Loss of POMC-mediated antinociception contributes to painful diabetic neuropathy.
Aged
Aged, 80 and over
Animals
Diabetes Mellitus, Experimental
/ chemically induced
Diabetic Neuropathies
/ etiology
Female
Ganglia, Spinal
/ cytology
Humans
Lysosomes
Male
Mice
Mice, Knockout
Nociception
/ physiology
Pro-Opiomelanocortin
/ deficiency
Proteolysis
Receptors, Opioid, mu
/ genetics
Sensory Receptor Cells
/ pathology
Streptozocin
/ toxicity
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 01 2021
18 01 2021
Historique:
received:
02
08
2019
accepted:
10
12
2020
entrez:
19
1
2021
pubmed:
20
1
2021
medline:
30
1
2021
Statut:
epublish
Résumé
Painful neuropathy is a frequent complication in diabetes. Proopiomelanocortin (POMC) is an endogenous opioid precursor peptide, which plays a protective role against pain. Here, we report dysfunctional POMC-mediated antinociception in sensory neurons in diabetes. In streptozotocin-induced diabetic mice the Pomc promoter is repressed due to increased binding of NF-kB p50 subunit, leading to a loss in basal POMC level in peripheral nerves. Decreased POMC levels are also observed in peripheral nervous system tissue from diabetic patients. The antinociceptive pathway mediated by POMC is further impaired due to lysosomal degradation of μ-opioid receptor (MOR). Importantly, the neuropathic phenotype of the diabetic mice is rescued upon viral overexpression of POMC and MOR in the sensory ganglia. This study identifies an antinociceptive mechanism in the sensory ganglia that paves a way for a potential therapy for diabetic neuropathic pain.
Identifiants
pubmed: 33462216
doi: 10.1038/s41467-020-20677-0
pii: 10.1038/s41467-020-20677-0
pmc: PMC7814083
doi:
Substances chimiques
Oprm protein, mouse
0
Receptors, Opioid, mu
0
Streptozocin
5W494URQ81
Pro-Opiomelanocortin
66796-54-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
426Commentaires et corrections
Type : ErratumIn
Références
Pham, M. et al. Magnetic resonance neurography detects diabetic neuropathy early and with proximal predominance. Ann. Neurol. 78, 939–948 (2015).
pubmed: 26381658
pmcid: 5132066
doi: 10.1002/ana.24524
Ziegler, D., Papanas, N., Vinik, A. I. & Shaw, J. E. Epidemiology of polyneuropathy in diabetes and prediabetes. Handb. Clin. Neurol. 126, 3–22 (2014).
pubmed: 25410210
doi: 10.1016/B978-0-444-53480-4.00001-1
Veves, A., Backonja, M. & Malik, R. A. Painful diabetic neuropathy: epidemiology, natural history, early diagnosis, and treatment options. Pain. Med. 9, 660–674 (2008).
pubmed: 18828198
doi: 10.1111/j.1526-4637.2007.00347.x
Waldfogel, J. M. et al. Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: a systematic review. Neurology 88, 1958–1967 (2017).
pubmed: 28341643
doi: 10.1212/WNL.0000000000003882
Boulton, A. J. M. et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 28, 956–962 (2005).
pubmed: 15793206
doi: 10.2337/diacare.28.4.956
Pop-Busui, R. et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care 40, 136–154 (2017).
pubmed: 27999003
doi: 10.2337/dc16-2042
Ziegler, D. & Fonseca, V. From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy. J. Diabetes Complications 29, 146–156 (2015).
pubmed: 25239450
doi: 10.1016/j.jdiacomp.2014.08.008
Ziegler, D. Painful diabetic neuropathy: advantage of novel drugs over old drugs? Diabetes Care 32, S414–S419 (2009).
pubmed: 19875591
pmcid: 2811478
doi: 10.2337/dc09-S350
Callaghan, B.C. & Little, A.A. & Feldman, E.L. & Hughes, R.A.C. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst. Rev. 6, CD007543 (2012).
