Advertisement

Activation of protease-activated receptor-1 causes chronic pain in lupus-prone mice via suppressing spinal glial glutamate transporter function and enhancing glutamatergic synaptic activity

Published:January 11, 2023DOI:https://doi.org/10.1016/j.jpain.2023.01.003

      Highlights

      • Spinal PAR1 plays an important role in the genesis of chronic pain in MRL/lpr mice.
      • Activation of PAR1 and suppression of AMPK activity in MRL/lpr mice with chronic pain.
      • Blockade of PAR1 or AMPK activation attenuated chronic pain in MRL/lpr mice.
      • Targeting the PAR1 and AMPK pathways may be a potent approach for treating chronic pain caused by SLE.

      Abstract

      Systemic lupus erythematosus (SLE) is an unpredictable autoimmune disease where the body's immune system mistakenly attacks healthy tissues in many parts of the body. Chronic pain is one of the most frequently reported symptoms among SLE patients. We previously reported that MRL lupus prone (MRL/lpr) mice develop hypersensitivity to mechanical and heat stimulation. In the present study, we found that the spinal protease-activated receptor-1(PAR1) plays an important role in the genesis of chronic pain in MRL/lpr mice. Female MRL/lpr mice with chronic pain had activation of astrocytes, over-expression of thrombin and PAR1, enhanced glutamatergic synaptic activity, as well as suppressed activity of adenosine monophosphate-activated protein kinase (AMPK) and glial glutamate transport function in the spinal cord. Intrathecal injection of either the PAR1 antagonist, or AMPK activator attenuated heat hyperalgesia and mechanical allodynia in MRL/lpr mice. Furthermore, we also identified that the enhanced glutamatergic synaptic activity and suppressed activity of glial glutamate transporters in the spinal dorsal horn of MRL/lpr mice are caused by activation of the PAR1 and suppression of AMPK signaling pathways. These findings suggest that targeting the PAR1and AMPK signaling pathways in the spinal cord may be a useful approach for treating chronic pain caused by SLE.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      Reference

        • Adolph O
        • Koster S
        • Rath M
        • Georgieff M
        • Weigt HU
        • Engele J
        • Senftleben U
        • Fohr KJ.
        Rapid increase of glial glutamate uptake via blockade of the protein kinase A pathway.
        Glia. 2007; 55: 1699-1707
        • Akeson AL
        • Woods CW
        • Hsieh LC
        • Bohnke RA
        • Ackermann BL
        • Chan KY
        • Robinson JL
        • Yanofsky SD
        • Jacobs JW
        • Barrett RW
        • Bowlin TL.
        AF12198, a novel low molecular weight antagonist, selectively binds the human type I interleukin (IL)-1 receptor and blocks in vivo responses to IL-1.
        J Biol Chem. 1996; 271: 30517-30523
        • Andrews N
        • Harper S
        • Issop Y
        • Rice AS.
        Novel, nonreflex tests detect analgesic action in rodents at clinically relevant concentrations.
        Ann N Y Acad Sci. 2011; 1245: 11-13
        • Bergles DE
        • Jahr CE.
        Synaptic activation of glutamate transporters in hippocampal astrocytes.
        Neuron. 1997; 19: 1297-1308
        • Binns BC
        • Huang Y
        • Goettl VM
        • Hackshaw KV
        • Stephens Jr., RL
        Glutamate uptake is attenuated in spinal deep dorsal and ventral horn in the rat spinal nerve ligation model.
        Brain Res. 2005; 1041: 38-47
        • Boven LA
        • Vergnolle N
        • Henry SD
        • Silva C
        • Imai Y
        • Holden J
        • Warren K
        • Hollenberg MD
        • Power C.
        Up-regulation of proteinase-activated receptor 1 expression in astrocytes during HIV encephalitis.
        J Immunol. 2003; 170: 2638-2646
        • Brusco I
        • Justino AB
        • Silva CR
        • Fischer S
        • Cunha TM
        • Scussel R
        • Machado-de-Avila RA
        • Ferreira J
        • Oliveira SM.
        Kinins and their B(1) and B(2) receptors are involved in fibromyalgia-like pain symptoms in mice.
        Biochem Pharmacol. 2019; 168: 119-132
        • Charan J
        • Kantharia ND.
        How to calculate sample size in animal studies?.
        J Pharmacol Pharmacother. 2013; 4: 303-306
        • Chen N
        • Sugihara H
        • Sharma J
        • Perea G
        • Petravicz J
        • Le C
        • Sur M.
