Abstract
Emerging evidence implicates the sphingosine-1-phosphate receptor subtype 1 (S1PR1) in the development of neuropathic pain. Continued investigation of the signaling pathways downstream of S1PR1 are needed to support development of S1PR1 antagonists. In rodents, intrathecal (i.th.) injection of SEW2871, a selective S1PR1 agonist, activates the nod-like receptor family, pyrin domain containing 3 inflammasome, increases interleukin-1β (IL-1β) and causes behavioral hypersensitivity. I.th. injection of a IL-1β receptor antagonist blocks SEW2871-induced hypersensitivity, suggesting that IL-1β contributes to S1PR1’s actions. Interestingly, previous studies have suggested that IL-1β increases the expression/activity of adenosine kinase (ADK), a key regulator of adenosine signaling at its receptors (ARs). Increased ADK expression reduces adenosine signaling whereas inhibiting ADK restores the action of adenosine. Here, we show that SEW287-induced behavioral hypersensitivity is associated with increased expression of ADK in astrocytes of the dorsal horn of the spinal cord. Moreover, the ADK inhibitor, ABT702, blocks SEW2871-induced hypersensitivity. These findings link ADK activation to S1PR1. If SEW2871-induced pain is mediated by IL-1β, which in turn activates ADK and leads to mechano-allodynia, then blocking ADK should attenuate IL-1β effects. In support of this idea, recombinant rat (rrIL-1β)-induced allodynia was blocked by at least 90% with ABT702, functionally linking ADK to IL-1β. Moreover, the selective A3AR antagonist, MRS1523, prevents the ability of ABT702 to block SEW2871 and IL-1β-induced allodynia, implicating A3AR signaling in the beneficial effects exerted by ABT702. Our findings provide novel mechanistic insight into how S1PR1 signaling in the spinal cord produces hypersensitivity through IL1-β and ADK activation.
References
Andrews NA, Latremoliere A, Basbaum AI, Mogil JS, Porreca F, Rice ASC, Woolf CJ, Currie GL, Dworkin RH, Eisenach JC, Evans S, Gewandter JS, Gover TD, Handwerker H, Huang W, Iyengar S, Jensen MP, Kennedy JD, Lee N, Levine J, Lidster K, Machin I, McDermott MP, McMahon SB, Price TJ, Ross SE, Scherrer G, Seal RP, Sena ES, Silva E, Stone L, Svensson CI, Turk DC, Whiteside G (2016) Ensuring transparency and minimization of methodologic bias in preclinical pain research: PPRECISE considerations. Pain 157(4):901–909. https://doi.org/10.1097/j.pain.0000000000000458
Aronica E, Zurolo E, Iyer A, de Groot M, Anink J, Carbonell C, van Vliet EA, Baayen JC, Boison D, Gorter JA (2011) Upregulation of adenosine kinase in astrocytes in experimental and human temporal lobe epilepsy. Epilepsia 52(9):1645–1655. https://doi.org/10.1111/j.1528-1167.2011.03115.x
Aronica E, Sandau US, Iyer A, Boison D (2013) Glial adenosine kinase—a neuropathological marker of the epileptic brain. Neurochem Int 63(7):688–695. https://doi.org/10.1016/j.neuint.2013.01.028
Bennett GJ, Xie YK (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33(1):87–107
Bigaud M, Guerini D, Billich A, Bassilana F, Brinkmann V (2014) Second generation S1P pathway modulators: research strategies and clinical developments. Biochim Biophys Acta 1841(5):745–758. https://doi.org/10.1016/j.bbalip.2013.11.001
Boison D (2013) Adenosine kinase: exploitation for therapeutic gain. Pharmacol Rev 65(3):906–943. https://doi.org/10.1124/pr.112.006361
Boison D, Chen JF, Fredholm BB (2010) Adenosine signaling and function in glial cells. Cell Death Differ 17(7):1071–1082. https://doi.org/10.1038/cdd.2009.131
Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, Aradhye S, Burtin P (2010) Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 9(11):883–897. https://doi.org/10.1038/nrd3248
Byers SL, Wiles MV, Dunn SL, Taft RA (2012) Mouse estrous cycle identification tool and images. PLoS ONE 7(4):e35538. https://doi.org/10.1371/journal.pone.0035538
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63
Chen Z, Doyle TM, Luongo L, Largent-Milnes TM, Giancotti LA, Kolar G, Squillace S, Boccella S, Walker JK, Pendleton A, Spiegel S, Neumann WL, Vanderah TW, Salvemini D (2019) Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1820466116
Chua KC, Xiong C, Ho C, Mushiroda T, Jiang C, Mulkey F, Lai D, Schneider BP, Rashkin SR, Witte JS, Friedman PN, Ratain MJ, McLeod HL, Rugo HS, Shulman LN, Kubo M, Owzar K, Kroetz DL (2020) Genomewide meta-analysis validates a role for S1PR1 in microtubule targeting agent-induced sensory peripheral neuropathy. Clin Pharmacol Ther 108(3):625–634. https://doi.org/10.1002/cpt.1958
Dahlhamer J, Lucas J, Zelaya C, Nahin R, Mackey S, DeBar L, Kerns R, Von Korff M, Porter L, Helmick C (2018) Prevalence of chronic pain and high-impact chronic pain among adults—United States. Morb Mortal Wkly Rep 67(36):1001–1006. https://doi.org/10.15585/mmwr.mm6736a2
Davis BK, Wen H, Ting JP (2011) The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol 29:707–735. https://doi.org/10.1146/annurev-immunol-031210-101405
Dixon WJ (1980) Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol 20:441–462. https://doi.org/10.1146/annurev.pa.20.040180.002301
Doolen S, Iannitti T, Donahue RR, Shaw BC, Grachen CM, Taylor BK (2018) Fingolimod reduces neuropathic pain behaviors in a mouse model of multiple sclerosis by a sphingosine-1 phosphate receptor 1-dependent inhibition of central sensitization in the dorsal horn. Pain 159(2):224–238. https://doi.org/10.1097/j.pain.0000000000001106
Doyle TM, Chen Z, Durante M, Salvemini D (2019) Activation of sphingosine-1-phosphate receptor 1 in the spinal cord produces mechanohypersensitivity through the activation of inflammasome and IL-1beta pathway. J Pain 20(8):956–964. https://doi.org/10.1016/j.jpain.2019.02.007
Doyle TM, Janes K, Chen Z, Grace PM, Esposito E, Cuzzocrea S, Largent-Milnes TM, Neumann WL, Watkins LR, Spiegel S, Vanderah TW, Salvemini D (2020a) Activation of sphingosine-1-phosphate receptor subtype 1 in the central nervous system contributes to morphine-induced hyperalgesia and antinociceptive tolerance in rodents. Pain. https://doi.org/10.1097/j.pain.0000000000001888
Doyle TM, Largent-Milnes TM, Chen Z, Staikopoulos V, Esposito E, Dalgarno R, Fan C, Tosh DK, Cuzzocrea S, Jacobson KA, Trang T, Hutchinson MR, Bennett GJ, Vanderah TW, Salvemini D (2020b) Chronic morphine-induced changes in signaling at the A3 adenosine receptor contribute to morphine-induced hyperalgesia, tolerance, and withdrawal. J Pharmacol Exp Ther 374(2):331–341. https://doi.org/10.1124/jpet.120.000004
Franchi L, Eigenbrod T, Munoz-Planillo R, Nunez G (2009) The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 10(3):241–247. https://doi.org/10.1038/ni.1703
Fujii Y, Hirayama T, Ohtake H, Ono N, Inoue T, Sakurai T, Takayama T, Matsumoto K, Tsukahara N, Hidano S, Harima N, Nakazawa K, Igarashi Y, Goitsuka R (2012a) Amelioration of collagen-induced arthritis by a novel S1P1 antagonist with immunomodulatory activities. J Immunol 188(1):206–215. https://doi.org/10.4049/jimmunol.1101537