Nawroth, P. P. et al. The quest for more research on painful diabetic neuropathy. Neuroscience 387, 28–37 (2018).
pubmed: 28942323
doi: 10.1016/j.neuroscience.2017.09.023
Azmi, S. et al. Pregabalin in the management of painful diabetic neuropathy: a narrative review. Diabetes Ther. 10, 35–56 (2019).
pubmed: 30565054
doi: 10.1007/s13300-018-0550-x
Cheung, C. Y. & Tang, F. The effect of streptozotocin-diabetes on beta-endorphin level and proopiomelanocortin gene expression in the rat pituitary. Neurosci. Lett. 261, 118–120 (1999).
pubmed: 10081941
doi: 10.1016/S0304-3940(98)01008-8
Berman, Y., Devi, L. & Carr, K. D. Effects of streptozotocin-induced diabetes on prodynorphin-derived peptides in rat brain regions. Brain Res. 685, 129–134 (1995).
pubmed: 7583238
doi: 10.1016/0006-8993(95)00419-Q
Timmers, K., Voyles, N. R., Zalenski, C., Wilkins, S. & Recant, L. Altered beta-endorphin, Met- and Leu-enkephalins, and enkephalin-containing peptides in pancreas and pituitary of genetically obese diabetic (db/db) mice during development of diabetic syndrome. Diabetes 35, 1143–1151 (1986).
pubmed: 2944783
doi: 10.2337/diab.35.10.1143
Fallucca, F., Tonnarini, G., Di Biase, N., D’Allessandro, M. & Negri, M. Plasma met-enkephalin levels in diabetic patients: influence of autonomic neuropathy. Metabolism 45, 1065–1068 (1996).
pubmed: 8781292
doi: 10.1016/S0026-0495(96)90004-9
Tsigos, C., Gibson, S., Crosby, S. R., White, A. & Young, R. J. Cerebrospinal fluid levels of beta endorphin in painful and painless diabetic polyneuropathy. J. Diabetes Complications 9, 92–96 (1995).
pubmed: 7599354
doi: 10.1016/1056-8727(94)00024-I
Williams, J. T. et al. Regulation of µ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol. Rev. 65, 223–254 (2013).
pubmed: 23321159
pmcid: 3565916
doi: 10.1124/pr.112.005942
Stein, C. & Machelska, H. Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharmacol. Rev. 63, 860–881 (2011).
pubmed: 21969325
doi: 10.1124/pr.110.003145
Celik, M. Ö. et al. Leukocyte opioid receptors mediate analgesia via Ca(2+)-regulated release of opioid peptides. Brain. Behav. Immun. 57, 227–242 (2016).
pubmed: 27139929
doi: 10.1016/j.bbi.2016.04.018
Liou, J.-T., Liu, F.-C., Mao, C.-C., Lai, Y.-S. & Day, Y.-J. Inflammation confers dual effects on nociceptive processing in chronic neuropathic pain model. Anesthesiology 114, 660–672 (2011).
pubmed: 21307767
doi: 10.1097/ALN.0b013e31820b8b1e
Frank, T., Nawroth, P. & Kuner, R. Structure-function relationships in peripheral nerve contributions to diabetic peripheral neuropathy. Pain 160, S29–S36 (2019).
pubmed: 31008847
doi: 10.1097/j.pain.0000000000001530
Scherrer, G. et al. Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell 137, 1148–1159 (2009).
pubmed: 19524516
pmcid: 3683597
doi: 10.1016/j.cell.2009.04.019
Jenks, B. G. Regulation of proopiomelanocortin gene expression. Ann. NY Acad. Sci. 1163, 17–30 (2009).
pubmed: 19456325
doi: 10.1111/j.1749-6632.2008.03620.x
Mann, A., Illing, S., Miess, E. & Schulz, S. Different mechanisms of homologous and heterologous μ-opioid receptor phosphorylation. Br. J. Pharmacol. 172, 311–316 (2015).
pubmed: 24517854
doi: 10.1111/bph.12627
Geraldes, P. & King, G. L. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ. Res. 106, 1319–1331 (2010).
pubmed: 20431074
pmcid: 2877591
doi: 10.1161/CIRCRESAHA.110.217117
Lupp, A., Richter, N., Doll, C., Nagel, F. & Schulz, S. UMB-3, a novel rabbit monoclonal antibody, for assessing μ-opioid receptor expression in mouse, rat and human formalin-fixed and paraffin-embedded tissues. Regul. Pept. 167, 9–13 (2011).
