Neural mechanisms underlying painful diabetic neuropathy
Abstract
Painful diabetic neuropathy (PDN), a prevalent complication of diabetes, has become a significant public health concern. It is characterized by nerve damage induced by chronic hyperglycemia, leading to pain, tingling, and numbness, predominantly in the hands and feet. This review comprehensively explores the neural mechanisms underlying PDN, emphasizing the dorsal root ganglion (DRG) as a central hub for pain initiation and transmission. In the periphery, dysregulated pathways in the DRG, including ion channel dysfunction, mitochondrial abnormalities, impaired glucose metabolism, and inflammatory disturbances, contribute to the hyperexcitability of nociceptors and the amplification of pain signals. In the central nervous system, PDN is characterized by structural and functional changes in the spinal dorsal horn and higher brain centers, leading to central sensitization and altered pain processing. The review also highlights the role of epigenetic regulation and emerging insights from single-cell RNA sequencing in understanding PDN. By integrating these peripheral and central mechanisms, future research can focus on developing targeted therapies and multimodal treatment strategies to improve patient outcomes.
References
- 1. Sun, H.; Saeedi, P.; Karuranga, S.; Pinkepank, M.; Ogurtsova, K.; Duncan, B.B.; Stein, C.; Basit, A.; Chan, J.C.N.; Mbanya, J.C.; et al. IDF Diabetes Atlas: Global, Regional and Country-Level Diabetes Prevalence Estimates for 2021 and Projections for 2045. Diabetes Res Clin Pract 2022, 183, 109119, doi:10.1016/j.diabres.2021.109119.
- 2. Wang, Q.; Ye, Y.; Yang, L.; Xiao, L.; Liu, J.; Zhang, W.; Du, G. Painful Diabetic Neuropathy: The Role of Ion Channels. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 2024, 173, 116417, doi:10.1016/j.biopha.2024.116417.
- 3. Ong, K.L.; Stafford, L.K.; McLaughlin, S.A.; Boyko, E.J.; Vollset, S.E.; Smith, A.E.; Dalton, B.E.; Duprey, J.; Cruz, J.A.; Hagins, H.; et al. Global, Regional, and National Burden of Diabetes from 1990 to 2021, with Projections of Prevalence to 2050: A Systematic Analysis for the Global Burden of Disease Study 2021. Lancet 2023, 402, 203–234, doi:10.1016/S0140-6736(23)01301-6.
- 4. Li, Y.; Teng, D.; Shi, X.; Qin, G.; Qin, Y.; Quan, H.; Shi, B.; Sun, H.; Ba, J.; Chen, B.; et al. Prevalence of Diabetes Recorded in Mainland China Using 2018 Diagnostic Criteria from the American Diabetes Association: National Cross Sectional Study. BMJ 2020, 369, m997, doi:10.1136/bmj.m997.
- 5. Pop-Busui, R.; Evans, G.W.; Gerstein, H.C.; Fonseca, V.; Fleg, J.L.; Hoogwerf, B.J.; Genuth, S.; Grimm, R.H.; Corson, M.A.; Prineas, R.; et al. Effects of Cardiac Autonomic Dysfunction on Mortality Risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial. Diabetes Care 2010, 33, 1578–1584, doi:10.2337/dc10-0125.
- 6. Alleman, C.J.M.; Westerhout, K.Y.; Hensen, M.; Chambers, C.; Stoker, M.; Long, S.; van Nooten, F.E. Humanistic and Economic Burden of Painful Diabetic Peripheral Neuropathy in Europe: A Review of the Literature. Diabetes Research and Clinical Practice 2015, 109, 215–225, doi:10.1016/j.diabres.2015.04.031.
- 7. Sloan, G.; Shillo, P.; Selvarajah, D.; Wu, J.; Wilkinson, I.D.; Tracey, I.; Anand, P.; Tesfaye, S. A New Look at Painful Diabetic Neuropathy. Diabetes Res. Clin. Pract. 2018, 144, 177–191, doi:10.1016/j.diabres.2018.08.020.
- 8. Peltier, A.; Goutman, S.A.; Callaghan, B.C. Painful Diabetic Neuropathy. BMJ 2014, 348, g1799–g1799, doi:10.1136/bmj.g1799.
- 9. Kiyani, M.; Yang, Z.; Charalambous, L.T.; Adil, S.M.; Lee, H.-J.; Yang, S.; Pagadala, P.; Parente, B.; Spratt, S.E.; Lad, S.P. Painful Diabetic Peripheral Neuropathy: Health Care Costs and Complications from 2010 to 2015. Neurol Clin Pract 2020, 10, 47–57, doi:10.1212/CPJ.0000000000000671.
- 10. England, J.D.; Asbury, A.K. Peripheral Neuropathy. Lancet 2004, 363, 2151–2161, doi:10.1016/S0140-6736(04)16508-2.
- 11. Duarte, R.V.; Nevitt, S.; Copley, S.; Maden, M.; de Vos, C.C.; Taylor, R.S.; Eldabe, S. Systematic Review and Network Meta-Analysis of Neurostimulation for Painful Diabetic Neuropathy. Diabetes Care 2022, 45, 2466–2475, doi:10.2337/dc22-0932.
- 12. Feldman, E.L.; Nave, K.-A.; Jensen, T.S.; Bennett, D.L.H. New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain. Neuron 2017, 93, 1296–1313, doi:10.1016/j.neuron.2017.02.005.
- 13. Wall and Melzack’s Textbook of Pain: Get Full Access and More at ExpertConsult.Com; McMahon, S.B., Wall, P.D., Melzack, R., McMahon, S.B., Eds.; 6. ed.; Elsevier, Saunders: Philadelphia, Pa, 2013; ISBN 978-0-7020-4059-7.
- 14. Basbaum, A.I.; Bautista, D.M.; Scherrer, G.; Julius, D. Cellular and Molecular Mechanisms of Pain. Cell 2009, 139, 267–284, doi:10.1016/j.cell.2009.09.028.
- 15. Krames, E.S. The Role of the Dorsal Root Ganglion in the Development of Neuropathic Pain. Pain Med. 2014, 15, 1669–1685, doi:10.1111/pme.12413.
- 16. Zochodne, D.W.; Ho, L.T. Unique Microvascular Characteristics of the Dorsal Root Ganglion in the Rat. Brain Research 1991, 559, 89–93, doi:10.1016/0006-8993(91)90290-c.
- 17. Abram, S.E.; Yi, J.; Fuchs, A.; Hogan, Q.H. Permeability of Injured and Intact Peripheral Nerves and Dorsal Root Ganglia. Anesthesiology 2006, 105, 146–153, doi:10.1097/00000542-200607000-00024.
- 18. Sapunar, D.; Kostic, S.; Banozic, A.; Puljak, L. Dorsal Root Ganglion - a Potential New Therapeutic Target for Neuropathic Pain. Journal of Pain Research 2012, 5, 31–38, doi:10.2147/JPR.S26603.
- 19. Ziegler, D.; Rathmann, W.; Dickhaus, T.; Meisinger, C.; Mielck, A. Neuropathic Pain in Diabetes, Prediabetes and Normal Glucose Tolerance: The MONICA/KORA Augsburg Surveys S2 and S3. Pain Med 2009, 10, 393–400, doi:10.1111/j.1526-4637.2008.00555.x.
- 20. Kobayashi, M.; Zochodne, D.W. Diabetic Neuropathy and the Sensory Neuron: New Aspects of Pathogenesis and Their Treatment Implications. Journal of Diabetes Investigation 2018, 9, 1239–1254, doi:10.1111/jdi.12833.
- 21. Miyashita, A.; Kobayashi, M.; Yokota, T.; Zochodne, D. Diabetic Polyneuropathy: New Strategies to Target Sensory Neurons in Dorsal Root Ganglia. International Journal of Molecular Sciences 2023, 24, 5977, doi:10.3390/ijms24065977.
