Skip to main content

Advertisement

Log in

Can FDA-Approved Immunomodulatory Drugs be Repurposed/Repositioned to Alleviate Chronic Pain?

  • INVITED REVIEW
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Pain is among the most widespread chronic health condition confronting society today and our inability to manage chronic pain contributes to the opioid abuse epidemic in America. The immune system is known to contribute to acute and chronic pain, but only limited therapeutic treatments such as non-steroid anti-inflammatory drugs have resulted from this knowledge. The last decade has shed light on neuro-immune interactions mediating the development, maintenance, and resolution of chronic pain. Here, we do not aim to perform a comprehensive review of all immune mechanisms involved in chronic pain, but to briefly review the contribution of the main cytokines and immune cells (macrophages, microglia, mast cells and T cells) to chronic pain. Given the urgent need to address the Pain crisis, we provocatively propose to repurpose/reposition FDA-approved immunomodulatory drugs for their potential to alleviate chronic pain. Repositioning or repurposing offers an attractive way to accelerate the arrival of new analgesics.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Aharoni R, Kayhan B, Brenner O, Domev H, Labunskay G, Arnon R (2006) Immunomodulatory therapeutic effect of glatiramer acetate on several murine models of inflammatory bowel disease. J Pharmacol Exp Ther 318(1):68–78

    Article  CAS  PubMed  Google Scholar 

  • Aharoni R, Sonego H, Brenner O, Eilam R, Arnon R (2007) The therapeutic effect of glatiramer acetate in a murine model of inflammatory bowel disease is mediated by anti-inflammatory T-cells. Immunol Lett 112(2):110–119

    Article  CAS  PubMed  Google Scholar 

  • Aharoni R, Teitelbaum D, Sela M, Arnon R (1997) Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci 94(20):10821–10826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aharoni R, Teitelbaum D, Sela M, Arnon R (1998) Bystander suppression of experimental autoimmune encephalomyelitis by T cell lines and clones of the Th2 type induced by copolymer 1. J Neuroimmunol 91(1–2):135–146

    Article  CAS  PubMed  Google Scholar 

  • Alexander GM, van Rijn MA, van Hilten JJ, Perreault MJ, Schwartzman RJ (2005) Changes in cerebrospinal fluid levels of pro-inflammatory cytokines in CRPS. Pain 116(3):213–219

    Article  CAS  PubMed  Google Scholar 

  • Allison DJ, Thomas A, Beaudry K, Ditor DS (2016) Targeting inflammation as a treatment modality for neuropathic pain in spinal cord injury: a randomized clinical trial. J Neuroinflammation 13(1):152

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Andoh T, Kuraishi Y (2004) Direct action of immunoglobulin G on primary sensory neurons through Fc gamma receptor I. Faseb j 18(1):182–184

    Article  CAS  PubMed  Google Scholar 

  • Ansboro S, Roelofs AJ, De Bari C (2017) Mesenchymal stem cells for the management of rheumatoid arthritis: immune modulation, repair or both? Curr Opin Rheumatol 29(2):201–207

    Article  CAS  PubMed  Google Scholar 

  • Bailey-Bucktrout SL, Martinez-Llordella M, Zhou X, Anthony B, Rosenthal W, Luche H, Fehling HJ, Bluestone JA (2013) Self-antigen-Driven Activation Induces Instability of Regulatory T Cells during an Inflammatory Autoimmune Response. Immunity 39(5):949–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baral P, Mills K, Pinho-Ribeiro FA, Chiu IM (2016) Pain and Itch: Beneficial or Harmful to Antimicrobial Defense? Cell Host Microbe 19(6):755–759

    Article  CAS  PubMed  Google Scholar 

  • Baron R, Schwarz K, Kleinert A, Schattschneider J, Wasner G (2001) Histamine-induced itch converts into pain in neuropathic hyperalgesia. NeuroReport 12(16):3475–3478

    Article  CAS  PubMed  Google Scholar 

  • Barragán-Iglesias P, Franco-Enzástiga Ú, Jeevakumar V, Shiers S, Wangzhou A, Granados-Soto V, Campbell ZT, Dussor G, Price TJ (2020) "Type I Interferons Act Directly on Nociceptors to Produce Pain Sensitization: Implications for Viral Infection-Induced Pain." J Neurosci JN-RM-3055–3019

  • Basso L, Boué J, Mahiddine K, Blanpied C, Robiou-du-Pont S, Vergnolle N, Deraison C, Dietrich G (2016) Endogenous analgesia mediated by CD4(+) T lymphocytes is dependent on enkephalins in mice. J Neuroinflammation 13(1):132

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bastos LF, Prazeres JD, Godin AM, Menezes RR, Soares DG, Ferreira WC, Dutra MM, Machado RR, Coelho MM (2013) Sex-independent suppression of experimental inflammatory pain by minocycline in two mouse strains. Neurosci Lett 553:110–114

    Article  CAS  PubMed  Google Scholar 

  • Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC (2002) Control of synaptic strength by glial TNFalpha. Science 295(5563):2282–2285

    Article  CAS  PubMed  Google Scholar 

  • Beggs S, Trang T, Salter MW (2012) P2X4R+ microglia drive neuropathic pain. Nat Neurosci 15(8):1068–1073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benner B, Good L, Quiroga D, Schultz TE, Kassem M, Carson WE, Cherian MA, Sardesai S, Wesolowski R (2020) Pexidartinib, a Novel Small Molecule CSF-1R Inhibitor in Use for Tenosynovial Giant Cell Tumor: A Systematic Review of Pre-Clinical and Clinical Development. Drug Des Dev Ther 14:1693–1704

    Article  CAS  Google Scholar 

  • Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, Glaser SE, Vallejo R (2008) Opioid complications and side effects. Pain Physician 11(2 Suppl):S105-120

    Article  PubMed  Google Scholar 

  • Biber K, Tsuda M, Tozaki-Saitoh H, Tsukamoto K, Toyomitsu E, Masuda T, Boddeke H, Inoue K (2011) Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. Embo j 30(9):1864–1873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bienenstock J, MacQueen G, Sestini P, Marshall JS, Stead RH, Perdue MH (1991) Mast cell/nerve interactions in vitro and in vivo. Am Rev Respir Dis 143(3 Pt 2):S55-58

    Article  CAS  PubMed  Google Scholar 

  • Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D, Shi L, Brenner GJ, Ji R-R, Bean BP, Woolf CJ, Samad TA (2008) Nociceptors Are Interleukin-1β Sensors. J Neurosci 28(52):14062–14073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blanchette F, Neuhaus O (2008) Glatiramer acetate: evidence for a dual mechanism of action. J Neurol 255(Suppl 1):26–36

    Article  CAS  PubMed  Google Scholar 

  • Bonfield TL, Caplan AI (2010) Adult mesenchymal stem cells: an innovative therapeutic for lung diseases. Discov Med 9(47):337–345