Fujii Y, Ueda Y, Ohtake H, Ono N, Takayama T, Nakazawa K, Igarashi Y, Goitsuka R (2012b) Blocking S1P interaction with S1P(1) receptor by a novel competitive S1P(1)-selective antagonist inhibits angiogenesis. Biochem Biophys Res Commun 419(4):754–760. https://doi.org/10.1016/j.bbrc.2012.02.096
Grenald SA, Doyle TM, Zhang H, Slosky LM, Chen Z, Largent-Milnes TM, Spiegel S, Vanderah TW, Salvemini D (2017) Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation. Pain 158(9):1733–1742. https://doi.org/10.1097/j.pain.0000000000000965
Healy LM, Antel JP (2016) Sphingosine-1-Phosphate Receptors in the Central Nervous and Immune Systems. Curr Drug Targets 17(16):1841–1850. https://doi.org/10.2174/1389450116666151001112710
Hylden JL, Wilcox GL (1980) Intrathecal morphine in mice: a new technique. Eur J Pharmacol 67(2–3):313–316. https://doi.org/10.1016/0014-2999(80)90515-4
Jacobson KA, Giancotti LA, Lauro F, Mufti F, Salvemini D (2020) Treatment of chronic neuropathic pain: purine receptor modulation. Pain. https://doi.org/10.1097/j.pain.0000000000001857
Janes K, Little JW, Li C, Bryant L, Chen C, Chen Z, Kamocki K, Doyle T, Snider A, Esposito E, Cuzzocrea S, Bieberich E, Obeid L, Petrache I, Nicol G, Neumann WL, Salvemini D (2014) The development and maintenance of paclitaxel-induced neuropathic pain require activation of the sphingosine 1-phosphate receptor subtype 1. J Biol Chem 289(30):21082–21097. https://doi.org/10.1074/jbc.M114.569574
Kim YK, Shin JS, Nahm MH (2016) NOD-like receptors in infection, immunity, and diseases. Yonsei Med J 57(1):5–14. https://doi.org/10.3349/ymj.2016.57.1.5
Kowaluk EA, Mikusa J, Wismer CT, Zhu CZ, Schweitzer E, Lynch JJ, Lee CH, Jiang M, Bhagwat SS, Gomtsyan A, McKie J, Cox BF, Polakowski J, Reinhart G, Williams M, Jarvis MF (2000) ABT-702 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin- 3-yl)pyrido[2,3-d]pyrimidine), a novel orally effective adenosine kinase inhibitor with analgesic and anti-inflammatory properties. II. In vivo characterization in the rat. J Pharmacol Exp Ther 295(3):1165–1174
Little JW, Ford A, Symons-Liguori AM, Chen Z, Janes K, Doyle T, Xie J, Luongo L, Tosh DK, Maione S, Bannister K, Dickenson AH, Vanderah TW, Porreca F, Jacobson KA, Salvemini D (2015) Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain 138(Pt 1):28–35. https://doi.org/10.1093/brain/awu330
Lopez-Castejon G, Brough D (2011) Understanding the mechanism of IL-1beta secretion. Cytokine Growth Factor Rev 22(4):189–195. https://doi.org/10.1016/j.cytogfr.2011.10.001
Muscoli C, Doyle T, Dagostino C, Bryant L, Chen Z, Watkins LR, Ryerse J, Bieberich E, Neumman W, Salvemini D (2010) Counter-regulation of opioid analgesia by glial-derived bioactive sphingolipids. J Neurosci 30(46):15400–15408. https://doi.org/10.1523/JNEUROSCI.2391-10.2010
Petucci C, Culver JA, Kapoor N, Sessions EH, Divlianska D, Gardell SJ (2019) Measurement of pyridine nucleotides in biological samples using LC-MS/MS. In: Bhattacharya SK (ed) Metabolomics, methods and protocols. Springer, New York, pp 61–73. https://doi.org/10.1007/978-1-4939-9488-5
Ren K, Torres R (2009) Role of interleukin-1beta during pain and inflammation. Brain Res Rev 60(1):57–64. https://doi.org/10.1016/j.brainresrev.2008.12.020
Rossi S, Motta C, Studer V, Macchiarulo G, Volpe E, Barbieri F, Ruocco G, Buttari F, Finardi A, Mancino R, Weiss S, Battistini L, Martino G, Furlan R, Drulovic J, Centonze D (2014) Interleukin-1beta causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53. Mol Neurodegener 9:56. https://doi.org/10.1186/1750-1326-9-56