- 22. Hall, B.E.; Macdonald, E.; Cassidy, M.; Yun, S.; Sapio, M.R.; Ray, P.; Doty, M.; Nara, P.; Burton, M.D.; Shiers, S.; et al. Transcriptomic Analysis of Human Sensory Neurons in Painful Diabetic Neuropathy Reveals Inflammation and Neuronal Loss. Sci Rep 2022, 12, 4729, doi:10.1038/s41598-022-08100-8.
- 23. Doty, M.; Yun, S.; Wang, Y.; Hu, M.; Cassidy, M.; Hall, B.; Kulkarni, A.B. Integrative Multiomic Analyses of Dorsal Root Ganglia in Diabetic Neuropathic Pain Using Proteomics, Phospho-Proteomics, and Metabolomics. Sci. Rep. 2022, 12, 17012, doi:10.1038/s41598-022-21394-y.
- 24. DiMeglio, L.A.; Evans-Molina, C.; Oram, R.A. Type 1 Diabetes. The Lancet 2018, 391, 2449–2462, doi:10.1016/S0140-6736(18)31320-5.
- 25. Athie, M.C.P.; Vieira, A.S.; Teixeira, J.M.; Dos Santos, G.G.; Dias, E.V.; Tambeli, C.H.; Sartori, C.R.; Parada, C.A. Transcriptome Analysis of Dorsal Root Ganglia’s Diabetic Neuropathy Reveals Mechanisms Involved in Pain and Regeneration. Life Sciences 2018, 205, 54–62, doi:10.1016/j.lfs.2018.05.016.
- 26. Ahmad, E.; Lim, S.; Lamptey, R.; Webb, D.R.; Davies, M.J. Type 2 Diabetes. The Lancet 2022, 400, 1803–1820, doi:10.1016/S0140-6736(22)01655-5.
- 27. Leal-Julià, M.; Vilches, J.J.; Onieva, A.; Verdés, S.; Sánchez, Á.; Chillón, M.; Navarro, X.; Bosch, A. Proteomic Quantitative Study of Dorsal Root Ganglia and Sciatic Nerve in Type 2 Diabetic Mice. Mol. Metab. 2022, 55, 101408, doi:10.1016/j.molmet.2021.101408.
- 28. Bali, K.K.; Gandla, J.; Rangel, D.R.; Castaldi, L.; Mouritzen, P.; Agarwal, N.; Schmelz, M.; Heppenstall, P.; Kuner, R. A Genome-Wide Screen Reveals microRNAs in Peripheral Sensory Neurons Driving Painful Diabetic Neuropathy. Pain 2021, 162, 1334–1351, doi:10.1097/j.pain.0000000000002159.
- 29. Price, S.A.; Zeef, L.A.H.; Wardleworth, L.; Hayes, A.; Tomlinson, D.R. Identification of Changes in Gene Expression in Dorsal Root Ganglia in Diabetic Neuropathy: Correlation with Functional Deficits. J. Neuropathol. Exp. Neurol. 2006, 65, 722–732, doi:10.1097/01.jnen.0000228199.89420.90.
- 30. Hinder, L.M.; Murdock, B.J.; Park, M.; Bender, D.E.; O’Brien, P.D.; Rumora, A.E.; Hur, J.; Feldman, E.L. Transcriptional Networks of Progressive Diabetic Peripheral Neuropathy in the Db/Db Mouse Model of Type 2 Diabetes: An Inflammatory Story. Experimental Neurology 2018, 305, 33–43, doi:10.1016/j.expneurol.2018.03.011.
- 31. Cheng, C.; Kobayashi, M.; Martinez, J.A.; Ng, H.; Moser, J.J.; Wang, X.; Singh, V.; Fritzler, M.J.; Zochodne, D.W. Evidence for Epigenetic Regulation of Gene Expression and Function in Chronic Experimental Diabetic Neuropathy. J. Neuropathol. Exp. Neurol. 2015, 74, 804–817, doi:10.1097/NEN.0000000000000219.
- 32. Zhang, H.-H.; Zhang, Y.; Wang, X.; Yang, P.; Zhang, B.-Y.; Hu, S.; Xu, G.-Y.; Hu, J. Circular RNA Profile in Diabetic Peripheral Neuropathy: Analysis of Coexpression Networks of Circular RNAs and mRNAs. Epigenomics 2020, 12, 843–857, doi:10.2217/epi-2020-0011.
- 33. Fernyhough, P.; McGavock, J. Mechanisms of Disease: Mitochondrial Dysfunction in Sensory Neuropathy and Other Complications in Diabetes. Handbook of Clinical Neurology 2014, 126, 353–377, doi:10.1016/B978-0-444-53480-4.00027-8.
- 34. Eftekharpour, E.; Fernyhough, P. Oxidative Stress and Mitochondrial Dysfunction Associated with Peripheral Neuropathy in Type 1 Diabetes. Antioxid. Redox Signaling 2022, 37, 578–596, doi:10.1089/ars.2021.0152.
- 35. Hinder, L.M.; Vivekanandan-Giri, A.; McLean, L.L.; Pennathur, S.; Feldman, E.L. Decreased Glycolytic and Tricarboxylic Acid Cycle Intermediates Coincide with Peripheral Nervous System Oxidative Stress in a Murine Model of Type 2 Diabetes. J Endocrinol 2013, 216, 1–11, doi:10.1530/JOE-12-0356.
- 36. George, D.S.; Hackelberg, S.; Jayaraj, N.D.; Ren, D.; Edassery, S.L.; Rathwell, C.A.; Miller, R.E.; Malfait, A.-M.; Savas, J.N.; Miller, R.J.; et al. Mitochondrial Calcium Uniporter Deletion Prevents Painful Diabetic Neuropathy by Restoring Mitochondrial Morphology and Dynamics. Pain 2022, 163, 560–578, doi:10.1097/j.pain.0000000000002391.
- 37. Akude, E.; Zherebitskaya, E.; Chowdhury, S.K.R.; Smith, D.R.; Dobrowsky, R.T.; Fernyhough, P. Diminished Superoxide Generation Is Associated with Respiratory Chain Dysfunction and Changes in the Mitochondrial Proteome of Sensory Neurons from Diabetic Rats. Diabetes 2011, 60, 288–297, doi:10.2337/db10-0818.
- 38. Feige, J.N.; Auwerx, J. Transcriptional Coregulators in the Control of Energy Homeostasis. Trends in Cell Biology 2007, 17, 292–301, doi:10.1016/j.tcb.2007.04.001.
- 39. Villena, J.A. New Insights into PGC-1 Coactivators: Redefining Their Role in the Regulation of Mitochondrial Function and Beyond. FEBS J 2015, 282, 647–672, doi:10.1111/febs.13175.
- 40. Roy Chowdhury, S.K.; Smith, D.R.; Saleh, A.; Schapansky, J.; Marquez, A.; Gomes, S.; Akude, E.; Morrow, D.; Calcutt, N.A.; Fernyhough, P. Impaired Adenosine Monophosphate-Activated Protein Kinase Signalling in Dorsal Root Ganglia Neurons Is Linked to Mitochondrial Dysfunction and Peripheral Neuropathy in Diabetes. Brain: A Journal of Neurology 2012, 135, 1751–1766, doi:10.1093/brain/aws097.
- 41. Patti, M.E.; Butte, A.J.; Crunkhorn, S.; Cusi, K.; Berria, R.; Kashyap, S.; Miyazaki, Y.; Kohane, I.; Costello, M.; Saccone, R.; et al. Coordinated Reduction of Genes of Oxidative Metabolism in Humans with Insulin Resistance and Diabetes: Potential Role of PGC1 and NRF1. Proc Natl Acad Sci U S A 2003, 100, 8466–8471, doi:10.1073/pnas.1032913100.
- 42. Mootha, V.K.; Lindgren, C.M.; Eriksson, K.-F.; Subramanian, A.; Sihag, S.; Lehar, J.; Puigserver, P.; Carlsson, E.; Ridderstråle, M.; Laurila, E.; et al. PGC-1alpha-Responsive Genes Involved in Oxidative Phosphorylation Are Coordinately Downregulated in Human Diabetes. Nat. Genet. 2003, 34, 267–273, doi:10.1038/ng1180.