    PubMed  Google Scholar 

  • Boué J, Blanpied C, Djata-Cabral M, Pelletier L, Vergnolle N, Dietrich G (2012) Immune conditions associated with CD4+ T effector-induced opioid release and analgesia. Pain 153(2):485–493

    Article  PubMed  CAS  Google Scholar 

  • Burma NE, Leduc-Pessah H, Fan CY, Trang T (2017) Animal models of chronic pain: Advances and challenges for clinical translation. J Neurosci Res 95(6):1242–1256

    Article  CAS  PubMed  Google Scholar 

  • Busse JW, Wang L, Kamaleldin M, Craigie S, Riva JJ, Montoya L, Mulla SM, Lopes LC, Vogel N, Chen E, Kirmayr K, De Oliveira K, Olivieri L, Kaushal A, Chaparro LE, Oyberman I, Agarwal A, Couban R, Tsoi L, Lam T, Vandvik PO, Hsu S, Bala MM, Schandelmaier S, Scheidecker A, Ebrahim S, Ashoorion V, Rehman Y, Hong PJ, Ross S, Johnston BC, Kunz R, Sun X, Buckley N, Sessler DI, Guyatt GH (2018) Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis. JAMA 320(23):2448–2460

    Article  PubMed  PubMed Central  Google Scholar 

  • Butowski N, Colman H, De Groot JF, Omuro AM, Nayak L, Wen PY, Cloughesy TF, Marimuthu A, Haidar S, Perry A, Huse J, Phillips J, West BL, Nolop KB, Hsu HH, Ligon KL, Molinaro AM, Prados M (2016) Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro Oncol 18(4):557–564

    Article  PubMed  Google Scholar 

  • Cao L, DeLeo JA (2008) CNS-infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection-induced neuropathic pain. Eur J Immunol 38(2):448–458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carlström KE, Ewing E, Granqvist M, Gyllenberg A, Aeinehband S, Enoksson SL, Checa A, Badam TVS, Huang J, Gomez-Cabrero D, Gustafsson M, Al Nimer F, Wheelock CE, Kockum I, Olsson T, Jagodic M, Piehl F (2019) Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes. Nat Commun 10(1):3081

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Carroll SY, O’Mahony SM, Grenham S, Cryan JF, Hyland NP (2013) Disodium cromoglycate reverses colonic visceral hypersensitivity and influences colonic ion transport in a stress-sensitive rat strain. PLoS ONE 8(12):e84718

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Celik MÖ, Labuz D, Keye J, Glauben R, Machelska H (2020) "IL-4 induces M2 macrophages to produce sustained analgesia via opioids." JCI Insight 5(4)

  • Chang M, Hamilton JA, Scholz GM, Masendycz P, Macaulay SL, Elsegood CL (2009) Phosphatidylinostitol-3 kinase and phospholipase C enhance CSF-1-dependent macrophage survival by controlling glucose uptake. Cell Signal 21(9):1361–1369

    Article  CAS  PubMed  Google Scholar 

  • Chatterjea D, Paredes L, Martinov T, Balsells E, Allen J, Sykes A, Ashbaugh A (2013) "TNF-alpha neutralizing antibody blocks thermal sensitivity induced by compound 48/80-provoked mast cell degranulation." F1000Res 2:178

  • Chatterjea D, Wetzel A, Mack M, Engblom C, Allen J, Mora-Solano C, Paredes L, Balsells E, Martinov T (2012) Mast cell degranulation mediates compound 48/80-induced hyperalgesia in mice. Biochem Biophys Res Commun 425(2):237–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen A, Ashburn MA (2015) Cardiac Effects of Opioid Therapy. Pain Med 16(Suppl 1):S27-31

    Article  PubMed  Google Scholar 

  • Chiu IM, von Hehn CA, Woolf CJ (2012) Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci 15(8):1063–1067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cho J, D’Antuono M, Glicksman M, Wang J, Jonklaas J (2018) A review of clinical trials: mesenchymal stem cell transplant therapy in type 1 and type 2 diabetes mellitus. Am J Stem Cells 7(4):82–93

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen SP, Wenzell D, Hurley RW, Kurihara C, Buckenmaier III CC, Griffith S, Larkin TM, Dahl E, Morlando BJ (2007) A double-blind, placebo-controlled, dose–response pilot study evaluating intradiscal etanercept in patients with chronic discogenic low back pain or lumbosacral radiculopathy. Anesthesiology 107(1):99–105

  • Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, Freeman R, Truini A, Attal N, Finnerup NB, Eccleston C, Kalso E, Bennett DL, Dworkin RH, Raja SN (2017) Neuropathic pain. Nat Rev Dis Primers 3:17002

    Article  PubMed  PubMed Central  Google Scholar 

  • Conti G, Scarpini E, Baron P, Livraghi S, Tiriticco M, Bianchi R, Vedeler C, Scarlato G (2002) Macrophage infiltration and death in the nerve during the early phases of experimental diabetic neuropathy: a process concomitant with endoneurial induction of IL-1beta and p75NTR. J Neurol Sci 195(1):35–40

    Article  CAS  PubMed  Google Scholar 

  • Cribbs AP, Kennedy A, Penn H, Amjadi P, Green P, Read JE, Brennan F, Gregory B, Williams RO (2015) Methotrexate Restores Regulatory T Cell Function Through Demethylation of the FoxP3 Upstream Enhancer in Patients With Rheumatoid Arthritis. Arthritis Rheumatol 67(5):1182–1192

    Article  CAS  PubMed  Google Scholar 

  • Dabbert D, Rösner S, Krämer M, Schöll U, Tumani H, Mäder M, Weber F (2000) Glatiramer acetate (copolymer-1)-specific, human T cell lines: cytokine profile and suppression of T cell lines reactive against myelin basic protein. Neurosci Lett 289(3):205–208

    Article  CAS  PubMed  Google Scholar 

  • Dothel G, Barbaro MR, Boudin H, Vasina V, Cremon C, Gargano L, Bellacosa L, De Giorgio R, Le Berre-Scoul C, Aubert P, Neunlist M, De Ponti F, Stanghellini V, Barbara G (2015) Nerve fiber outgrowth is increased in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology 148(5):1002-1011.e1004

    Article  CAS  PubMed  Google Scholar 

  • Dowell D, Haegerich TM, Chou R (2016) CDC Guideline for Prescribing Opioids for Chronic Pain-United States, 2016. JAMA 315(15):1624–1645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Edwards AM (1994) Sodium cromoglycate (Intal) as an anti-inflammatory agent for the treatment of chronic asthma. Clin Exp Allergy 24(7):612–623

    Article  CAS  PubMed  Google Scholar 

  • Enthoven WT, Roelofs PD, Deyo RA, van Tulder MW, Koes BW (2016) "Non-steroidal anti-inflammatory drugs for chronic low back pain." Cochrane Database Syst Rev 2(2):Cd012087