Sanna MG, Liao J, Jo E, Alfonso C, Ahn MY, Peterson MS, Webb B, Lefebvre S, Chun J, Gray N, Rosen H (2004) Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem 279(14):13839–13848. https://doi.org/10.1074/jbc.M311743200
Squillace S, Spiegel S, Salvemini D (2020) Targeting the sphingosine-1-phosphate axis for developing non-narcotic pain therapeutics. Trends Pharmacol Sci 41(11):851–867. https://doi.org/10.1016/j.tips.2020.09.006
Stockstill K, Doyle TM, Yan X, Chen Z, Janes K, Little JW, Braden K, Lauro F, Giancotti LA, Harada CM, Yadav R, Xiao WH, Lionberger JM, Neumann WL, Bennett GJ, Weng HR, Spiegel S, Salvemini D (2018) Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain. J Exp Med 215(5):1301–1313. https://doi.org/10.1084/jem.20170584
Stockstill K, Wahlman C, Braden K, Chen Z, Yosten GL, Tosh DK, Jacobson KA, Doyle TM, Samson WK, Salvemini D (2020) Sexually dimorphic therapeutic response in bortezomib-induced neuropathic pain reveals altered pain physiology in female rodents. Pain 161(1):177–184. https://doi.org/10.1097/j.pain.0000000000001697
Tsuchiya K, Hara H (2014) The inflammasome and its regulation. Crit Rev Immunol 34(1):41–80. https://doi.org/10.1615/critrevimmunol.2013008686
Van Doorn R, Van Horssen J, Verzijl D, Witte M, Ronken E, Van Het Hof B, Lakeman K, Dijkstra CD, Van Der Valk P, Reijerkerk A, Alewijnse AE, Peters SL, De Vries HE (2010) Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia 58(12):1465–1476. https://doi.org/10.1002/glia.21021
Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di Luca M, Galli CL, Marinovich M (2003) Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 23(25):8692–8700
Voet S, Srinivasan S, Lamkanfi M, van Loo G (2019) Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Mol Med 11(6):e10248. https://doi.org/10.15252/emmm.201810248
Wahlman C, Doyle TM, Little JW, Luongo L, Janes K, Chen Z, Esposito E, Tosh DK, Cuzzocrea S, Jacobson KA, Salvemini D (2018) Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms. Pain 159(6):1025–1034. https://doi.org/10.1097/j.pain.0000000000001177
Walsh JG, Muruve DA, Power C (2014) Inflammasomes in the CNS. Nat Rev Neurosci 15(2):84–97. https://doi.org/10.1038/nrn3638
Acknowledgements
The authors thank Dr. Zhoumou Chen (Saint Louis University, St. Louis, Missouri, USA) for his technical support during the experiments and Dr. Joel Eissenberg (Saint Louis University, St. Louis, Missouri, USA) for editing the manuscript.
Funding
This research was supported by Saint Louis University Start Up Fund (DS), NIH/NIDA grant R01DA043543 (DS) and Training Grant T32GM008306-28 (CMH).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
DS has patents submitted by Saint Louis University that cover some of the intellectual property described in this manuscript (U.S. patent number 8,747,844 and its divisional, U.S. patent number 8,945,549). All other authors declare no competing financial interests.
Ethical Approval
All animal experiments were conducted in accordance with the National Institutes of Health, the International Association for the Study of Pain guidelines for laboratory animal welfare, and the Saint Louis University Institutional Animal Care and Use Committee.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Lauro, F., Giancotti, L.A., Kolar, G. et al. Role of Adenosine Kinase in Sphingosine-1-Phosphate Receptor 1-Induced Mechano-Hypersensitivities. Cell Mol Neurobiol 42, 2909–2918 (2022). https://doi.org/10.1007/s10571-021-01162-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-021-01162-8