- 43. Choi, J.; Chandrasekaran, K.; Inoue, T.; Muragundla, A.; Russell, J.W. PGC-1α Regulation of Mitochondrial Degeneration in Experimental Diabetic Neuropathy. Neurobiol. Dis. 2014, 64, 118–130, doi:10.1016/j.nbd.2014.01.001.
- 44. Clayton, D.A. Transcription and Replication of Mitochondrial DNA. Human Reproduction 2000, 15, 11–17, doi:10.1093/humrep/15.suppl_2.11.
- 45. Campbell, C.T.; Kolesar, J.E.; Kaufman, B.A. Mitochondrial Transcription Factor a Regulates Mitochondrial Transcription Initiation, DNA Packaging, and Genome Copy Number. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 2012, 1819, 921–929, doi:10.1016/j.bbagrm.2012.03.002.
- 46. Kang, I.; Chu, C.T.; Kaufman, B.A. The Mitochondrial Transcription Factor TFAM in Neurodegeneration: Emerging Evidence and Mechanisms. FEBS Letters 2018, 592, 793–811, doi:10.1002/1873-3468.12989.
- 47. Chandrasekaran, K.; Anjaneyulu, M.; Inoue, T.; Choi, J.; Sagi, A.R.; Chen, C.; Ide, T.; Russell, J.W. Mitochondrial Transcription Factor A Regulation of Mitochondrial Degeneration in Experimental Diabetic Neuropathy. Am J Physiol Endocrinol Metab 2015, 309, E132-141, doi:10.1152/ajpendo.00620.2014.
- 48. Ikeuchi, M.; Matsusaka, H.; Kang, D.; Matsushima, S.; Ide, T.; Kubota, T.; Fujiwara, T.; Hamasaki, N.; Takeshita, A.; Sunagawa, K.; et al. Overexpression of Mitochondrial Transcription Factor a Ameliorates Mitochondrial Deficiencies and Cardiac Failure after Myocardial Infarction. Circulation 2005, 112, 683–690, doi:10.1161/CIRCULATIONAHA.104.524835.
- 49. Hirschey, M.D.; Shimazu, T.; Capra, J.A.; Pollard, K.S.; Verdin, E. SIRT1 and SIRT3 Deacetylate Homologous Substrates: AceCS1,2 and HMGCS1,2. Aging (milano) 2011, 3, 635–642, doi:10.18632/aging.100339.
- 50. Chandrasekaran, K.; Salimian, M.; Konduru, S.R.; Choi, J.; Kumar, P.; Long, A.; Klimova, N.; Ho, C.-Y.; Kristian, T.; Russell, J.W. Overexpression of Sirtuin 1 Protein in Neurons Prevents and Reverses Experimental Diabetic Neuropathy. Brain 2019, 142, 3737–3752, doi:10.1093/brain/awz324.
- 51. Schartner, E.; Sabbir, M.G.; Saleh, A.; Silva, R.V.; Roy Chowdhury, S.; Smith, D.R.; Fernyhough, P. High Glucose Concentration Suppresses a SIRT2 Regulated Pathway That Enhances Neurite Outgrowth in Cultured Adult Sensory Neurons. Exp Neurol 2018, 309, 134–147, doi:10.1016/j.expneurol.2018.08.001.
- 52. Grabauskas, G.; Heldsinger, A.; Wu, X.; Xu, D.; Zhou, S.; Owyang, C. Diabetic Visceral Hypersensitivity Is Associated with Activation of Mitogen-Activated Kinase in Rat Dorsal Root Ganglia. Diabetes 2011, 60, 1743–1751, doi:10.2337/db10-1507.
- 53. Zochodne, D.W. Mechanisms of Diabetic Neuron Damage: Molecular Pathways. Handbook of Clinical Neurology 2014, 126, 379–399, doi:10.1016/B978-0-444-53480-4.00028-X.
- 54. Todorovic, S.M. Painful Diabetic Neuropathy: Prevention or Suppression? Int. Rev. Neurobiol. 2016, 127, 211–225, doi:10.1016/bs.irn.2016.03.005.
- 55. Hoeijmakers, J.G.J.; Faber, C.G.; Merkies, I.S.J.; Waxman, S.G. Channelopathies, Painful Neuropathy, and Diabetes: Which Way Does the Causal Arrow Point? Trends Mol. Med. 2014, 20, 544–550, doi:10.1016/j.molmed.2014.06.003.
- 56. Hong, S.; Morrow, T.J.; Paulson, P.E.; Isom, L.L.; Wiley, J.W. Early Painful Diabetic Neuropathy Is Associated with Differential Changes in Tetrodotoxin-Sensitive and -Resistant Sodium Channels in Dorsal Root Ganglion Neurons in the Rat. J. Biol. Chem. 2004, 279, 29341–29350, doi:10.1074/jbc.M404167200.
- 57. Craner, M.J.; Klein, J.P.; Renganathan, M.; Black, J.A.; Waxman, S.G. Changes of Sodium Channel Expression in Experimental Painful Diabetic Neuropathy. Ann Neurol 2002, 52, 786–792, doi:10.1002/ana.10364.
- 58. Pang, B.; Qiao, L.; Wang, S.; Guo, X.; Xie, Y.; Han, L. MiR-214-3p Plays a Protective Role in Diabetic Neuropathic Rats by Regulating Nav1.3 and TLR4. Cell Biol Int 2021, 45, 2294–2303, doi:10.1002/cbin.11677.
- 59. Han, C.; Hoeijmakers, J.G.J.; Ahn, H.-S.; Zhao, P.; Shah, P.; Lauria, G.; Gerrits, M.M.; Te Morsche, R.H.M.; Dib-Hajj, S.D.; Drenth, J.P.H.; et al. Nav 1.7-Related Small Fiber Neuropathy: Impaired Slow-Inactivation and DRG Neuron Hyperexcitability. Neurology 2012, 78, 1635–1643, doi:10.1212/WNL.0b013e3182574f12.
- 60. Rush, A.M.; Cummins, T.R.; Waxman, S.G. Multiple Sodium Channels and Their Roles in Electrogenesis within Dorsal Root Ganglion Neurons. J. Physiol. (lond.) 2007, 579, 1–14, doi:10.1113/jphysiol.2006.121483.
- 61. Sun, W.; Miao, B.; Wang, X.-C.; Duan, J.-H.; Wang, W.-T.; Kuang, F.; Xie, R.-G.; Xing, J.-L.; Xu, H.; Song, X.-J.; et al. Reduced Conduction Failure of the Main Axon of Polymodal Nociceptive C-Fibres Contributes to Painful Diabetic Neuropathy in Rats. Brain 2012, 135, 359–375, doi:10.1093/brain/awr345.
- 62. Cheng, K.-I.; Wang, H.-C.; Chuang, Y.-T.; Chou, C.-W.; Tu, H.-P.; Yu, Y.-C.; Chang, L.-L.; Lai, C.-S. Persistent Mechanical Allodynia Positively Correlates with an Increase in Activated Microglia and Increased P-P38 Mitogen-Activated Protein Kinase Activation in Streptozotocin-Induced Diabetic Rats. Eur J Pain 2014, 18, 162–173, doi:10.1002/j.1532-2149.2013.00356.x.
- 63. Ri-Ge-le, A.; Guo, Z.-L.; Wang, Q.; Zhang, B.-J.; Kong, D.-W.; Yang, W.-Q.; Yu, Y.-B.; Zhang, L. Tanshinone IIA Improves Painful Diabetic Neuropathy by Suppressing the Expression and Activity of Voltage-Gated Sodium Channel in Rat Dorsal Root Ganglia. Exp Clin Endocrinol Diabetes 2018, 126, 632–639, doi:10.1055/s-0044-100722.
- 64. Tsantoulas, C.; McMahon, S.B. Opening Paths to Novel Analgesics: The Role of Potassium Channels in Chronic Pain. Trends in Neurosciences 2014, 37, 146–158, doi:10.1016/j.tins.2013.12.002.