  • Fan XL, Zeng QX, Li X, Li CL, Xu ZB, Deng XQ, Shi J, Chen D, Zheng SG, Fu QL (2018) Induced pluripotent stem cell-derived mesenchymal stem cells activate quiescent T cells and elevate regulatory T cell response via NF-κB in allergic rhinitis patients. Stem Cell Res Ther 9(1):170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpaa M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M (2015) Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14(2):162–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fischer R, Sendetski M, del Rivero T, Martinez GF, Bracchi-Ricard V, Swanson KA, Pruzinsky EK, Delguercio N, Rosalino MJ, Padutsch T, Kontermann RE, Pfizenmaier K, Bethea JR (2019) TNFR2 promotes Treg-mediated recovery from neuropathic pain across sexes. Proc Natl Acad Sci 116(34):17045–17050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Olmo D, Herreros D, Pascual I, Pascual JA, Del-Valle E, Zorrilla J, De-La-Quintana P, Garcia-Arranz M, Pascual M (2009) Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum 52(1):79–86

    Article  PubMed  Google Scholar 

  • Ge A, Wang S, Miao B, Yan M (2018) Effects of metformin on the expression of AMPK and STAT3 in the spinal dorsal horn of rats with neuropathic pain. Mol Med Rep 17(4):5229–5237

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: Intrinsic immuneffector cell of the brain. Brain Res Rev 20(3):269–287

    Article  CAS  PubMed  Google Scholar 

  • Gelhorn HL, Tong S, McQuarrie K, Vernon C, Hanlon J, Maclaine G, Lenderking W, Ye X, Speck RM, Lackman RD, Bukata SV, Healey JH, Keedy VL, Anthony SP, Wagner AJ, Von Hoff DD, Singh AS, Becerra CR, Hsu HH, Lin PS, Tap WD (2016) Patient-reported Symptoms of Tenosynovial Giant Cell Tumors. Clin Ther 38(4):778–793

    Article  PubMed  PubMed Central  Google Scholar 

  • Gold MS, Gebhart GF (2010) Nociceptor sensitization in pain pathogenesis. Nat Med 16(11):1248–1257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gonçalves Dos Santos G, Delay L, Yaksh TL, Corr M (2020) Neuraxial Cytokines in Pain States. Front Immunol 10:3061–3061

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Green DP, Limjunyawong N, Gour N, Pundir P, Dong X (2019) A Mast-Cell-Specific Receptor Mediates Neurogenic Inflammation and Pain. Neuron 101(3):412-420.e413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grund VR, Hunninghake DB (1981) Inhibition of histamine-stimulated increases in heart rate in man with the H2-histamine receptor antagonist cimetidine. J Clin Pharmacol 21(2):87–91

    Article  CAS  PubMed  Google Scholar 

  • Guan Z, Kuhn JA, Wang X, Colquitt B, Solorzano C, Vaman S, Guan AK, Evans-Reinsch Z, Braz J, Devor M, Abboud-Werner SL, Lanier LL, Lomvardas S, Basbaum AI (2016) Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat Neurosci 19(1):94–101

    Article  CAS  PubMed  Google Scholar 

  • Han D, Wei T, Zhang S, Wang M, Tian H, Cheng J, Xiao J, Hu Y, Chen M (2016) The therapeutic effects of sodium cromoglycate against influenza A virus H5N1 in mice. Influenza Other Respir Viruses 10(1):57–66

    Article  CAS  PubMed  Google Scholar 

  • Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8(10):774–785

    Article  CAS  PubMed  Google Scholar 

  • Harrell CR, Sadikot R, Pascual J, Fellabaum C, Jankovic MG, Jovicic N, Djonov V, Arsenijevic N, Volarevic V (2019) Mesenchymal Stem Cell-Based Therapy of Inflammatory Lung Diseases: Current Understanding and Future Perspectives. Stem Cells Int 2019:4236973

    Article  PubMed  PubMed Central  Google Scholar 

  • Held M, Karl F, Vlckova E, Rajdova A, Escolano-Lozano F, Stetter C, Bharti R, Förstner KU, Leinders M, Dušek L, Birklein F, Bednarik J, Sommer C, Üçeyler N (2019) Sensory profiles and immune-related expression patterns of patients with and without neuropathic pain after peripheral nerve lesion. Pain 160(10):2316–2327

    Article  PubMed  Google Scholar 

  • Hendriksen E, van Bergeijk D, Oosting RS, Redegeld FA (2017) Mast cells in neuroinflammation and brain disorders. Neurosci Biobehav Rev 79:119–133

    Article  CAS  PubMed  Google Scholar 

  • Heussner MJ, Folger JK, Dias C, Massri N, Dahdah A, Vermeer PD, Laumet G (2020) A Novel Syngeneic Immunocompetent Mouse Model of Head and Neck Cancer Pain Independent of Interleukin-1 Signaling. Anesth Analg. https://doi.org/10.1213/ANE.0000000000005302

    Article  Google Scholar 

  • Hirota H, Kiyama H, Kishimoto T, Taga T (1996) Accelerated Nerve Regeneration in Mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma. J Exp Med 183(6):2627–2634

    Article  CAS  PubMed  Google Scholar 

  • Hoffmeister RT (1983) Methotrexate therapy in rheumatoid arthritis: 15 years experience. Am J Med 75(6a):69–73

    Article  CAS  PubMed  Google Scholar 

  • Honjoh K, Nakajima H, Hirai T, Watanabe S, Matsumine A (2019) Relationship of Inflammatory Cytokines From M1-Type Microglia/Macrophages at the Injured Site and Lumbar Enlargement With Neuropathic Pain After Spinal Cord Injury in the CCL21 Knockout (plt) Mouse. Front Cell Neurosci 13:525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horan RF, Sheffer AL, Austen KF (1990) Cromolyn sodium in the management of systemic mastocytosis. J Allergy Clin Immunol 85(5):852–855

    Article  CAS  PubMed  Google Scholar 

  • Hu P, McLachlan EM (2003) Distinct functional types of macrophage in dorsal root ganglia and spinal nerves proximal to sciatic and spinal nerve transections in the rat. Exp Neurol 184(2):590–605

    Article  PubMed  Google Scholar 

  • Hung AL, Lim M, Doshi TL (2017) Targeting cytokines for treatment of neuropathic pain. Scand J Pain 17:287–93

  • Inoue K, Tsuda M (2018) Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci 19(3):138–152

    Article  CAS  PubMed  Google Scholar 

  • Inta D, Lang UE, Borgwardt S, Meyer-Lindenberg A, Gass P (2017) Microglia Activation and Schizophrenia: Lessons From the Effects of Minocycline on Postnatal Neurogenesis, Neuronal Survival and Synaptic Pruning. Schizophr Bull 43(3):493–496