pubmed: 20851148
doi: 10.1016/j.regpep.2010.09.004
Corder, G. et al. Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia. Nat. Med. 23, 164–173 (2017).
pubmed: 28092666
pmcid: 5296291
doi: 10.1038/nm.4262
Bierhaus, A. et al. Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. J. Clin. Invest. 114, 1741–1751 (2004).
pubmed: 15599399
pmcid: 535062
doi: 10.1172/JCI18058
Meister, M. et al. Dickkopf-3, a tissue-derived modulator of local T-cell responses. Front. Immunol. 6, 78 (2015).
pubmed: 25759692
pmcid: 4338807
doi: 10.3389/fimmu.2015.00078
Vicuña, L. et al. The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase. Nat. Med. 21, 518–523 (2015).
pubmed: 25915831
pmcid: 4450999
doi: 10.1038/nm.3852
Igumenova, T. I. Dynamics and membrane interactions of protein kinase C. Biochemistry 54, 4953–4968 (2015).
pubmed: 26214365
doi: 10.1021/acs.biochem.5b00565
Simonetti, M. et al. Wnt-Fzd signaling sensitizes peripheral sensory neurons via distinct noncanonical pathways. Neuron 83, 104–121 (2014).
pubmed: 24991956
doi: 10.1016/j.neuron.2014.05.037
Harati, Y. et al. Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy. J. Diabetes Complications 14, 65–70 (2000).
pubmed: 10959067
doi: 10.1016/S1056-8727(00)00060-X
Gimbel, J. S., Richards, P. & Portenoy, R. K. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 60, 927–934 (2003).
pubmed: 12654955
doi: 10.1212/01.WNL.0000057720.36503.2C
Duehmke, R. M. et al. Tramadol for neuropathic pain in adults. Cochrane Database Syst. Rev. 6, CD003726 (2017).
pubmed: 28616956
Dembla, S. et al. Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels. eLife 6, e26280 (2017).
pubmed: 28826482
pmcid: 5593507
doi: 10.7554/eLife.26280
Yakovleva, T. et al. Dysregulation of dynorphins in Alzheimer disease. Neurobiol. Aging 28, 1700–1708 (2007).
pubmed: 16914231
doi: 10.1016/j.neurobiolaging.2006.07.002
Carlton, S. M. & Coggeshall, R. E. Immunohistochemical localization of enkephalin in peripheral sensory axons in the rat. Neurosci. Lett. 221, 121–124 (1997).
pubmed: 9121679
doi: 10.1016/S0304-3940(96)13304-8
Selvaraj, D. et al. A functional role for VEGFR1 expressed in peripheral sensory neurons in cancer pain. Cancer Cell 27, 780–796 (2015).
pubmed: 26058077
pmcid: 4469373
doi: 10.1016/j.ccell.2015.04.017
Du, X. et al. Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission. J. Clin. Invest. 127, 1741–1756 (2017).
pubmed: 28375159
pmcid: 5409786
doi: 10.1172/JCI86812
Pereira, P. J. S. & Lerner, E. A. Gate control theory springs a leak. Neuron 93, 723–724 (2017).
pubmed: 28231458
pmcid: 5474310
doi: 10.1016/j.neuron.2017.02.016
Freeman, O. J. et al. Metabolic dysfunction is restricted to the sciatic nerve in experimental diabetic neuropathy. Diabetes 65, 228–238 (2016).
pubmed: 26470786
doi: 10.2337/db15-0835
Cho, K. et al. Antihyperglycemic mechanism of metformin occurs via the AMPK/LXRα/POMC pathway. Sci. Rep. 5, 8145 (2015).
pubmed: 25634597
pmcid: 4311245
doi: 10.1038/srep08145
Sabbir, M. G., Calcutt, N. A. & Fernyhough, P. Muscarinic acetylcholine type 1 receptor activity constrains neurite outgrowth by inhibiting microtubule polymerization and mitochondrial trafficking in adult sensory neurons. Front. Neurosci. 12, 402 (2018).
pubmed: 29997469
pmcid: 6029366
doi: 10.3389/fnins.2018.00402
Jang, P.-G. et al. NF-kappaB activation in hypothalamic pro-opiomelanocortin neurons is essential in illness- and leptin-induced anorexia. J. Biol. Chem. 285, 9706–9715 (2010).