- 65. Ocaña, M.; Cendán, C.M.; Cobos, E.J.; Entrena, J.M.; Baeyens, J.M. Potassium Channels and Pain: Present Realities and Future Opportunities. Eur. J. Pharmacol. 2004, 500, 203–219, doi:10.1016/j.ejphar.2004.07.026.
- 66. Cao, X.; Byun, H.; Chen, S.; Cai, Y.; Pan, H. Reduction in Voltage‐gated K+ Channel Activity in Primary Sensory Neurons in Painful Diabetic Neuropathy: Role of Brain‐derived Neurotrophic Factor. J. Neurochem. 2010, 114, 1460–1475, doi:10.1111/j.1471-4159.2010.06863.x.
- 67. Xu, X.; Xu, X.; Hao, Y.; Zhu, X.; Lu, J.; Ouyang, X.; Lu, Y.; Huang, X.; Li, Y.; Wang, J.; et al. Antispasmodic Drug Drofenine as an Inhibitor of Kv2.1 Channel Ameliorates Peripheral Neuropathy in Diabetic Mice. iScience 2020, 23, 101617, doi:10.1016/j.isci.2020.101617.
- 68. Yu, T.; Li, L.; Liu, H.; Li, H.; Liu, Z.; Li, Z. KCNQ2/3/5 Channels in Dorsal Root Ganglion Neurons Can Be Therapeutic Targets of Neuropathic Pain in Diabetic Rats. Mol Pain 2018, 14, 1744806918793229, doi:10.1177/1744806918793229.
- 69. Djouhri, L.; Zeidan, A.; Abd El-Aleem, S.A. Changes in Expression of Kv7.5 and Kv7.2 Channels in Dorsal Root Ganglion Neurons in the Streptozotocin Rat Model of Painful Diabetic Neuropathy. Neurosci Lett 2020, 736, 135277, doi:10.1016/j.neulet.2020.135277.
- 70. Noguchi, K. Faculty Opinions Recommendation of the Increased Trafficking of the Calcium Channel Subunit Alpha2delta-1 to Presynaptic Terminals in Neuropathic Pain Is Inhibited by the Alpha2delta Ligand Pregabalin. 2009, 620430.
- 71. Obradovic, A.L.; Hwang, S.M.; Scarpa, J.; Hong, S.J.; Todorovic, S.M.; Jevtovic-Todorovic, V. CaV3.2 T-Type Calcium Channels in Peripheral Sensory Neurons Are Important for Mibefradil-Induced Reversal of Hyperalgesia and Allodynia in Rats with Painful Diabetic Neuropathy. PLoS One 2014, 9, e91467, doi:10.1371/journal.pone.0091467.
- 72. Todorovic, S.M.; Jevtovic-Todorovic, V. Targeting of CaV3.2 T-Type Calcium Channels in Peripheral Sensory Neurons for the Treatment of Painful Diabetic Neuropathy. Pflugers Arch 2014, 466, 701–706, doi:10.1007/s00424-014-1452-z.
- 73. Ivasiuk, A.; Matvieienko, M.; Kononenko, N.I.; Duzhyy, D.E.; Korogod, S.M.; Voitenko, N.; Belan, P. Diabetes-Induced Amplification of Nociceptive DRG Neuron Output by Upregulation of Somatic T-Type Ca2+ Channels. Biomolecules 2023, 13, 1320, doi:10.3390/biom13091320.
- 74. Stringer, R.N.; Lazniewska, J.; Weiss, N. Transcriptomic Analysis of Glycan-Processing Genes in the Dorsal Root Ganglia of Diabetic Mice and Functional Characterization on Cav 3.2 Channels. Channels 2020, 14, 132–140, doi:10.1080/19336950.2020.1745406.
- 75. Messinger, R.B.; Naik, A.K.; Jagodic, M.M.; Nelson, M.T.; Lee, W.Y.; Choe, W.J.; Orestes, P.; Latham, J.R.; Todorovic, S.M.; Jevtovic-Todorovic, V. In Vivo Silencing of the Ca(V)3.2 T-Type Calcium Channels in Sensory Neurons Alleviates Hyperalgesia in Rats with Streptozocin-Induced Diabetic Neuropathy. Pain 2009, 145, 184–195, doi:10.1016/j.pain.2009.06.012.
- 76. Latham, J.R.; Pathirathna, S.; Jagodic, M.M.; Choe, W.J.; Levin, M.E.; Nelson, M.T.; Lee, W.Y.; Krishnan, K.; Covey, D.F.; Todorovic, S.M.; et al. Selective T-Type Calcium Channel Blockade Alleviates Hyperalgesia in Ob/Ob Mice. Diabetes 2009, 58, 2656–2665, doi:10.2337/db08-1763.
- 77. Jagodic, M.M.; Pathirathna, S.; Nelson, M.T.; Mancuso, S.; Joksovic, P.M.; Rosenberg, E.R.; Bayliss, D.A.; Jevtovic-Todorovic, V.; Todorovic, S.M. Cell-Specific Alterations of T-Type Calcium Current in Painful Diabetic Neuropathy Enhance Excitability of Sensory Neurons. J Neurosci 2007, 27, 3305–3316, doi:10.1523/JNEUROSCI.4866-06.2007.
- 78. Moran, M.M. TRP Channels as Potential Drug Targets. Annu. Rev. Pharmacol. Toxicol. 2018, 58, 309–330, doi:10.1146/annurev-pharmtox-010617-052832.
- 79. Roa-Coria, J.E.; Pineda-Farias, J.B.; Barragán-Iglesias, P.; Quiñonez-Bastidas, G.N.; Zúñiga-Romero, Á.; Huerta-Cruz, J.C.; Reyes-García, J.G.; Flores-Murrieta, F.J.; Granados-Soto, V.; Rocha-González, H.I. Possible Involvement of Peripheral TRP Channels in the Hydrogen Sulfide-Induced Hyperalgesia in Diabetic Rats. BMC neuroscience 2019, 20, 1, doi:10.1186/s12868-018-0483-3.
- 80. Hong, S.; Wiley, J.W. Early Painful Diabetic Neuropathy Is Associated with Differential Changes in the Expression and Function of Vanilloid Receptor 1. J Biol Chem 2005, 280, 618–627, doi:10.1074/jbc.M408500200.
- 81. Zhang, B.-Y.; Zhang, Y.-L.; Sun, Q.; Zhang, P.-A.; Wang, X.-X.; Xu, G.-Y.; Hu, J.; Zhang, H.-H. Alpha-Lipoic Acid Downregulates TRPV1 Receptor via NF-κB and Attenuates Neuropathic Pain in Rats with Diabetes. CNS neuroscience & therapeutics 2020, 26, 762–772, doi:10.1111/cns.13303.
- 82. Li, X.; Yuan, D.; Zhang, P.; Luo, C.; Xie, X.; Zhang, Y.; Wei, Z.; Wang, M.; Cai, Y.; Zeng, Y.; et al. A Neuron-Mast Cell Axis Regulates Skin Microcirculation in Diabetes. Diabetes 2024, 73, 1728–1741, doi:10.2337/db23-0862.
- 83. Barrière, D.A.; Rieusset, J.; Chanteranne, D.; Busserolles, J.; Chauvin, M.-A.; Chapuis, L.; Salles, J.; Dubray, C.; Morio, B. Paclitaxel Therapy Potentiates Cold Hyperalgesia in Streptozotocin-Induced Diabetic Rats through Enhanced Mitochondrial Reactive Oxygen Species Production and TRPA1 Sensitization. Pain 2012, 153, 553–561, doi:10.1016/j.pain.2011.11.019.
- 84. Andersson, D.A.; Gentry, C.; Light, E.; Vastani, N.; Vallortigara, J.; Bierhaus, A.; Fleming, T.; Bevan, S. Methylglyoxal Evokes Pain by Stimulating TRPA1. PloS One 2013, 8, e77986, doi:10.1371/journal.pone.0077986.