    PubMed  Google Scholar 

  • Inyang KE, Szabo-Pardi T, Wentworth E, McDougal TA, Dussor G, Burton MD, Price TJ (2019) The antidiabetic drug metformin prevents and reverses neuropathic pain and spinal cord microglial activation in male but not female mice. Pharmacol Res 139:1–16

    Article  CAS  PubMed  Google Scholar 

  • Isoardi KZ, Harris K, Carmichael KE, Dimeski G, Chan BSH, Page CB (2018) Acute bone marrow suppression and gastrointestinal toxicity following acute oral methotrexate overdose. Clin Toxicol (phila) 56(12):1204–1206

    Article  CAS  Google Scholar 

  • Jaggi AS, Kaur G, Bali A, Singh N (2017) Pharmacological investigations on mast cell stabilizer and histamine receptor antagonists in vincristine-induced neuropathic pain. Naunyn Schmiedebergs Arch Pharmacol 390(11):1087–1096

    Article  CAS  PubMed  Google Scholar 

  • Ji RR, Xu ZZ, Gao YJ (2014) Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov 13(7):533–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji RR, Xu ZZ, Strichartz G, Serhan CN (2011) Emerging roles of resolvins in the resolution of inflammation and pain. Trends Neurosci 34(11):599–609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413(6852):203–210

    Article  CAS  PubMed  Google Scholar 

  • Karimi M, Zekavat OR, Sharifzadeh S, Mousavizadeh K (2006) Clinical response of patients with sickle cell anemia to cromolyn sodium nasal spray. Am J Hematol 81(11):809–816

    Article  CAS  PubMed  Google Scholar 

  • Karl F, Stoll A, Böttcher-Loschinski R, Böttcher M, Baur R, Jacobs B, Völkl S, Jitschin R, Rösler W, Mackensen A, Mougiakakos D (2021) Impact of Nrf2 expression in reconstituting T-cells of allogeneic hematopoietic stem cell transplanted patients. Leukemia 35(3):910–915

    Article  CAS  PubMed  Google Scholar 

  • Kashiba H, Fukui H, Morikawa Y, Senba E (1999) Gene expression of histamine H1 receptor in guinea pig primary sensory neurons: a relationship between H1 receptor mRNA-expressing neurons and peptidergic neurons. Brain Res Mol Brain Res 66(1–2):24–34

    Article  CAS  PubMed  Google Scholar 

  • Kawasaki Y, Zhang L, Cheng JK, Ji RR (2008) Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 28(20):5189–5194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keppel Hesselink JM, Schatman ME (2017) EMA401: an old antagonist of the AT2R for a new indication in neuropathic pain. J Pain Res 10:439–443

    Article  PubMed  PubMed Central  Google Scholar 

  • Khoutorsky A, Price TJ (2018) Translational Control Mechanisms in Persistent Pain. Trends Neurosci 41(2):100–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim H, Thompson J, Ji G, Ganapathy V, Neugebauer V (2017) Monomethyl fumarate inhibits pain behaviors and amygdala activity in a rat arthritis model. Pain 158(12):2376–2385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klein SL (2012) Immune cells have sex and so should journal articles. Endocrinology 153(6):2544–2550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, Tanaka S, Bluestone JA, Takayanagi H (2014) Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med 20(1):62–68

    Article  CAS  PubMed  Google Scholar 

  • Krukowski K, Eijkelkamp N, Laumet G, Hack CE, Li Y, Dougherty PM, Heijnen CJ, Kavelaars A (2016) CD8<sup>+</sup> T Cells and Endogenous IL-10 Are Required for Resolution of Chemotherapy-Induced Neuropathic Pain. J Neurosci 36(43):11074–11083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Łabuzek K, Liber S, Gabryel B, Okopień B (2010) Metformin has adenosine-monophosphate activated protein kinase (AMPK)-independent effects on LPS-stimulated rat primary microglial cultures. Pharmacol Rep 62(5):827–848

    Article  PubMed  Google Scholar 

  • Lamb YN (2019) Pexidartinib: First Approval. Drugs 79(16):1805–1812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Langjahr M, Schubert AL, Sommer C, Üçeyler N (2018) Increased pro-inflammatory cytokine gene expression in peripheral blood mononuclear cells of patients with polyneuropathies. J Neurol 265(3):618–627

    Article  CAS  PubMed  Google Scholar 

  • Laube BL, Edwards AM, Dalby RN, Creticos PS, Norman PS (1998) The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma. J Allergy Clin Immunol 101(4 Pt 1):475–483

    Article  CAS  PubMed  Google Scholar 

  • Laumet G, Bavencoffe A, Edralin JD, Huo X-J, Walters ET, Dantzer R, Heijnen CJ, Kavelaars A (2020) Interleukin-10 resolves pain hypersensitivity induced by cisplatin by reversing sensory neuron hyperexcitability. Pain 161(10):2344–2352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laumet G, Chen S-R, Pan H-L (2017) NMDA Receptors and Signaling in Chronic Neuropathic Pain. Springer International Publishing, The NMDA Receptors. K. Hashimoto. Cham, pp 103–119

    Google Scholar 

  • Laumet G, Edralin JD, Chiang AC-A, Dantzer R, Heijnen CJ, Kavelaars A (2018) Resolution of inflammation-induced depression requires T lymphocytes and endogenous brain interleukin-10 signaling. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology 43(13):2597–2605

    Article  CAS  Google Scholar 

  • Laumet G, Ma J, Robison AJ, Kumari S, Heijnen CJ, Kavelaars A (2019) T Cells as an Emerging Target for Chronic Pain Therapy. Front Mol Neurosci 12:216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ledeboer A, Jekich BM, Sloane EM, Mahoney JH, Langer SJ, Milligan ED, Martin D, Maier SF, Johnson KW, Leinwand LA, Chavez RA, Watkins LR (2007) Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats. Brain Behav Immun 21(5):686–698

    Article  CAS  PubMed  Google Scholar 

  • Lee S, Shi XQ, Fan A, West B, Zhang J (2018) Targeting macrophage and microglia activation with colony stimulating factor 1 receptor inhibitor is an effective strategy to treat injury-triggered neuropathic pain. Mol Pain 14:1744806918764979–1744806918764979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leger T, Grist J, D’Acquisto F, Clark AK, Malcangio M (2011) Glatiramer acetate attenuates neuropathic allodynia through modulation of adaptive immune cells. J Neuroimmunol 234(1–2):19–26

    Article  CAS  PubMed  Google Scholar 

  • Levy D, Kainz V, Burstein R, Strassman AM (2012) Mast cell degranulation distinctly activates trigemino-cervical and lumbosacral pain pathways and elicits widespread tactile pain hypersensitivity. Brain Behav Immun 26(2):311–317