pubmed: 20097762
pmcid: 2843220
doi: 10.1074/jbc.M109.070706
Takayasu, S. et al. Involvement of nuclear factor-ĸB and Nurr-1 in cytokine-induced transcription of proopiomelanocortin gene in AtT20 corticotroph cells. Neuroimmunomodulation 17, 88–96 (2010).
pubmed: 19923853
doi: 10.1159/000258691
Shi, X. et al. Nuclear factor κB (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the POMC promoter. Diabetologia 56, 925–936 (2013).
pubmed: 23370526
doi: 10.1007/s00125-013-2831-2
Karalis, K. P., Venihaki, M., Zhao, J., van Vlerken, L. E. & Chandras, C. NF-κB participates in the corticotropin-releasing, hormone-induced regulation of the pituitary proopiomelanocortin gene. J. Biol. Chem. 279, 10837–10840 (2004).
pubmed: 14711817
doi: 10.1074/jbc.M313063200
Zbytek, B., Pfeffer, L. M. & Slominski, A. T. CRH inhibits NF-κB signaling in human melanocytes. Peptides 27, 3276–3283 (2006).
pubmed: 16959375
pmcid: 1839005
doi: 10.1016/j.peptides.2006.07.017
Asaba, K. et al. High glucose activates pituitary proopiomelanocortin gene expression: possible role of free radical-sensitive transcription factors. Diabetes Metab. Res. Rev. 23, 317–323 (2007).
pubmed: 16921546
doi: 10.1002/dmrr.677
Berti-Mattera, L. N., Kern, T. S., Siegel, R. E., Nemet, I. & Mitchell, R. Sulfasalazine blocks the development of tactile allodynia in diabetic rats. Diabetes 57, 2801–2808 (2008).
pubmed: 18633115
pmcid: 2551692
doi: 10.2337/db07-1274
Grundström, S., Anderson, P., Scheipers, P. & Sundstedt, A. Bcl-3 and NFκB p50-p50 homodimers act as transcriptional repressors in tolerant CD4+ T cells. J. Biol. Chem. 279, 8460–8468 (2004).
pubmed: 14668329
doi: 10.1074/jbc.M312398200
Zhang, H.-H. et al. Promoted interaction of nuclear factor-κB with demethylated purinergic P2X3 receptor gene contributes to neuropathic pain in rats with diabetes. Diabetes 64, 4272–4284 (2015).
pubmed: 26130762
doi: 10.2337/db15-0138
Illing, S., Mann, A. & Schulz, S. Heterologous regulation of agonist-independent μ-opioid receptor phosphorylation by protein kinase C. Br. J. Pharmacol. 171, 1330–1340 (2014).
pubmed: 24308893
pmcid: 3952808
doi: 10.1111/bph.12546
Mousa, S. A. et al. Protein kinase C-mediated mu-opioid receptor phosphorylation and desensitization in rats, and its prevention during early diabetes. Pain 157, 910–921 (2016).
pubmed: 26713421
doi: 10.1097/j.pain.0000000000000459
Mousa, S. A. et al. Rab7 silencing prevents μ-opioid receptor lysosomal targeting and rescues opioid responsiveness to strengthen diabetic neuropathic pain therapy. Diabetes 62, 1308–1319 (2013).
pubmed: 23230081
pmcid: 3609597
doi: 10.2337/db12-0590
Li, L., Hasan, R. & Zhang, X. The basal thermal sensitivity of the TRPV1 ion channel is determined by PKCβII. J. Neurosci. 34, 8246–8258 (2014).
pubmed: 24920628
pmcid: 4051976
doi: 10.1523/JNEUROSCI.0278-14.2014
Vellani, V. et al. Protease activated receptors 1 and 4 sensitize TRPV1 in nociceptive neurones. Mol. Pain. 6, 61 (2010).
pubmed: 20875131
pmcid: 2956715
doi: 10.1186/1744-8069-6-61
Wu, D.-F. et al. PKCε phosphorylation of the sodium channel NaV1.8 increases channel function and produces mechanical hyperalgesia in mice. J. Clin. Invest. 122, 1306–1315 (2012).
pubmed: 22426212
pmcid: 3315445
doi: 10.1172/JCI61934
Breitinger, U. et al. PKA and PKC modulators affect ion channel function and internalization of recombinant Alpha1 and Alpha1-Beta glycine receptors.Front. Mol. Neurosci. 11, 154 (2018).