- 85. Petruska, J.C.; Cooper, B.Y.; Johnson, R.D.; Gu, J.G. Distribution Patterns of Different P2x Receptor Phenotypes in Acutely Dissociated Dorsal Root Ganglion Neurons of Adult Rats. Exp Brain Res 2000, 134, 126–132, doi:10.1007/s002210000414.
- 86. Chen, M.; Gu, J.G. A P2X Receptor-Mediated Nociceptive Afferent Pathway to Lamina I of the Spinal Cord. Mol Pain 2005, 1, 4, doi:10.1186/1744-8069-1-4.
- 87. Migita, K.; Moriyama, T.; Koguchi, M.; Honda, K.; Katsuragi, T.; Takano, Y.; Ueno, S. Modulation of P2X Receptors in Dorsal Root Ganglion Neurons of Streptozotocin-Induced Diabetic Neuropathy. Neurosci. Lett. 2009, 452, 200–203, doi:10.1016/j.neulet.2009.01.048.
- 88. Shi, L.; Zhang, H.-H.; Hu, J.; Jiang, X.-H.; Xu, G.-Y. Purinergic P2X Receptors and Diabetic Neuropathic Pain. Sheng Li Xue Bao: [Acta Physiologica Sinica] 2012, 64, 531–542.
- 89. Xu, G.-Y.; Li, G.; Liu, N.; Huang, L.-Y.M. Mechanisms Underlying Purinergic P2X3 Receptor-Mediated Mechanical Allodynia Induced in Diabetic Rats. Mol Pain 2011, 7, 60, doi:10.1186/1744-8069-7-60.
- 90. Teixeira, J.M.; Dos Santos, G.G.; Neves, A.F.; Athie, M.C.P.; Bonet, I.J.M.; Nishijima, C.M.; Farias, F.H.; Figueiredo, J.G.; Hernandez-Olmos, V.; Alshaibani, S.; et al. Diabetes-Induced Neuropathic Mechanical Hyperalgesia Depends on P2X4 Receptor Activation in Dorsal Root Ganglia. Neuroscience 2019, 398, 158–170, doi:10.1016/j.neuroscience.2018.12.003.
- 91. Aghanoori, M.-R.; Agarwal, P.; Gauvin, E.; Nagalingam, R.S.; Bonomo, R.; Yathindranath, V.; Smith, D.R.; Hai, Y.; Lee, S.; Jolivalt, C.G.; et al. CEBPβ Regulation of Endogenous IGF-1 in Adult Sensory Neurons Can Be Mobilized to Overcome Diabetes-Induced Deficits in Bioenergetics and Axonal Outgrowth. Cell Mol Life Sci 2022, 79, 193, doi:10.1007/s00018-022-04201-9.
- 92. Vincent, A.M.; Perrone, L.; Sullivan, K.A.; Backus, C.; Sastry, A.M.; Lastoskie, C.; Feldman, E.L. Receptor for Advanced Glycation End Products Activation Injures Primary Sensory Neurons via Oxidative Stress. Endocrinology 2007, 148, 548–558, doi:10.1210/en.2006-0073.
- 93. Grote, C.W.; Wilson, N.M.; Katz, N.K.; Guilford, B.L.; Ryals, J.M.; Novikova, L.; Stehno-Bittel, L.; Wright, D.E. Deletion of the Insulin Receptor in Sensory Neurons Increases Pancreatic Insulin Levels. Exp Neurol 2018, 305, 97–107, doi:10.1016/j.expneurol.2018.04.002.
- 94. Kim, B.; Feldman, E.L. Insulin Resistance in the Nervous System. Trends Endocrinol. Metab. 2012, 23, 133–141, doi:10.1016/j.tem.2011.12.004.
- 95. Toth, C.; Brussee, V.; Martinez, J.A.; McDonald, D.; Cunningham, F.A.; Zochodne, D.W. Rescue and Regeneration of Injured Peripheral Nerve Axons by Intrathecal Insulin. Neuroscience 2006, 139, 429–449, doi:10.1016/j.neuroscience.2005.11.065.
- 96. Sugimoto, K.; Murakawa, Y.; Zhang, W.; Xu, G.; Sima, A.A. Insulin Receptor in Rat Peripheral Nerve: Its Localization and Alternatively Spliced Isoforms. Diabetes Metab. Res. Rev. 2000, 16, 354–363, doi:10.1002/1520-7560(200009/10)16:5<354::aid-dmrr149>3.0.co;2-h.
- 97. Sugimoto, K.; Murakawa, Y.; Sima, A.A.F. Expression and Localization of Insulin Receptor in Rat Dorsal Root Ganglion and Spinal Cord. Journal of the peripheral nervous system: JPNS 2002, 7, 44–53, doi:10.1046/j.1529-8027.2002.02005.x.
- 98. Boucher, J.; Kleinridders, A.; Kahn, C.R. Insulin Receptor Signaling in Normal and Insulin-Resistant States. Cold Spring Harbor Perspectives in Biology 2014, 6, a009191–a009191, doi:10.1101/cshperspect.a009191.
- 99. Grote, C.W.; Morris, J.K.; Ryals, J.M.; Geiger, P.C.; Wright, D.E. Insulin Receptor Substrate 2 Expression and Involvement in Neuronal Insulin Resistance in Diabetic Neuropathy. Exp. Diabetes Res. 2011, 2011, 212571, doi:10.1155/2011/212571.
- 100. Kim, B.; McLean, L.L.; Philip, S.S.; Feldman, E.L. Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons. Endocrinology 2011, 152, 3638–3647, doi:10.1210/en.2011-0029.
- 101. Kim, B.; Sullivan, K.A.; Backus, C.; Feldman, E.L. Cortical Neurons Develop Insulin Resistance and Blunted Akt Signaling: A Potential Mechanism Contributing to Enhanced Ischemic Injury in Diabetes. Antioxidants & Redox Signaling 2011, 14, 1829–1839, doi:10.1089/ars.2010.3816.
- 102. Sesti, G. Pathophysiology of Insulin Resistance. Best Practice & Research. Clinical Endocrinology & Metabolism 2006, 20, 665–679, doi:10.1016/j.beem.2006.09.007.
- 103. Liu, C.; Liu, S.; Wang, S.; Sun, Y.; Lu, X.; Li, H.; Li, G. IGF-1 Via PI3K/Akt/S6K Signaling Pathway Protects DRG Neurons with High Glucose-Induced Toxicity. Open Life Sciences 2019, 14, 502–514, doi:10.1515/biol-2019-0056.
- 104. Lee, W.; Frank, C.W.; Park, J. Directed Axonal Outgrowth Using a Propagating Gradient of IGF‐1. Advanced Materials 2014, 26, 4936–4940, doi:10.1002/adma.201305995.
- 105. Bei, F.; Lee, H.H.C.; Liu, X.; Gunner, G.; Jin, H.; Ma, L.; Wang, C.; Hou, L.; Hensch, T.K.; Frank, E.; et al. Restoration of Visual Function by Enhancing Conduction in Regenerated Axons. Cell 2016, 164, 219–232, doi:10.1016/j.cell.2015.11.036.
- 106. Simon, C.M.; Rauskolb, S.; Gunnersen, J.M.; Holtmann, B.; Drepper, C.; Dombert, B.; Braga, M.; Wiese, S.; Jablonka, S.; Pühringer, D.; et al. Dysregulated IGFBP5 Expression Causes Axon Degeneration and Motoneuron Loss in Diabetic Neuropathy. Acta Neuropathol. (berl.) 2015, 130, 373–387, doi:10.1007/s00401-015-1446-8.
- 107. Craner, M.J.; Klein, J.P.; Black, J.A.; Waxman, S.G. Preferential Expression of IGF-I in Small DRG Neurons and down-Regulation Following Injury. Neuroreport 2002, 13, 1649–1652, doi:10.1097/00001756-200209160-00016.