    Article  PubMed  Google Scholar 

  • Li J, Ma J, Lacagnina MJ, Lorca S, Odem MA, Walters ET, Kavelaars A, Grace PM (2020) Oral Dimethyl Fumarate Reduces Peripheral Neuropathic Pain in Rodents via NFE2L2 Antioxidant Signaling. Anesthesiology 132(2):343–356

    Article  CAS  PubMed  Google Scholar 

  • Li M, Li Z, Ren H, Jin WN, Wood K, Liu Q, Sheth KN, Shi FD (2017) Colony stimulating factor 1 receptor inhibition eliminates microglia and attenuates brain injury after intracerebral hemorrhage. J Cereb Blood Flow Metab 37(7):2383–2395

    Article  CAS  PubMed  Google Scholar 

  • Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, Hou Y, Zeng X, Gilkeson GS, Sun L (2010) Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis 69(8):1423–1429

    Article  PubMed  Google Scholar 

  • Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G, Brück W, Dawson K, Goelz S, Wiese S, Scannevin RH, Lukashev M, Gold R (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134(Pt 3):678–692

    Article  PubMed  Google Scholar 

  • Loane DJ, Byrnes KR (2010) Role of Microglia in Neurotrauma. Neurotherapeutics 7(4):366–377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luchting B, Heyn J, Woehrle T, Rachinger-Adam B, Kreth S, Hinske LC, Azad SC (2016) Differential expression of P2X7 receptor and IL-1β in nociceptive and neuropathic pain. J Neuroinflammation 13(1):100

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ma W, Quirion R (2005) Up-regulation of interleukin-6 induced by prostaglandin E2 from invading macrophages following nerve injury: an in vivo and in vitro study. J Neurochem 93(3):664–673

    Article  CAS  PubMed  Google Scholar 

  • Maier SF, Wiertelak EP, Martin D, Watkins LR (1993) Interleukin-1 mediates the behavioral hyperalgesia produced by lithium chloride and endotoxin. Brain Res 623(2):321–324

    Article  CAS  PubMed  Google Scholar 

  • Mailhot B, Christin M, Tessandier N, Sotoudeh C, Bretheau F, Turmel R, Pellerin È, Wang F, Bories C, Joly-Beauparlant C, De Koninck Y, Droit A, Cicchetti F, Scherrer G, Boilard E, Sharif-Naeini R, Lacroix S (2020) "Neuronal interleukin-1 receptors mediate pain in chronic inflammatory diseases." J Exp Med 217(9)

  • Martinez V, Szekely B, Lemarié J, Martin F, Gentili M, Ben Ammar S, Lepeintre JF, Garreau de Loubresse C, Chauvin M, Bouhassira D, Fletcher D (2013) The efficacy of a glial inhibitor, minocycline, for preventing persistent pain after lumbar discectomy: a randomized, double-blind, controlled study. Pain 154(8):1197–1203

    Article  CAS  PubMed  Google Scholar 

  • McMahon SB (1996) NGF as a mediator of inflammatory pain. Philos Trans R Soc Lond B Biol Sci 351(1338):431–440

    Article  CAS  PubMed  Google Scholar 

  • Melemedjian OK, Asiedu MN, Tillu DV, Sanoja R, Yan J, Lark A, Khoutorsky A, Johnson J, Peebles KA, Lepow T, Sonenberg N, Dussor G, Price TJ (2011) Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain. Mol Pain 7:70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Metcalfe DD, Boyce JA (2006) Mast cell biology in evolution. J Allergy Clin Immunol 117(6):1227–1229

    Article  CAS  PubMed  Google Scholar 

  • Milligan ED, Soderquist RG, Malone SM, Mahoney JH, Hughes TS, Langer SJ, Sloane EM, Maier SF, Leinwand LA, Watkins LR, Mahoney MJ (2006) Intrathecal polymer-based interleukin-10 gene delivery for neuropathic pain. Neuron Glia Biol 2(4):293–308

    Article  PubMed  PubMed Central  Google Scholar 

  • Miyao T, Floess S, Setoguchi R, Luche H, Fehling HJ, Waldmann H, Huehn J, Hori S (2012) Plasticity of Foxp3+ T Cells Reflects Promiscuous Foxp3 Expression in Conventional T Cells but Not Reprogramming of Regulatory T Cells. Immunity 36(2):262–275

    Article  CAS  PubMed  Google Scholar 

  • Moalem G, Xu K, Yu L (2004) T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats. Neuroscience 129(3):767–777

    Article  CAS  PubMed  Google Scholar 

  • Mogil JS (2020) Qualitative sex differences in pain processing: emerging evidence of a biased literature. Nat Rev Neurosci 21(7):353–365

    Article  CAS  PubMed  Google Scholar 

  • Montes Diaz G, Hupperts R, Fraussen J, Somers V (2018) Dimethyl fumarate treatment in multiple sclerosis: Recent advances in clinical and immunological studies. Autoimmun Rev 17(12):1240–1250

    Article  CAS  PubMed  Google Scholar 

  • Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765

    Article  CAS  PubMed  Google Scholar 

  • Moore RA, Chi CC, Wiffen PJ, Derry S, Rice AS (2015) "Oral nonsteroidal anti-inflammatory drugs for neuropathic pain." Cochrane Database Syst Rev 2015 (10):Cd010902

  • Moriarty O, Tu Y, Sengar AS, Salter MW, Beggs S, Walker SM (2019) Priming of Adult Incision Response by Early-Life Injury: Neonatal Microglial Inhibition Has Persistent But Sexually Dimorphic Effects in Adult Rats. J Neurosci 39(16):3081–3093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nalleweg N, Chiriac MT, Podstawa E, Lehmann C, Rau TT, Atreya R, Krauss E, Hundorfean G, Fichtner-Feigl S, Hartmann A, Becker C, Mudter J (2015) IL-9 and its receptor are predominantly involved in the pathogenesis of UC. Gut 64(5):743–755

    Article  CAS  PubMed  Google Scholar 

  • Nathan C (2002) Points of control in inflammation. Nature 420(6917):846–852

    Article  CAS  PubMed  Google Scholar 

  • Nozu T, Miyagishi D, Nozu R, Takakusaki K, Okumura T (2020) "Losartan improves visceral sensation and gut barrier in a rat model of irritable bowel syndrome." Neurogastroenterol Motil: e13819

  • Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H, Guo CJ, Chen S, Trier AM, Xu AZ, Tripathi SV, Luo J, Gao X, Yang L, Hamilton SL, Wang PL, Brestoff JR, Council ML, Brasington R, Schaffer A, Brombacher F, Hsieh CS, R. W. t. Gereau, M. J. Miller, Z. F. Chen, H. Hu, S. Davidson, Q. Liu and B. S. Kim, (2017) Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell 171(1):217-228.e213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okayama Y, Benyon RC, Rees PH, Lowman MA, Hillier K, Church MK (1992) Inhibition profiles of sodium cromoglycate and nedocromil sodium on mediator release from mast cells of human skin, lung, tonsil, adenoid and intestine. Clin Exp Allergy 22(3):401–409

