor antagonist CM304 using liquid chromatography tandem mass spectrometry and its application to a pre-clinical pharmacokinetic study.Drug Test Anal.2017;9:1236-42.

[138] Shen B,Behera D,James ML,Reyes ST,Andrews L,Cipriano PW,et al.Visualizing Nerve Injury in a Neuropathic Pain Model with [¹⁸F]FTC-146 PET/MRI.Theranostics.2017;7:2794-805.

[139] Shen B,Park JH,Hjørnevik T,Cipriano PW,Yoon D,Gulaka PK,et al.Radiosynthesis and First-In-Human PET/MRI Evaluation with Clinical-Grade [¹⁸F]FTC-146.Mol Imaging Biol.2017;19:779-86.

[140] Shen B,James ML,Andrews L,Lau C,Chen S,Palner M,et al.Further validation to support clinical translation of [¹⁸F]FTC-146 for imaging sigma-1 receptors.EJNMMI Res.2015;5:49.

[141] Cipriano PW,Lee S,Yoon D,Shen B,Tawfik VL,Curtin CM,et al.Successful treatment of chronic knee pain following localization by a sigma-1 receptor radioligand and PET/MRI: a case report.J Pain Res.2018;11:2353-7.

[142] Yoon D,Fast AM,Cipriano P,Shen B,Castillo JB,McCurdy CR,et al.Sigma-1 Receptor Changes Observed in Chronic Pelvic Pain Patients: A Pilot PET/MRI Study.Front Pain Res (Lausanne).2021;2:711748.

[143] Díaz JL,García M,Torrens A,Caamaño AM,Enjo J,Sicre C,et al.EST64454: a Highly Soluble σ₁ Receptor Antagonist Clinical Candidate for Pain Management.J Med Chem.2020;63:14979-88.