- 108. Aghanoori, M.-R.; Smith, D.R.; Shariati-Ievari, S.; Ajisebutu, A.; Nguyen, A.; Desmond, F.; Jesus, C.H.A.; Zhou, X.; Calcutt, N.A.; Aliani, M.; et al. Insulin-like Growth Factor-1 Activates AMPK to Augment Mitochondrial Function and Correct Neuronal Metabolism in Sensory Neurons in Type 1 Diabetes. Mol. Metab. 2019, 20, 149–165, doi:10.1016/j.molmet.2018.11.008.
- 109. Aghanoori, M.-R.; Margulets, V.; Smith, D.R.; Kirshenbaum, L.A.; Gitler, D.; Fernyhough, P. Sensory Neurons Derived from Diabetic Rats Exhibit Deficits in Functional Glycolysis and ATP That Are Ameliorated by IGF-1. Mol. Metab. 2021, 49, 101191, doi:10.1016/j.molmet.2021.101191.
- 110. Delaney, C.L.; Russell, J.W.; Cheng, H.L.; Feldman, E.L. Insulin-like Growth Factor-I and over-Expression of Bcl-xL Prevent Glucose-Mediated Apoptosis in Schwann Cells. J Neuropathol Exp Neurol 2001, 60, 147–160, doi:10.1093/jnen/60.2.147.
- 111. Ma, J.; Pan, P.; Anyika, M.; Blagg, B.S.J.; Dobrowsky, R.T. Modulating Molecular Chaperones Improves Mitochondrial Bioenergetics and Decreases the Inflammatory Transcriptome in Diabetic Sensory Neurons. ACS Chem. Neurosci. 2015, 6, 1637–1648, doi:10.1021/acschemneuro.5b00165.
- 112. Jančálek, R.; Dubový, P.; Svíženská, I.; Klusáková, I. Bilateral Changes of TNF-α and IL-10 Protein in the Lumbar and Cervical Dorsal Root Ganglia Following a Unilateral Chronic Constriction Injury of the Sciatic Nerve. Journal of Neuroinflammation 2010, 7, 11, doi:10.1186/1742-2094-7-11.
- 113. Üçeyler, N.; Riediger, N.; Kafke, W.; Sommer, C. Differential Gene Expression of Cytokines and Neurotrophic Factors in Nerve and Skin of Patients with Peripheral Neuropathies. J Neurol 2015, 262, 203–212, doi:10.1007/s00415-014-7556-8.
- 114. Shechter, R.; London, A.; Varol, C.; Raposo, C.; Cusimano, M.; Yovel, G.; Rolls, A.; Mack, M.; Pluchino, S.; Martino, G.; et al. Infiltrating Blood-Derived Macrophages Are Vital Cells Playing an Anti-Inflammatory Role in Recovery from Spinal Cord Injury in Mice. PLoS Med 2009, 6, e1000113, doi:10.1371/journal.pmed.1000113.
- 115. Yanik, B.M.; Dauch, J.R.; Cheng, H.T. Interleukin-10 Reduces Neurogenic Inflammation and Pain Behavior in a Mouse Model of Type 2 Diabetes. J Pain Res 2020, 13, 3499–3512, doi:10.2147/JPR.S264136.
- 116. Spranger, J.; Kroke, A.; Möhlig, M.; Hoffmann, K.; Bergmann, M.M.; Ristow, M.; Boeing, H.; Pfeiffer, A.F.H. Inflammatory Cytokines and the Risk to Develop Type 2 Diabetes: Results of the Prospective Population-Based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 2003, 52, 812–817, doi:10.2337/diabetes.52.3.812.
- 117. Hasanvand, A.; Amini-Khoei, H.; Hadian, M.-R.; Abdollahi, A.; Tavangar, S.M.; Dehpour, A.R.; Semiei, E.; Mehr, S.E. Anti-Inflammatory Effect of AMPK Signaling Pathway in Rat Model of Diabetic Neuropathy. Inflammopharmacology 2016, 24, 207–219, doi:10.1007/s10787-016-0275-2.
- 118. Black, B.J.; Atmaramani, R.; Kumaraju, R.; Plagens, S.; Romero-Ortega, M.; Dussor, G.; Price, T.J.; Campbell, Z.T.; Pancrazio, J.J. Adult Mouse Sensory Neurons on Microelectrode Arrays Exhibit Increased Spontaneous and Stimulus-Evoked Activity in the Presence of Interleukin-6. J Neurophysiol 2018, 120, 1374–1385, doi:10.1152/jn.00158.2018.
- 119. O’Brien, P.D.; Hur, J.; Hayes, J.M.; Backus, C.; Sakowski, S.A.; Feldman, E.L. BTBR Ob/Ob Mice as a Novel Diabetic Neuropathy Model: Neurological Characterization and Gene Expression Analyses. Neurobiol Dis 2015, 73, 348–355, doi:10.1016/j.nbd.2014.10.015.
- 120. Martini, R.; Willison, H. Neuroinflammation in the Peripheral Nerve: Cause, Modulator, or Bystander in Peripheral Neuropathies? Glia 2016, 64, 475–486, doi:10.1002/glia.22899.
- 121. Cuellar, M.J.; Montesano, X.P.; Carstens, E. Role of TNF-Alpha in Sensitization of Nociceptive Dorsal Horn Neurons Induced by Application of Nucleus Pulposus to L5 Dorsal Root Ganglion in Rats. Pain 2004, 110, 578–587, doi:10.1016/j.pain.2004.03.029.
- 122. Saleh, A.; Smith, D.R.; Balakrishnan, S.; Dunn, L.; Martens, C.; Tweed, C.W.; Fernyhough, P. Tumor Necrosis Factor-α Elevates Neurite Outgrowth through an NF-κB-Dependent Pathway in Cultured Adult Sensory Neurons: Diminished Expression in Diabetes May Contribute to Sensory Neuropathy. Brain Research 2011, 1423, 87–95, doi:10.1016/j.brainres.2011.09.029.
- 123. Ortmann, K.L.M.; Chattopadhyay, M. Decrease in Neuroimmune Activation by HSV-Mediated Gene Transfer of TNFα Soluble Receptor Alleviates Pain in Rats with Diabetic Neuropathy. Brain, Behavior, and Immunity 2014, 41, 144–151, doi:10.1016/j.bbi.2014.05.009.
- 124. Wang, K.; Cai, B.; Song, Y.; Chen, Y.; Zhang, X. Somatosensory Neuron Types and Their Neural Networks as Revealed via Single-Cell Transcriptomics. Trends in Neurosciences 2023, 46, 654–666, doi:10.1016/j.tins.2023.05.005.
- 125. Wang, K.; Wang, S.; Chen, Y.; Wu, D.; Hu, X.; Lu, Y.; Wang, L.; Bao, L.; Li, C.; Zhang, X. Single-Cell Transcriptomic Analysis of Somatosensory Neurons Uncovers Temporal Development of Neuropathic Pain. Cell Res 2021, 31, 904–918, doi:10.1038/s41422-021-00479-9.
- 126. Li, C.-L.; Li, K.-C.; Wu, D.; Chen, Y.; Luo, H.; Zhao, J.-R.; Wang, S.-S.; Sun, M.-M.; Lu, Y.-J.; Zhong, Y.-Q.; et al. Somatosensory Neuron Types Identified by High-Coverage Single-Cell RNA-Sequencing and Functional Heterogeneity. Cell Res 2016, 26, 83–102, doi:10.1038/cr.2015.149.
- 127. Zhou, H.; Yang, X.; Liao, C.; Chen, H.; Wu, Y.; Xie, B.; Ma, F.; Zhang, W. The Development of Mechanical Allodynia in Diabetic Rats Revealed by Single-Cell RNA-Seq. Front. Mol. Neurosci. 2022, 15, 856299, doi:10.3389/fnmol.2022.856299.
- 128. Béguin, P.; Crambert, G.; Monnet-Tschudi, F.; Uldry, M.; Horisberger, J.-D.; Garty, H.; Geering, K. FXYD7 Is a Brain-Specific Regulator of Na,K-ATPase Alpha 1-Beta Isozymes. EMBO J 2002, 21, 3264–3273, doi:10.1093/emboj/cdf330.