    Article  CAS  PubMed  Google Scholar 

  • Okubo M, Yamanaka H, Kobayashi K, Dai Y, Kanda H, Yagi H, Noguchi K (2016) Macrophage-Colony Stimulating Factor Derived from Injured Primary Afferent Induces Proliferation of Spinal Microglia and Neuropathic Pain in Rats. PLoS ONE 11(4):e0153375

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Old EA, Nadkarni S, Grist J, Gentry C, Bevan S, Kim KW, Mogg AJ, Perretti M, Malcangio M (2014) Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain. J Clin Invest 124(5):2023–2036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oliveira SM, Drewes CC, Silva CR, Trevisan G, Boschen SL, Moreira CG, de Almeida Cabrini D, Da Cunha C, Ferreira J (2011) Involvement of mast cells in a mouse model of postoperative pain. Eur J Pharmacol 672(1–3):88–95

    Article  CAS  PubMed  Google Scholar 

  • Pachman DR, Dockter T, Zekan PJ, Fruth B, Ruddy KJ, Ta LE, Lafky JM, Dentchev T, Le-Lindqwister NA, Sikov WM, Staff N, Beutler AS, Loprinzi CL (2017) A pilot study of minocycline for the prevention of paclitaxel-associated neuropathy: ACCRU study RU221408I. Support Care Cancer 25(11):3407–3416

    Article  PubMed  Google Scholar 

  • Park J, Decker JT, Margul DJ, Smith DR, Cummings BJ, Anderson AJ, Shea LD (2018) Local Immunomodulation with Anti-inflammatory Cytokine-Encoding Lentivirus Enhances Functional Recovery after Spinal Cord Injury. Mol Ther 26(7):1756–1770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Penatti A, Facciotti F, De Matteis R, Larghi P, Paroni M, Murgo A, De Lucia O, Pagani M, Pierannunzii L, Truzzi M, Ioan-Facsinay A, Abrignani S, Geginat J, Meroni PL (2017) Differences in serum and synovial CD4+ T cells and cytokine profiles to stratify patients with inflammatory osteoarthritis and rheumatoid arthritis. Arthritis Res Ther 19(1):103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Peng J, Gu N, Zhou LBEU, Murugan M, Gan WB, Wu LJ (2016) Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury. Nat Commun 7:12029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Percie du Sert N, Rice AS (2014) Improving the translation of analgesic drugs to the clinic: animal models of neuropathic pain. Br J Pharmacol 171(12):2951–2963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pillemer SR, Fowler SE, Tilley BC, Alarcón GS, Heyse SP, Trentham DE, Neuner R, Clegg DO, Leisen JC, Cooper SM, Duncan H, Tuttleman M (1997) Meaningful improvement criteria sets in a rheumatoid arthritis clinical trial. MIRA Trial Group. Minocycline in Rheumatoid Arthritis. Arthritis Rheum 40(3):419–425

    Article  CAS  PubMed  Google Scholar 

  • Pinho-Ribeiro FA, Verri WA Jr, Chiu IM (2017) Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation. Trends Immunol 38(1):5–19

    Article  CAS  PubMed  Google Scholar 

  • Plane JM, Shen Y, Pleasure DE, Deng W (2010) Prospects for minocycline neuroprotection. Arch Neurol 67(12):1442–1448

    Article  PubMed  PubMed Central  Google Scholar 

  • Raghavendra V, Tanga F, DeLeo JA (2003) Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 306(2):624–630

    Article  CAS  PubMed  Google Scholar 

  • Raoof R, van der Vlist M, Willemen HLDM, Prado J, Versteeg S, Vos M, Lokhorst R, Pasterkamp J, Khoury-Hanold W, MeyaardL, Eijkelkamp N (2020) Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain, bioRxiv

  • Rice ASC, Dworkin RH, McCarthy TD, Anand P, Bountra C, McCloud PI, Hill J, Cutter G, Kitson G, Desem N, Raff M (2014) EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet 383(9929):1637–1647

    Article  CAS  PubMed  Google Scholar 

  • Robinson CR, Zhang H, Dougherty PM (2014) Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy in the rat. Neuroscience 274:308–317

    Article  CAS  PubMed  Google Scholar 

  • Rosen SF, Ham B, Haichin M, Walters IC, Tohyama S, Sotocinal SG, Mogil JS (2019) Increased pain sensitivity and decreased opioid analgesia in T-cell-deficient mice and implications for sex differences. Pain 160(2):358–366

    Article  CAS  PubMed  Google Scholar 

  • Saito M, Saito M, Das BC (2019) Involvement of AMP-activated protein kinase in neuroinflammation and neurodegeneration in the adult and developing brain. Int J Dev Neurosci 77:48–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santa-Cecília FV, Ferreira DW, Guimaraes RM, Cecilio NT, Fonseca MM, Lopes AH, Davoli-Ferreira M, Kusuda R, Souza GR, Nachbur U, Alves-Filho JC, Teixeira MM, Zamboni DS, Cunha FQ, Cunha TM (2019) The NOD2 signaling in peripheral macrophages contributes to neuropathic pain development. Pain 160(1):102–116

    Article  PubMed  CAS  Google Scholar 

  • Sawicki CM, Kim JK, Weber MD, Faw TD, McKim DB, Madalena KM, Lerch JK, Basso DM, Humeidan ML, Godbout JP, Sheridan JF (2019) Microglia Promote Increased Pain Behavior through Enhanced Inflammation in the Spinal Cord during Repeated Social Defeat Stress. J Neurosci 39(7):1139–1149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schäfers M, Sommer C (2007) Anticytokine therapy in neuropathic pain management. Expert Rev Neurother 7(11):1613–1627

    Article  PubMed  CAS  Google Scholar 

  • Scott TJ, O’Connor AC, Link AN, Beaulieu TJ (2014) Economic analysis of opportunities to accelerate Alzheimer’s disease research and development. Ann N Y Acad Sci 1313(1):17–34

    Article  PubMed  PubMed Central  Google Scholar 

  • Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L, Borg C, Saas P, Tiberghien P, Rouas-Freiss N, Carosella ED, Deschaseaux F (2008) Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells 26(1):212–222