        Nucleus basalis-enabled stimulus-specific plasticity in the visual cortex is mediated by astrocytes.
        Proc Natl Acad Sci U S A. 2012; 109: E2832-E2841
        • Choi MS
        • Kim YE
        • Lee WJ
        • Choi JW
        • Park GH
        • Kim SD
        • Jeon SJ
        • Go HS
        • Shin SM
        • Kim WK
        • Shin CY
        • Ko KH.
        Activation of protease-activated receptor1 mediates induction of matrix metalloproteinase-9 by thrombin in rat primary astrocytes.
        Brain Res Bull. 2008; 76: 368-375
        • Coughlin SR.
        Thrombin signalling and protease-activated receptors.
        Nature. 2000; 407: 258-264
        • uptake Danbolt NC.Glutamate
        Prog Neurobiol. 2001; 65: 1-105
        • Deacon RM.
        Burrowing in rodents: a sensitive method for detecting behavioral dysfunction.
        Nat Protoc. 2006; 1: 118-121
        • Donovan FM
        • Pike CJ
        • Cotman CW
        • Cunningham DD.
        Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities.
        J Neurosci. 1997; 17: 5316-5326
        • Dugina TN
        • Kiseleva EV
        • Lange MA
        • Vasil'eva TV
        • Grandfils C
        • Markvicheva EA
        • Bespalova Zh D
        • Pal'keeva ME
        • Strukova SM
        Effect of synthetic peptide thrombin receptor agonist encapsulated in microparticles based on lactic and glycolic acid copolymer on healing of experimental skin wounds in mice.
        Bull Exp Biol Med. 2004; 138: 463-466
        • Fan Y
        • Zhang W
        • Mulholland M.
        Thrombin and PAR-1-AP increase proinflammatory cytokine expression in C6 cells.
        J Surg Res. 2005; 129: 196-201
        • Fang H
        • Huang Y
        • Zuo Z.
        The different responses of rat glutamate transporter type 2 and its mutant (tyrosine 403 to histidine) activity to volatile anesthetics and activation of protein kinase C.
        Brain Res. 2002; 953: 255-264
        • Greco CM
        • Rudy TE
        • Manzi S.
        Adaptation to chronic pain in systemic lupus erythematosus: applicability of the multidimensional pain inventory.
        Pain Med. 2003; 4: 39-50
        • Greco CM
        • Rudy TE
        • Manzi S.
        Effects of disease activity, pain, and distress on activity limitations in patients with systemic lupus erythematosus.
        J Rheumatol. 2004; 31: 260-267
        • Hargreaves K
        • Dubner R
        • Brown F
        • Flores C
        • Joris J.
        A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.
        Pain. 1988; 32: 77-88
        • Hylden JL
        • Wilcox GL.
        Intrathecal morphine in mice: a new technique.
        Eur J Pharmacol. 1980; 67: 313-316
        • Jacques SL
        • LeMasurier M
        • Sheridan PJ
        • Seeley SK
        • Kuliopulos A.
        Substrate-assisted catalysis of the PAR1 thrombin receptor. Enhancement of macromolecular association and cleavage.
        J Biol Chem. 2000; 275: 40671-40678
        • Ji RR
        • Berta T
        • Nedergaard M.
        Glia and pain: is chronic pain a gliopathy?.
        Pain. 2013; 1: S10-S28
        • Junge CE
        • Lee CJ
        • Hubbard KB
        • Zhang Z
        • Olson JJ
        • Hepler JR
        • Brat DJ
        • Traynelis SF.
        Protease-activated receptor-1 in human brain: localization and functional expression in astrocytes.
        Exp Neurol. 2004; 188: 94-103
        • Kim HN
        • Kim YR
        • Jang JY
        • Shin HK
        • Choi BT.
        Electroacupuncture Confers Antinociceptive Effects via Inhibition of Glutamate Transporter Downregulation in Complete Freund's Adjuvant-Injected Rats.
        Evid Based Complement Alternat Med. 2012; 2012643973
        • Kumazawa T
        • Perl ER.
        Primate cutaneous receptors with unmyelinated (C) fibres and their projection to the substantia gelatinosa.
        J Physiol (Paris). 1977; 73: 287-304
        • Levy LM
        • Warr O
        • Attwell D.
        Stoichiometry of the glial glutamate transporter GLT-1 expressed inducibly in a Chinese hamster ovary cell line selected for low endogenous Na+-dependent glutamate uptake.
        J Neurosci. 1998; 18: 9620-9628
        • Lissin DV
        • Carroll RC
        • Nicoll RA
        • Malenka RC
        • von Zastrow M.