- 129. Krishnan, A.V.; Lin, C.S.-Y.; Kiernan, M.C. Activity-Dependent Excitability Changes Suggest Na+/K+ Pump Dysfunction in Diabetic Neuropathy. Brain 2008, 131, 1209–1216, doi:10.1093/brain/awn052.
- 130. Taub, M.; Springate, J.E.; Cutuli, F. Targeting of Renal Proximal Tubule Na,K-ATPase by Salt-Inducible Kinase. Biochem Biophys Res Commun 2010, 393, 339–344, doi:10.1016/j.bbrc.2010.02.037.
- 131. Shiina, N.; Yamaguchi, K.; Tokunaga, M. RNG105 Deficiency Impairs the Dendritic Localization of mRNAs for Na+/K+ ATPase Subunit Isoforms and Leads to the Degeneration of Neuronal Networks. J Neurosci 2010, 30, 12816–12830, doi:10.1523/JNEUROSCI.6386-09.2010.
- 132. George, D.S.; Jayaraj, N.D.; Pacifico, P.; Ren, D.; Sriram, N.; Miller, R.E.; Malfait, A.-M.; Miller, R.J.; Menichella, D.M. The Mas-Related G Protein–Coupled Receptor d (Mrgprd) Mediates Pain Hypersensitivity in Painful Diabetic Neuropathy. Pain 2023, doi:10.1097/j.pain.0000000000003120.
- 133. Price, T.; Shiers, S.; Mazhar, K.; Wangzhou, A.; Haberberger, R.; Lesnak, J.; Sankaranarayanan, I.; Tavares-Ferreira, D.; Cervantes, A.; Funk, G.; et al. Nageotte Nodules in Human DRG Reveal Neurodegeneration in Painful Diabetic Neuropathy. Research Square 2024, rs.3.rs-5006011, doi:10.21203/rs.3.rs-5006011/v1.
- 134. Agalave, N.M.; Mody, P.H.; Szabo-Pardi, T.A.; Jeong, H.S.; Burton, M.D. Neuroimmune Consequences of eIF4E Phosphorylation on Chemotherapy-Induced Peripheral Neuropathy. Front Immunol 2021, 12, 642420, doi:10.3389/fimmu.2021.642420.
- 135. Shiers, S.; Mwirigi, J.; Pradhan, G.; Kume, M.; Black, B.; Barragan-Iglesias, P.; Moy, J.K.; Dussor, G.; Pancrazio, J.J.; Kroener, S.; et al. Reversal of Peripheral Nerve Injury-Induced Neuropathic Pain and Cognitive Dysfunction via Genetic and Tomivosertib Targeting of MNK. Neuropsychopharmacology 2020, 45, 524–533, doi:10.1038/s41386-019-0537-y.
- 136. Li, Y.; Uhelski, M.L.; North, R.Y.; Mwirigi, J.M.; Tatsui, C.E.; Cata, J.P.; Corrales, G.; Price, T.J.; Dougherty, P.M. MNK Inhibitor eFT508 (Tomivosertib) Suppresses Ectopic Activity in Human Dorsal Root Ganglion Neurons from Dermatomes with Radicular Neuropathic Pain. bioRxiv 2023, 2023.06.13.544811, doi:10.1101/2023.06.13.544811.
- 137. Brina, D.; Ponzoni, A.; Troiani, M.; Calì, B.; Pasquini, E.; Attanasio, G.; Mosole, S.; Mirenda, M.; D’Ambrosio, M.; Colucci, M.; et al. The Akt/mTOR and MNK/eIF4E Pathways Rewire the Prostate Cancer Translatome to Secrete HGF, SPP1 and BGN and Recruit Suppressive Myeloid Cells. Nat Cancer 2023, 4, 1102–1121, doi:10.1038/s43018-023-00594-z.
- 138. Peirs, C.; Seal, R.P. Neural Circuits for Pain: Recent Advances and Current Views. Science 2016, 354, 578–584, doi:10.1126/science.aaf8933.
- 139. Häring, M.; Zeisel, A.; Hochgerner, H.; Rinwa, P.; Jakobsson, J.E.T.; Lönnerberg, P.; La Manno, G.; Sharma, N.; Borgius, L.; Kiehn, O.; et al. Neuronal Atlas of the Dorsal Horn Defines Its Architecture and Links Sensory Input to Transcriptional Cell Types. Nat. Neurosci. 2018, 21, 869–880, doi:10.1038/s41593-018-0141-1.
- 140. Gatto, G.; Bourane, S.; Ren, X.; Di Costanzo, S.; Fenton, P.K.; Halder, P.; Seal, R.P.; Goulding, M.D. A Functional Topographic Map for Spinal Sensorimotor Reflexes. Neuron 2021, 109, 91-104.e5, doi:10.1016/j.neuron.2020.10.003.
- 141. Todd, A.J. Identifying Functional Populations among the Interneurons in Laminae I-III of the Spinal Dorsal Horn. Mol Pain 2017, 13, 1744806917693003, doi:10.1177/1744806917693003.
- 142. Woolf, C.J. Central Sensitization: Implications for the Diagnosis and Treatment of Pain. Pain 2011, 152, S2–S15, doi:10.1016/j.pain.2010.09.030.
- 143. Tan, A.M.; Samad, O.A.; Fischer, T.Z.; Zhao, P.; Persson, A.-K.; Waxman, S.G. Maladaptive Dendritic Spine Remodeling Contributes to Diabetic Neuropathic Pain. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 2012, 32, 6795–6807, doi:10.1523/JNEUROSCI.1017-12.2012.
- 144. Li, J.-Q.; Chen, S.-R.; Chen, H.; Cai, Y.-Q.; Pan, H.-L. Regulation of Increased Glutamatergic Input to Spinal Dorsal Horn Neurons by mGluR5 in Diabetic Neuropathic Pain. J Neurochem 2010, 112, 162–172, doi:10.1111/j.1471-4159.2009.06437.x.
- 145. Gao, Z.; Feng, Y.; Ju, H. The Different Dynamic Changes of Nerve Growth Factor in the Dorsal Horn and Dorsal Root Ganglion Leads to Hyperalgesia and Allodynia in Diabetic Neuropathic Pain. Pain Physician 2017, 20, E551–E561, doi:10.36076/ppj.2017.e561.
- 146. Wan, F.-P.; Bai, Y.; Kou, Z.-Z.; Zhang, T.; Li, H.; Wang, Y.-Y.; Li, Y.-Q. Endomorphin-2 Inhibition of Substance P Signaling within Lamina I of the Spinal Cord Is Impaired in Diabetic Neuropathic Pain Rats. Front. Mol. Neurosci. 2017, 9, 167, doi:10.3389/fnmol.2016.00167.
- 147. Beggs, S.; Trang, T.; Salter, M.W. P2X4R+ Microglia Drive Neuropathic Pain. Nat. Neurosci. 2012, 15, 1068–1073, doi:10.1038/nn.3155.
- 148. Tsuda, M.; Ueno, H.; Kataoka, A.; Tozaki-Saitoh, H.; Inoue, K. Activation of Dorsal Horn Microglia Contributes to Diabetes-Induced Tactile Allodynia via Extracellular Signal-Regulated Protein Kinase Signaling. Glia 2008, 56, 378–386, doi:10.1002/glia.20623.
- 149. Cheng, K.-I.; Wang, H.-C.; Chuang, Y.-T.; Chou, C.-W.; Tu, H.-P.; Yu, Y.-C.; Chang, L.-L.; Lai, C.-S. Persistent Mechanical Allodynia Positively Correlates with an Increase in Activated Microglia and Increased P-P38 Mitogen-Activated Protein Kinase Activation in Streptozotocin-Induced Diabetic Rats. Eur J Pain 2014, 18, 162–173, doi:10.1002/j.1532-2149.2013.00356.x.
- 150. Turgut, N.; Altun, B.U. Cortical Disinhibition in Diabetic Patients with Neuropathic Pain. Acta Neurol Scand 2009, 120, 383–388, doi:10.1111/j.1600-0404.2009.01235.x.