pubmed: 29867346
pmcid: 5961436
doi: 10.3389/fnmol.2018.00154
Zhou, Y. et al. Suppressing PKC-dependent membrane P2X3 receptor upregulation in dorsal root ganglia mediated electroacupuncture analgesia in rat painful diabetic neuropathy. Purinergic Signal. 14, 359–369 (2018).
pubmed: 30084084
pmcid: 6298917
doi: 10.1007/s11302-018-9617-4
Dikshtein, Y. et al. β-endorphin via the delta opioid receptor is a major factor in the incubation of cocaine craving. Neuropsychopharmacolgy 38, 2508–2514 (2013).
doi: 10.1038/npp.2013.155
Cardinez, N. et al. Sex differences in neuropathic pain in longstanding diabetes: results from the Canadian study of longevity in Type 1 diabetes. J. Diabetes Complications 32, 660–664 (2018).
pubmed: 29929836
doi: 10.1016/j.jdiacomp.2018.05.001
Belfer, I. Sex-specific genetic control of diabetic neuropathic pain suggests subsequent development of men-only and women-only analgesic strategies. EBioMedicine 2, 1280 (2015).
pubmed: 26629507
pmcid: 4634357
doi: 10.1016/j.ebiom.2015.08.038
Abbott, C. A., Malik, R. A., van Ross, E. R. E., Kulkarni, J. & Boulton, A. J. M. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K. Diabetes Care 34, 2220–2224 (2011).
pubmed: 21852677
pmcid: 3177727
doi: 10.2337/dc11-1108
Sorensen, L., Molyneaux, L. & Yue, D. K. Insensate versus painful diabetic neuropathy: the effects of height, gender, ethnicity and glycaemic control. Diabetes Res. Clin. Pract. 57, 45–51 (2002).
pubmed: 12007729
doi: 10.1016/S0168-8227(02)00010-4
Aaberg, M. L., Burch, D. M., Hud, Z. R. & Zacharias, M. P. Gender differences in the onset of diabetic neuropathy. J. Diabetes Complications 22, 83–87 (2008).
pubmed: 18280437
doi: 10.1016/j.jdiacomp.2007.06.009
Pesaresi, M. et al. Axonal transport in a peripheral diabetic neuropathy model: sex-dimorphic features. Biol. Sex. Differ. 9, 6 (2018).
pubmed: 29351809
pmcid: 5775621
doi: 10.1186/s13293-018-0164-z
Joseph, E. K. & Levine, J. D. Sexual dimorphism in the contribution of protein kinase c isoforms to nociception in the streptozotocin diabetic rat. Neuroscience 120, 907–913 (2003).
pubmed: 12927197
doi: 10.1016/S0306-4522(03)00400-7
Tsantoulas, C. et al. Hyperpolarization-activated cyclic nucleotide–gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy. Sci. Transl. Med. 9, eaam6072 (2017).
pubmed: 28954930
pmcid: 5720342
doi: 10.1126/scitranslmed.aam6072
Hunt, S. P., Pini, A. & Evan, G. Induction of c-Fos protein in spinal cord neurons following sensory stimulation. Nature 328, 632–634 (1987).
pubmed: 3112583
doi: 10.1038/328632a0
Suzuki, Y., Sato, J., Kawanishi, M. & Mizumura, K. Lowered response threshold and increased responsiveness to mechanical stimulation of cutaneous nociceptive fibers in streptozotocin-diabetic rat skin in vitro—correlates of mechanical allodynia and hyperalgesia observed in the early stage of diabetes. Neurosci. Res. 43, 171–178 (2002).
pubmed: 12067753
doi: 10.1016/S0168-0102(02)00033-0
Ørstavik, K. et al. Abnormal function of C-fibers in patients with diabetic neuropathy. J. Neurosci. 26, 11287–11294 (2006).
pubmed: 17079656
pmcid: 6674548
doi: 10.1523/JNEUROSCI.2659-06.2006
Blair, N. T. & Bean, B. P. Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci. 22, 10277–10290 (2002).
pubmed: 12451128
pmcid: 6758735
doi: 10.1523/JNEUROSCI.22-23-10277.2002
Bierhaus, A. et al. Methylglyoxal modification of Na v 1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat. Med. 18, 926–933 (2012).