        Rapid, activation-induced redistribution of ionotropic glutamate receptors in cultured hippocampal neurons.
        J Neurosci. 1999; 19: 1263-1272
        • Liu XJ
        • Gingrich JR
        • Vargas-Caballero M
        • Dong YN
        • Sengar A
        • Beggs S
        • Wang SH
        • Ding HK
        • Frankland PW
        • Salter MW.
        Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex.
        Nat Med. 2008; 14: 1325-1332
        • Liu Y
        • Li J
        • Li H
        • Shang Y
        • Guo Y
        • Li Z
        • Liu Z.
        AMP-Activated Protein Kinase Activation in Dorsal Root Ganglion Suppresses mTOR/p70S6K Signaling and Alleviates Painful Radiculopathies in Lumbar Disc Herniation Rat Model.
        Spine (Phila Pa 1976). 2019; 44: E865-E872
        • Luo W
        • Wang Y
        • Reiser G.
        Protease-activated receptors in the brain: receptor expression, activation, and functions in neurodegeneration and neuroprotection.
        Brain Res Rev. 2007; 56: 331-345
        • Macfarlane SR
        • Seatter MJ
        • Kanke T
        • Hunter GD
        • Plevin R.
        Proteinase-activated receptors.
        Pharmacol Rev. 2001; 53: 245-282
        • Maixner DW
        • Yan X
        • Gao M
        • Yadav R
        • Weng HR.
        Adenosine Monophosphate-activated Protein Kinase Regulates Interleukin-1beta Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain.
        Anesthesiology. 2015; 122: 1401-1413
        • Mao J
        • Sung B
        • Ji RR
        • Lim G.
        Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity.
        J Neurosci. 2002; 22: 8312-8323
        • Martorell L
        • Martinez-Gonzalez J
        • Rodriguez C
        • Gentile M
        • Calvayrac O
        • Badimon L.
        Thrombin and protease-activated receptors (PARs) in atherothrombosis.
        Thromb Haemost. 2008; 99: 305-315
        • Narita M
        • Usui A
        • Narita M
        • Niikura K
        • Nozaki H
        • Khotib J
        • Nagumo Y
        • Yajima Y
        • Suzuki T.
        Protease-activated receptor-1 and platelet-derived growth factor in spinal cord neurons are implicated in neuropathic pain after nerve injury.
        J Neurosci. 2005; 25: 10000-10009
        • Nicole O
        • Goldshmidt A
        • Hamill CE
        • Sorensen SD
        • Sastre A
        • Lyuboslavsky P
        • Hepler JR
        • McKeon RJ
        • Traynelis SF.
        Activation of protease-activated receptor-1 triggers astrogliosis after brain injury.
        J Neurosci. 2005; 25: 4319-4329
        • Nie H
        • Weng HR.
        Glutamate transporters prevent excessive activation of NMDA receptors and extrasynaptic glutamate spillover in the spinal dorsal horn.
        J Neurophysiol. 2009; 101: 2041-2051
        • Nie H
        • Weng HR.
        Impaired glial glutamate uptake induces extrasynaptic glutamate spillover in the spinal sensory synapses of neuropathic rats.
        J Neurophysiol. 2010; 103: 2570-2580
        • Patwardhan AM
        • Diogenes A
        • Berg KA
        • Fehrenbacher JC
        • Clarke WP
        • Akopian AN
        • Hargreaves KM.
        PAR-2 agonists activate trigeminal nociceptors and induce functional competence in the delta opioid receptor.
        Pain. 2006; 125: 114-124
        • Poduslo JF
        • Curran GL
        • Berg CT.
        Macromolecular permeability across the blood-nerve and blood-brain barriers.
        Proc Natl Acad Sci U S A. 1994; 91: 5705-5709
        • Pompili E
        • Fabrizi C
        • Nori SL
        • Panetta B
        • Geloso MC
        • Corvino V
        • Michetti F
        • Fumagalli L.
        Protease-activated receptor-1 expression in rat microglia after trimethyltin treatment.
        J Histochem Cytochem. 2011; 59: 302-311
        • Radulovic M
        • Yoon H
        • Wu J
        • Mustafa K
        • Scarisbrick IA.
        Targeting the thrombin receptor modulates inflammation and astrogliosis to improve recovery after spinal cord injury.
        Neurobiol Dis. 2016; 93: 226-242
        • Ren K
        • Dubner R.
        Interactions between the immune and nervous systems in pain.