    Article  CAS  PubMed  Google Scholar 

  • Sharma R, Kim SY, Sharma A, Zhang Z, Kambhampati SP, Kannan S, Kannan RM (2017) Activated Microglia Targeting Dendrimer-Minocycline Conjugate as Therapeutics for Neuroinflammation. Bioconjug Chem 28(11):2874–2886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shepherd AJ, Copits BA, Mickle AD, Karlsson P, Kadunganattil S, Haroutounian S, Tadinada SM, de Kloet AD, Valtcheva MV, McIlvried LA, Sheahan TD, Jain S, Ray PR, Usachev YM, Dussor G, Krause EG, Price TJ, Gereau RW, Mohapatra DP (2018a) Angiotensin II Triggers Peripheral Macrophage-to-Sensory Neuron Redox Crosstalk to Elicit Pain. J Neurosci 38(32):7032–7057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shepherd AJ, Mickle AD, Golden JP, Mack MR, Halabi CM, de Kloet AD, Samineni VK, Kim BS, Krause EG, R. W. t. Gereau and D. P. Mohapatra, (2018b) Macrophage angiotensin II type 2 receptor triggers neuropathic pain. Proc Natl Acad Sci U S A 115(34):E8057-e8066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shepherd AJ, Mohapatra DP (2019) Attenuation of Unevoked Mechanical and Cold Pain Hypersensitivities Associated With Experimental Neuropathy in Mice by Angiotensin II Type-2 Receptor Antagonism. Anesth Analg 128(6):e84–e87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shu X, Mendell LM (1999) Nerve growth factor acutely sensitizes the response of adult rat sensory neurons to capsaicin. Neurosci Lett 274(3):159–162

    Article  CAS  PubMed  Google Scholar 

  • Simeoli R, Montague K, Jones HR, Castaldi L, Chambers D, Kelleher JH, Vacca V, Pitcher T, Grist J, Al-Ahdal H, Wong LF, Perretti M, Lai J, Mouritzen P, Heppenstall P, Malcangio M (2017) Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma. Nat Commun 8(1):1778

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Simon LS (2012) Relieving pain in America: A blueprint for transforming prevention, care, education, and research. J Pain Palliat Care Pharmacother 26(2):197–198

  • Simons FE (2004) Advances in H1-antihistamines. N Engl J Med 351(21):2203–2217

    Article  CAS  PubMed  Google Scholar 

  • Sisignano M, Parnham MJ, Geisslinger G (2016) Drug Repurposing for the Development of Novel Analgesics. Trends Pharmacol Sci 37(3):172–183

    Article  CAS  PubMed  Google Scholar 

  • Smith MT, Anand P, Rice AS (2016) Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain: preclinical and clinical studies. Pain 157(Suppl 1):S33-41

    Article  CAS  PubMed  Google Scholar 

  • Soderquist RG, Milligan ED, Harrison JA, Chavez RA, Johnson KW, Watkins LR, Mahoney MJ (2010) PEGylation of interleukin-10 for the mitigation of enhanced pain states. J Biomed Mater Res, Part A 93(3):1169–1179

    Google Scholar 

  • Sommer C (2003) Painful neuropathies. Curr Opin Neurol 16(5):623–628

    Article  PubMed  Google Scholar 

  • Sorge RE (2015) Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci 18:1081–1083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spanier JA, Howden CW, Jones MP (2003) A systematic review of alternative therapies in the irritable bowel syndrome. Arch Intern Med 163(3):265–274

    Article  PubMed  Google Scholar 

  • Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440(7087):1054–1059

    Article  CAS  PubMed  Google Scholar 

  • Sumitani M, Ueda H, Hozumi J, Inoue R, Kogure T, Yamada Y, Kogure T (2016) Minocycline Does Not Decrease Intensity of Neuropathic Pain Intensity, But Does Improve Its Affective Dimension. J Pain Palliat Care Pharmacother 30(1):31–35

    PubMed  Google Scholar 

  • Sun S, Chen D, Lin F, Chen M, Yu H, Hou L, Li C (2016) Role of interleukin-4, the chemokine CCL3 and its receptor CCR5 in neuropathic pain. Mol Immunol 77:184–192

    Article  CAS  PubMed  Google Scholar 

  • Suzuki T, Murakami S, Biswal SS, Sakaguchi S, Harigae H, Yamamoto M, Motohashi H (2017) "Systemic Activation of NRF2 Alleviates Lethal Autoimmune Inflammation in Scurfy Mice." Mol Cell Biol 37(15)

  • Takeura N, Nakajima H, Watanabe S, Honjoh K, Takahashi A, Matsumine A (2019) Role of macrophages and activated microglia in neuropathic pain associated with chronic progressive spinal cord compression. Sci Rep 9(1):15656

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tap WD, Gelderblom H, Palmerini E, Desai J, Bauer S, Blay JY, Alcindor T, Ganjoo K, Martín-Broto J, Ryan CW, Thomas DM, Peterfy C, Healey JH, van de Sande M, Gelhorn HL, Shuster DE, Wang Q, Yver A, Hsu HH, Lin PS, Tong-Starksen S, Stacchiotti S, Wagner AJ (2019) Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. Lancet 394(10197):478–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thakur V, Gonzalez M, Pennington K, Chattopadhyay M (2016) Viral vector mediated continuous expression of interleukin-10 in DRG alleviates pain in type 1 diabetic animals. Mol Cell Neurosci 72:46–53

    Article  CAS  PubMed  Google Scholar 

  • Thompson ML, Jimenez-Andrade JM, Chartier S, Tsai J, Burton EA, Habets G, Lin PS, West BL, Mantyh PW (2015) Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer. Pain 156(9):1692–1702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424(6950):778–783

    Article  CAS  PubMed  Google Scholar 

  • Uçeyler N, Rogausch JP, Toyka KV, Sommer C (2007) Differential expression of cytokines in painful and painless neuropathies. Neurology 69(1):42–49

    Article  PubMed  CAS  Google Scholar 

  • Üçeyler N, Topuzoğlu T, Schiesser P, Hahnenkamp S, Sommer C (2011) IL-4 deficiency is associated with mechanical hypersensitivity in mice. PLoS ONE 6(12):e28205

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Uceyler N, Valenza R, Stock M, Schedel R, Sprotte G, Sommer C (2006) Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain. Arthritis Rheum 54(8):2656–2664

    Article  PubMed  CAS  Google Scholar 

  • Vanelderen P, Van Zundert J, Kozicz T, Puylaert M, De Vooght P, Mestrum R, Heylen R, Roubos E, Vissers K (2015) Effect of minocycline on lumbar radicular neuropathic pain: a randomized, placebo-controlled, double-blind clinical trial with amitriptyline as a comparator. Anesthesiology 122(2):399–406

    Article  CAS  PubMed  Google Scholar 

  • Vicuña L, Strochlic DE, Latremoliere A, Bali KK, Simonetti M, Husainie D, Prokosch S, Riva P, Griffin RS, Njoo C, Gehrig S, Mall MA, Arnold B, Devor M, Woolf CJ, Liberles SD, Costigan M, Kuner R (2015) The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase. Nat Med 21(5):518–523