- 151. Tesfaye, S.; Boulton, A.J.M.; Dickenson, A.H. Mechanisms and Management of Diabetic Painful Distal Symmetrical Polyneuropathy. Diabetes Care 2013, 36, 2456–2465, doi:10.2337/dc12-1964.
- 152. Selvarajah, D.; Wilkinson, I.D.; Maxwell, M.; Davies, J.; Sankar, A.; Boland, E.; Gandhi, R.; Tracey, I.; Tesfaye, S. Magnetic Resonance Neuroimaging Study of Brain Structural Differences in Diabetic Peripheral Neuropathy. Diabetes Care 2014, 37, 1681–1688, doi:10.2337/dc13-2610.
- 153. Sorensen, L.; Siddall, P.J.; Trenell, M.I.; Yue, D.K. Differences in Metabolites in Pain-Processing Brain Regions in Patients with Diabetes and Painful Neuropathy. Diabetes Care 2008, 31, 980–981, doi:10.2337/dc07-2088.
- 154. Cauda, F.; Sacco, K.; Duca, S.; Cocito, D.; D’Agata, F.; Geminiani, G.C.; Canavero, S. Altered Resting State in Diabetic Neuropathic Pain. PloS One 2009, 4, e4542, doi:10.1371/journal.pone.0004542.
- 155. Cauda, F.; D’Agata, F.; Sacco, K.; Duca, S.; Cocito, D.; Paolasso, I.; Isoardo, G.; Geminiani, G. Altered Resting State Attentional Networks in Diabetic Neuropathic Pain. Journal of Neurology, Neurosurgery, and Psychiatry 2010, 81, 806–811, doi:10.1136/jnnp.2009.188631.
- 156. Feldman, E.L.; Callaghan, B.C.; Pop-Busui, R.; Zochodne, D.W.; Wright, D.E.; Bennett, D.L.; Bril, V.; Russell, J.W.; Viswanathan, V. Diabetic Neuropathy. Nature Reviews Disease Primers 2019, 5, 41, doi:10.1038/s41572-019-0092-1.
- 157. Fischer, T.Z.; Tan, A.M.; Waxman, S.G. Thalamic Neuron Hyperexcitability and Enlarged Receptive Fields in the STZ Model of Diabetic Pain. Brain Res. 2009, 1268, 154–161, doi:10.1016/j.brainres.2009.02.063.
- 158. Selvarajah, D.; Wilkinson, I.D.; Emery, C.J.; Shaw, P.J.; Griffiths, P.D.; Gandhi, R.; Tesfaye, S. Thalamic Neuronal Dysfunction and Chronic Sensorimotor Distal Symmetrical Polyneuropathy in Patients with Type 1 Diabetes Mellitus. Diabetologia 2008, 51, 2088–2092, doi:10.1007/s00125-008-1139-0.
- 159. West, S.J.; Bannister, K.; Dickenson, A.H.; Bennett, D.L. Circuitry and Plasticity of the Dorsal Horn – Toward a Better Understanding of Neuropathic Pain. Neuroscience 2015, 300, 254–275, doi:10.1016/j.neuroscience.2015.05.020.
- 160. Paulson, P.E.; Wiley, J.W.; Morrow, T.J. Concurrent Activation of the Somatosensory Forebrain and Deactivation of Periaqueductal Gray Associated with Diabetes-Induced Neuropathic Pain. Experimental Neurology 2007, 208, 305–313, doi:10.1016/j.expneurol.2007.09.001.
- 161. Silva, M.; Amorim, D.; Almeida, A.; Tavares, I.; Pinto-Ribeiro, F.; Morgado, C. Pronociceptive Changes in the Activity of Rostroventromedial Medulla (RVM) Pain Modulatory Cells in the Streptozotocin-Diabetic Rat. Brain Res Bull 2013, 96, 39–44, doi:10.1016/j.brainresbull.2013.04.008.
- 162. Vileikyte, L.; Gonzalez, J.S. Recognition and Management of Psychosocial Issues in Diabetic Neuropathy. Handbook of Clinical Neurology 2014, 126, 195–209, doi:10.1016/B978-0-444-53480-4.00013-8.
- 163. Sieberg, C.B.; Taras, C.; Gomaa, A.; Nickerson, C.; Wong, C.; Ward, C.; Baskozos, G.; Bennett, D.L.H.; Ramirez, J.D.; Themistocleous, A.C.; et al. Neuropathic Pain Drives Anxiety Behavior in Mice, Results Consistent with Anxiety Levels in Diabetic Neuropathy Patients. Pain Reports 2018, 3, e651, doi:10.1097/PR9.0000000000000651
- 164. Shi, L.; Zhang, H.; Xiao, Y.; Hu, J.; Xu, G. Electroacupuncture Suppresses Mechanical Allodynia and Nuclear Factor Kappa B Signaling in Streptozotocin‐induced Diabetic Rats. Cns Neurosci. Ther. 2013, 19, 83–90, doi:10.1111/cns.12035
- 165. Vieira, W.F.; Malange, K.F.; de Magalhães, S.F.; Lemes, J.B.P.; Dos Santos, G.G.; Nishijima, C.M.; de Oliveira, A.L.R.; da Cruz-Höfling, M.A.; Tambeli, C.H.; Parada, C.A. Anti-Hyperalgesic Effects of Photobiomodulation Therapy (904 Nm) on Streptozotocin-Induced Diabetic Neuropathy Imply MAPK Pathway and Calcium Dynamics Modulation. Sci Rep 2022, 12, 16730, doi:10.1038/s41598-022-19947-2
- 166. Nagpal, A.; Clements, N.; Duszynski, B.; Boies, B. The Effectiveness of Dorsal Root Ganglion Neurostimulation for the Treatment of Chronic Pelvic Pain and Chronic Neuropathic Pain of the Lower Extremity: A Comprehensive Review of the Published Data. Pain Medicine (Malden, Mass.) 2021, 22, 49–59, doi:10.1093/pm/pnaa369
How to Cite
How to Cite
Downloads
Article Details
Most Read This Month
Most read articles by the same author(s)
- Fan Liu, Xiang-Sha Yin, Cong Cong, Yuanzhuo Wang, Chao Ma, Human Brain Banking as a Convergence Platform of Neuroscience and Neuropsychiatric Research , Human Brain: Vol. 1 No. 1 (2022): Human Brain
- Wenqi Pan, Yan Chen, Yuesi Xu, Wei-Min Tong, Yamei Niu, RNA m6A Methylation and Alzheimer's Disease: Current Evidence and Future Perspectives , Human Brain: Vol. 3 No. 1 (2024): Human Brain
- Fei Han, Wen-Ying Qiu, Li-Xin Zhou, Jun Ni, Ming Yao, Yong-Tai Liu, Bo Hou, Rui-Xue Cui, Feng Feng, Fang Li, Chao Ma, Yi-Cheng Zhu, The Brain Aging National Cohort-PUMC: study design and baseline characteristics , Human Brain: Vol. 2 No. 2 (2023): Human Brain
- Chao Ma, Yi-Cheng Zhu, Highlights in the Inaugural Issue of Human Brain , Human Brain: Vol. 1 No. 1 (2022): Human Brain
- Donghang Li, Hongfeng Tong, Yaoguang Sun, Qingjun Wu, Chao Ma, Wenxin Tian, Chuan Huang, Hanbo Yu, Yi Tian, Peng Jiao, Brain metastasis from non-small cell lung cancer: management and prognosis of primary lung tumor resection , Human Brain: Vol. 2 No. 4 (2023): Human Brain
- Chao Ma, Yi-Cheng Zhu, Highlights in Human Brain 2023 , Human Brain: Vol. 3 No. 1 (2024): Human Brain
- Lijing Fang, Chao Ma, Yi-Cheng Zhu, To Probe, Protect & Promote the Human Brain , Human Brain: Vol. 3 No. 3 (2024): Human Brain
License
Copyright (c) 2025 Peng Liu, Yan Chen, Xu Zhang, Chao Ma

This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License.