        Nat Med. 2010; 16: 1267-1276
        • Rothstein JD
        • Dykes-Hoberg M
        • Pardo CA
        • Bristol LA
        • Jin L
        • Kuncl RW
        • Kanai Y
        • Hediger MA
        • Wang Y
        • Schielke JP
        • Welty DF
        Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate.
        Neuron. 1996; 16: 675-686
        • Salter MW
        • Pitcher GM.
        Dysregulated Src upregulation of NMDA receptor activity: a common link in chronic pain and schizophrenia.
        FEBS J. 2012; 279: 2-11
        • Shavit E
        • Michaelson DM
        • Chapman J.
        Anatomical localization of protease-activated receptor-1 and protease-mediated neuroglial crosstalk on peri-synaptic astrocytic endfeet.
        J Neurochem. 2011; 119: 460-473
        • Simmons S
        • Lee RV
        • Moller T
        • Weinstein JR.
        Thrombin induces release of proinflammatory chemokines interleukin-8 and interferon-gamma-induced protein-10 from cultured human fetal astrocytes.
        Neuroreport. 2013; 24: 36-40
        • Smith JR
        • Winkelstein BA.
        The role of spinal thrombin through protease-activated receptor 1 in hyperalgesia after neural injury.
        J Neurosurg Spine. 2017; 26: 532-541
        • Stassen JM
        • Arnout J
        • Deckmyn H.
        The hemostatic system.
        Curr Med Chem. 2004; 11: 2245-2260
        • Sung B
        • Lim G
        • Mao J.
        Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats.
        J Neurosci. 2003; 23: 2899-2910
        • Suo Z
        • Citron BA
        • Festoff BW.
        Thrombin: a potential proinflammatory mediator in neurotrauma and neurodegenerative disorders.
        Curr Drug Targets Inflamm Allergy. 2004; 3: 105-114
        • Tanaka K
        • Watase K
        • Manabe T
        • Yamada K
        • Watanabe M
        • Takahashi K
        • Iwama H
        • Nishikawa T
        • Ichihara N
        • Kikuchi T
        • Okuyama S
        • Kawashima N
        • Hori S
        • Takimoto M
        • Wada K.
        Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1.
        Science. 1997; 276: 1699-1702
        • Taoka Y
        • Okajima K
        • Uchiba M.
        Antithrombin reduces compression-induced spinal cord injury in rats.
        J Neurotrauma. 2004; 21: 1818-1830
        • Tawfik VL
        • Regan MR
        • Haenggeli C
        • Lacroix-Fralish ML
        • Nutile-McMenemy N
        • Perez N
        • Rothstein JD
        • DeLeo JA.
        Propentofylline-induced astrocyte modulation leads to alterations in glial glutamate promoter activation following spinal nerve transection.
        Neuroscience. 2008; 152: 1086-1092
        • Tegeder I
        • Adolph J
        • Schmidt H
        • Woolf CJ
        • Geisslinger G
        • Lotsch J.
        Reduced hyperalgesia in homozygous carriers of a GTP cyclohydrolase 1 haplotype.
        Eur J Pain. 2008; 12: 1069-1077
        • Theofilopoulos AN
        • Dixon FJ.
        Murine models of systemic lupus erythematosus.
        Adv Immunol. 1985; 37: 269-390
        • Traynelis SF
        • Trejo J.
        Protease-activated receptor signaling: new roles and regulatory mechanisms.
        Curr Opin Hematol. 2007; 14: 230-235
        • Vellani V
        • Kinsey AM
        • Prandini M
        • Hechtfischer SC
        • Reeh P
        • Magherini PC
        • Giacomoni C
        • McNaughton PA.
        Protease activated receptors 1 and 4 sensitize TRPV1 in nociceptive neurones.
        Mol Pain. 2010; 6: 61
        • Viatchenko-Karpinski V
        • Kong L
        • Weng HR.
        Activation of microglial GPR109A alleviates thermal hyperalgesia in female lupus mice by suppressing IL-18 and glutamatergic synaptic activity.
        Glia. 2022; 70: 634-649
        • Wadiche JI
        • Arriza JL
        • Amara SG
        • Kavanaugh MP.
        Kinetics of a human glutamate transporter.
        Neuron. 1995; 14: 1019-1027
        • Wang H
        • Ubl JJ
        • Reiser G.
        Four subtypes of protease-activated receptors, co-expressed in rat astrocytes, evoke different physiological signaling.
        Glia. 2002; 37: 53-63
        • Wang S
        • Dai Y.
        Roles of AMPK and Its Downstream Signals in Pain Regulation.
        Life (Basel). 2021; 11: 836
        • Wang S
        • Lim G
        • Yang L
        • Sung B
        • Mao J.