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vincent L, Vang D, Nguyen J, Gupta M, Luk K, Ericson ME, Simone DA, Gupta K (2013) Mast cell activation contributes to sickle cell pathobiology and pain in mice. Blood 122(11):1853–1862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Voicu VA, Mircioiu C, Plesa C, Jinga M, Balaban V, Sandulovici R, Costache AM, Anuta V, Mircioiu I (2019) Effect of a New Synergistic Combination of Low Doses of Acetylsalicylic Acid, Caffeine, Acetaminophen, and Chlorpheniramine in Acute Low Back Pain. Front Pharmacol 10:607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Voicu VA, Mircioiu I, Sandulovici R, Mircioiu C, Plesa C, Velescu BS, Anuta V (2017) Chlorpheniramine Potentiates the Analgesic Effect in Migraine of Usual Caffeine, Acetaminophen, and Acetylsalicylic Acid Combination. Front Pharmacol 8:758

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • von Hehn CA, Baron R, Woolf CJ (2012) Deconstructing the Neuropathic Pain Phenotype to Reveal Neural Mechanisms. Neuron 73(4):638–652

    Article  CAS  Google Scholar 

  • Vukman KV, Försönits A, Oszvald Á, Tóth E, Buzás EI (2017) Mast cell secretome: Soluble and vesicular components. Semin Cell Dev Biol 67:65–73

    Article  CAS  PubMed  Google Scholar 

  • Watkins LR, Chavez RA, Landry R, Fry M, Green-Fulgham SM, Coulson JD, Collins SD, Glover DK, Rieger J, Forsayeth JR (2020) Targeted interleukin-10 plasmid DNA therapy in the treatment of osteoarthritis: Toxicology and pain efficacy assessments. Brain Behav Immun 90:155–166

    Article  CAS  PubMed  Google Scholar 

  • Watkins LR, Maier SF (2002) Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 82(4):981–1011

    Article  CAS  PubMed  Google Scholar 

  • Watkins LR, Wiertelak EP, Goehler LE, Smith KP, Martin D, Maier SF (1994) Characterization of cytokine-induced hyperalgesia. Brain Res 654(1):15–26

    Article  CAS  PubMed  Google Scholar 

  • West RB, Rubin BP, Miller MA, Subramanian S, Kaygusuz G, Montgomery K, Zhu S, Marinelli RJ, De Luca A, Downs-Kelly E, Goldblum JR, Corless CL, Brown PO, Gilks CB, Nielsen TO, Huntsman D, van de Rijn M (2006) A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc Natl Acad Sci U S A 103(3):690–695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Willemen HLDM, Eijkelkamp N, Wang H, Dantzer R, Dorn GW 2nd, Kelley KW, Heijnen CJ, Kavelaars A (2010) Microglial/macrophage GRK2 determines duration of peripheral IL-1beta-induced hyperalgesia: contribution of spinal cord CX3CR1, p38 and IL-1 signaling. Pain 150(3):550–560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Willkens RF, Watson MA (1982) Methotrexate: a perspective of its use in the treatment of rheumatic diseases. J Lab Clin Med 100(3):314–321

    CAS  PubMed  Google Scholar 

  • Willkens RF, Watson MA, Paxson CS (1980) Low dose pulse methotrexate therapy in rheumatoid arthritis. J Rheumatol 7(4):501–505

    CAS  PubMed  Google Scholar 

  • Woodroofe MN (1995) Cytokine production in the central nervous system. Neurology 45(6 Suppl 6):S6–S10

    Article  CAS  PubMed  Google Scholar 

  • Woolf CJ, Ma Q (2007) Nociceptors–noxious stimulus detectors. Neuron 55(3):353–364

    Article  CAS  PubMed  Google Scholar 

  • Xu Z, Zhang F, Sun F, Gu K, Dong S, He D (2015) "Dimethyl fumarate for multiple sclerosis." Cochrane Database Syst Rev(4): Cd011076

  • Xu ZZ, Zhang L, Liu T, Park JY, Berta T, Yang R, Serhan CN, Ji RR (2010) "Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions." Nat Med 16(5): 592–597, 591p following 597

  • Yang L, Sugama S, Chirichigno JW, Gregorio J, Lorenzl S, Shin DH, Browne SE, Shimizu Y, Joh TH, Beal MF, Albers DS (2003) Minocycline enhances MPTP toxicity to dopaminergic neurons. J Neurosci Res 74(2):278–285

    Article  CAS  PubMed  Google Scholar 

  • Yeh CC, Jao SW, Huh BK, Wong CS, Yang CP, White WD, Wu CT (2005) "Preincisional dextromethorphan combined with thoracic epidural anesthesia and analgesia improves postoperative pain and bowel function in patients undergoing colonic surgery." Anesth Analg 100(5): 1384–1389, table of contents

  • Yoo SH, Lee SH, Lee S, Park JH, Lee S, Jin H, Park HJ (2020) The effect of human mesenchymal stem cell injection on pain behavior in chronic post-ischemia pain mice. Korean J Pain 33(1):23–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yrjänheikki J, Tikka T, Keinänen R, Goldsteins G, Chan PH, Koistinaho J (1999) A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A 96(23):13496–13500

    Article  PubMed  PubMed Central  Google Scholar 

  • Yu D, Zhu J, Zhu M, Wei K, Chen Q, Wu X, Miao X, Lu Z (2019) Inhibition of Mast Cell Degranulation Relieves Visceral Hypersensitivity Induced by Pancreatic Carcinoma in Mice. J Mol Neurosci 69(2):235–245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu H, Fischer G, Ebert AD, Wu HE, Bai X, Hogan QH (2015) Analgesia for neuropathic pain by dorsal root ganglion transplantation of genetically engineered mesenchymal stem cells: initial results. Mol Pain 11:5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yu X, Liu H, Hamel KA, Morvan MG, Yu S, Leff J, Guan Z, Braz JM, Basbaum AI (2020) Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain. Nat Commun 11(1):264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yue JX, Wang RR, Yu J, Tang YY, Hou WW, Lou GD, Zhang SH, Chen Z (2014) Histamine upregulates Nav1.8 expression in primary afferent neurons via H2 receptors: involvement in neuropathic pain. CNS Neurosci Ther 20(10):883–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Li Y, de Carvalho-Barbosa M, Kavelaars A, Heijnen CJ, Albrecht PJ, Dougherty PM (2016) Dorsal Root Ganglion Infiltration by Macrophages Contributes to Paclitaxel Chemotherapy-Induced Peripheral Neuropathy. J Pain 17(7):775–786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the Rita Allen foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Geoffroy Laumet.

Ethics declarations

Competing interests

The authors declare no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Inyang, K., Folger, J.K. & Laumet, G. Can FDA-Approved Immunomodulatory Drugs be Repurposed/Repositioned to Alleviate Chronic Pain?. J Neuroimmune Pharmacol 16, 531–547 (2021). https://doi.org/10.1007/s11481-021-10000-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-021-10000-z

Keywords

Navigation