pubmed: 22581285
doi: 10.1038/nm.2750
Orestes, P. et al. Reversal of neuropathic pain in diabetes by targeting glycosylation of Cav3.2 T-type calcium channels. Diabetes 62, 3828–3838 (2013).
pubmed: 23835327
pmcid: 3806612
doi: 10.2337/db13-0813
Papanas, N. & Ziegler, D. Emerging drugs for diabetic peripheral neuropathy and neuropathic pain. Expert Opin. Emerg. Drugs 21, 393–407 (2016).
pubmed: 27813425
doi: 10.1080/14728214.2016.1257605
Colao, A. et al. Corticotropin-releasing hormone administration increases alpha-melanocyte-stimulating hormone levels in the inferior petrosal sinuses in a subset of patients with Cushing’s disease. Horm. Res. 46, 26–32 (1996).
pubmed: 8854136
doi: 10.1159/000184972
Kühnen, P. et al. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N. Engl. J. Med. 375, 240–246 (2016).
pubmed: 27468060
doi: 10.1056/NEJMoa1512693
Müller, T. D., Tschöp, M. H. & O’Rahilly, S. Metabolic precision medicines: curing POMC deficiency. Cell Metab. 24, 194–195 (2016).
pubmed: 27452145
doi: 10.1016/j.cmet.2016.07.006
Kumar, V. et al. Compromised DNA repair is responsible for diabetes-associated fibrosis. EMBO J 39, e103477 (2020).
pubmed: 32338774
pmcid: 7265245
doi: 10.15252/embj.2019103477
Weibel, R. et al. Mu opioid receptors on primary afferent Nav1.8 neurons contribute to opiate-induced analgesia: insight from conditional knockout mice. PLoS ONE 8, e74706 (2013).
pubmed: 24069332
pmcid: 3771900
doi: 10.1371/journal.pone.0074706
Fenselau, H. et al. A rapidly-acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH. Nat. Neurosci. 20, 42–51 (2017).
pubmed: 27869800
doi: 10.1038/nn.4442
Schweizerhof, M. et al. Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. Nat. Med. 15, 802–807 (2009).
pubmed: 19525966
doi: 10.1038/nm.1976
Njoo, C., Heinl, C. & Kuner, R. In vivo SiRNA transfection and gene knockdown in spinal cord via rapid noninvasive lumbar intrathecal injections in mice. J. Vis. Exp. 85, 51229 (2014) https://doi.org/10.3791/51229 .
Abdallah, K. et al. Adeno-associated virus 2/9 delivery of Cre recombinase in mouse primary afferents.Sci. Rep. 8, 7321 (2018).
pubmed: 29743652
pmcid: 5943452
doi: 10.1038/s41598-018-25626-y
Agarwal, N. et al. SUMOylation of enzymes and ion channels in sensory neurons protects against metabolic dysfunction, neuropathy, and sensory loss in diabetes. Neuron 107, 1141–1159.e7 (2020).
pubmed: 32735781
doi: 10.1016/j.neuron.2020.06.037
Hargreaves, K., Dubner, R., Brown, F., Flores, C. & Joris, J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32, 77–88 (1988).
pubmed: 3340425
doi: 10.1016/0304-3959(88)90026-7
Emery, M. A., Shawn Bates, M. L., Wellman, P. J. & Eitan, S. Hydrocodone is more effective than Morphine or Oxycodone in suppressing the development of burn-induced mechanical allodynia. Pain. Med. 18, 2170–2180 (2017).
pubmed: 28340258
doi: 10.1093/pm/pnx050
Sliwinski, C., Nees, T. A., Puttagunta, R., Weidner, N. & Blesch, A. Sensorimotor activity partially ameliorates pain and reduces nociceptive fiber density in the chronically injured spinal cord. J. Neurotrauma 35, 2222–2238 (2018).
pubmed: 29706124
pmcid: 6119231
doi: 10.1089/neu.2017.5431
Pitzer, C., Kuner, R. & Tappe-Theodor, A. Voluntary and evoked behavioral correlates in inflammatory pain conditions under different social housing conditions. Pain Rep. 1, e564 (2016).
pubmed: 29392189
pmcid: 5741310
doi: 10.1097/PR9.0000000000000564