        Downregulation of spinal glutamate transporter EAAC1 following nerve injury is regulated by central glucocorticoid receptors in rats.
        Pain. 2006; 120: 78-85
        • Ward MM.
        Prevalence of physician-diagnosed systemic lupus erythematosus in the United States: results from the third national health and nutrition examination survey.
        J Womens Health (Larchmt). 2004; 13: 713-718
        • Weng HR
        • Aravindan N
        • Cata JP
        • Chen JH
        • Shaw AD
        • Dougherty PM.
        Spinal glial glutamate transporters downregulate in rats with taxol-induced hyperalgesia.
        Neurosci Lett. 2005; 386: 18-22
        • Weng HR
        • Chen JH
        • Cata JP.
        Inhibition of glutamate uptake in the spinal cord induces hyperalgesia and increased responses of spinal dorsal horn neurons to peripheral afferent stimulation.
        Neuroscience. 2006; 138: 1351-1360
        • Weng HR
        • Chen JH
        • Pan ZZ
        • Nie H.
        Glial glutamate transporter 1 regulates the spatial and temporal coding of glutamatergic synaptic transmission in spinal lamina II neurons.
        Neuroscience. 2007; 149: 898-907
        • Xu JJ
        • Walla BC
        • Diaz MF
        • Fuller GN
        • Gutstein HB.
        Intermittent lumbar puncture in rats: a novel method for the experimental study of opioid tolerance.
        Anesth Analg. 2006; 103: 714-720
        • Yan X
        • Jiang E
        • Gao M
        • Weng HR.
        Endogenous activation of presynaptic NMDA receptors enhances glutamate release from the primary afferents in the spinal dorsal horn in a rat model of neuropathic pain.
        J Physiol. 2013; 591: 2001-2019
        • Yan X
        • Maixner DW
        • Li F
        • Weng HR.
        Chronic pain and impaired glial glutamate transporter function in lupus-prone mice are ameliorated by blocking macrophage colony-stimulating factor-1 receptors.
        J Neurochem. 2017; 140: 963-976
        • Yan X
        • Maixner DW
        • Yadav R
        • Gao M
        • Li P
        • Bartlett MG
        • Weng H-R.
        Paclitaxel induces acute pain via directly activating toll like receptor 4.
        Molecular Pain. 2015; 11: 10
        • Yan X
        • Weng HR.
        Endogenous interleukin-1beta in neuropathic rats enhances glutamate release from the primary afferents in the spinal dorsal horn through coupling with presynaptic N-methyl-D-aspartic acid receptors.
        J Biol Chem. 2013; 288: 30544-30557
        • Yan X
        • Yadav R
        • Gao M
        • Weng HR.
        Interleukin-1 beta enhances endocytosis of glial glutamate transporters in the spinal dorsal horn through activating protein kinase C.
        Glia. 2014; 62: 1093-1109
        • Yang T
        • Jiang H
        • Luo X
        • Hou Y
        • Li A
        • He B
        • Zhang X
        • Hao H
        • Song H
        • Cai R
        • Wang X
        • Wang Y
        • Yao C
        • Qi L
        • Wang Y.
        Thrombin acts as inducer of proinflammatory macrophage migration inhibitory factor in astrocytes following rat spinal cord injury.
        J Neuroinflammation. 2022; 19: 120
        • Ye G
        • Lin C
        • Zhang Y
        • Ma Z
        • Chen Y
        • Kong L
        • Yuan L
        • Ma T.
        Quercetin Alleviates Neuropathic Pain in the Rat CCI Model by Mediating AMPK/MAPK Pathway.
        J Pain Res. 2021; 14: 1289-1301
        • Yin X
        • Jing Y
        • Chen Q
        • Abbas AB
        • Hu J
        • Xu H.
        The intraperitoneal administration of MOTS-c produces antinociceptive and anti-inflammatory effects through the activation of AMPK pathway in the mouse formalin test.
        Eur J Pharmacol. 2020; 870172909
        • Zhang H
        • Xin W
        • Dougherty PM.
        Synaptically evoked glutamate transporter currents in Spinal Dorsal Horn Astrocytes.
        Mol Pain. 2009; 5: 36
        • Zheng T
        • Wang Q
        • Bian F
        • Zhao Y
        • Ma W
        • Zhang Y
        • Lu W
        • Lei P
        • Zhang L
        • Hao X
        • Chen L.
        Salidroside alleviates diabetic neuropathic pain through regulation of the AMPK-NLRP3 inflammasome axis.
        Toxicol Appl Pharmacol. 2021; 416115468