Descending controls modulate inflammatory joint pain and regulate CXC chemokine and iNOS expression in the dorsal horn

Molecular Pain

Stephen P Hunt¹  Sandrine M Géranton¹  Fiona B Carr¹ 

[1] Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK

关键词: CXCR3;    iNOS;    CXCL10;    CXCL9;    Mu opioid receptor;    5-HT;    Joint pain;    RVM;   

Others  :  861371
DOI  :  10.1186/1744-8069-10-39

 received in 2014-02-15, accepted in 2014-06-09,  发布年份 2014

【 摘 要 】

Background

Descending control of nociceptive processing, by pathways originating in the rostral ventromedial medulla (RVM) and terminating in the dorsal horn, contributes to behavioural hypersensitivity in a number of pain models. Two facilitatory pathways have been identified and are characterized by serotonin (5-HT) content or expression of the mu opiate receptor. Here we investigated the contribution of these pathways to inflammatory joint pain behaviour and gene expression changes in the dorsal horn.

Results

Selective lesion of the descending serotonergic (5-HT) pathway by prior intrathecal administration of 5,7-dihydroxytryptamine attenuated hypersensitivity at early time points following ankle injection of CFA. In a separate study ablation of the mu opioid receptor expressing (MOR+) cells of the RVM, by microinjection of the toxin dermorphin-saporin, resulted in a more prolonged attenuation of hypersensitivity post CFA. Microarray analysis was carried out to identify changes in dorsal horn gene expression associated with descending facilitation by the MOR+ pathway at 7d post joint inflammation. This analysis led to the identification of a number of genes including the chemokines Cxcl9 and Cxcl10, their common receptor Cxcr3, and the proinflammatory gene Nos2 (inducible nitric oxide synthase, iNOS).

Conclusions

These findings demonstrate that joint pain behaviour is dependent in part on descending facilitation via the RVM, and identify a novel pathway driving CXC chemokine and iNOS expression in the dorsal horn.

【 授权许可】

   
2014 Carr et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D: Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. Eur J Pain 2006, 10:287-287.
• [2]Bennell KL, Hunter DJ, Hinman RS: Management of osteoarthritis of the knee. BMJ 2012, 345:e4934-e4934.
• [3]Lee DM, Weinblatt ME: Rheumatoid arthritis. Lancet 2001, 358:903-911.
• [4]Wolfe F, Michaud K: Assessment of pain in rheumatoid arthritis: minimal clinically significant difference, predictors, and the effect of anti-tumor necrosis factor therapy. J Rheumatol 2007, 34:1674-1683.
• [5]Bedson J, Croft PR: The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature. BMC Musculoskelet Disord 2008, 9:116.
• [6]Neugebauer V, Han JS, Adwanikar H, Fu Y, Ji G: Techniques for assessing knee joint pain in arthritis. Mol Pain 2007, 3:8.
• [7]Schaible HG, Schmidt RF: Time course of mechanosensitivity changes in articular afferents during a developing experimental arthritis. J Neurophysiol 1988, 60:2180-2195.
• [8]Grubb BD, Stiller RU, Schaible HG: Dynamic changes in the receptive field properties of spinal cord neurons with ankle input in rats with chronic unilateral inflammation in the ankle region. Exp Brain Res 1993, 92:441-452.
• [9]Obreja O, Biasio W, Andratsch M, Lips KS, Rathee PK, Ludwig A, Rose-John S, Kress M: Fast modulation of heat-activated ionic current by proinflammatory interleukin 6 in rat sensory neurons. Brain 2005, 128(Pt 7):1634-1641.
• [10]Brenn D, Richter F, Schaible H-G: Sensitization of unmyelinated sensory fibers of the joint nerve to mechanical stimuli by interleukin-6 in the rat: an inflammatory mechanism of joint pain. Arthritis Rheum 2007, 56:351-359.
• [11]Boettger MK, Hensellek S, Richter F, Gajda M, Stöckigt R, von Banchet GS, Bräuer R, Schaible H-G: Antinociceptive effects of tumor necrosis factor alpha neutralization in a rat model of antigen-induced arthritis: evidence of a neuronal target. Arthritis Rheum 2008, 58:2368-2378.
• [12]Inglis JJ, Notley CA, Essex D, Wilson AW, Feldmann M, Anand P, Williams R: Collagen-induced arthritis as a model of hyperalgesia: functional and cellular analysis of the analgesic actions of tumor necrosis factor blockade. Arthritis Rheum 2007, 56:4015-4023.
• [13]Fernihough J, Gentry C, Malcangio M, Fox A, Rediske J, Pellas T, Kidd B, Bevan S, Winter J: Pain related behaviour in two models of osteoarthritis in the rat knee. Pain 2004, 112:83-93.
• [14]Neugebauer V, Lücke T, Schaible HG: Differential effects of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists on the responses of rat spinal neurons with joint input. Neurosci Lett 1993, 155:29-32.
• [15]Schaible HG, Schmidt RF, Willis WD: Enhancement of the responses of ascending tract cells in the cat spinal cord by acute inflammation of the knee joint. Exp Brain Res 1987, 66:489-499.
• [16]Clark AK, Grist J, Al-Kashi A, Perretti M, Malcangio M: Spinal cathepsin S and fractalkine contribute to chronic pain in the collagen-induced arthritis model. Arthritis Rheumatism 2012, 64:2038-2047.
• [17]Sagar DR, Burston JJ, Hathway GJ, Woodhams SG, Pearson RG, Bennett AJ, Kendall DA, Scammell BE, Chapman V: The contribution of spinal glial cells to chronic pain behaviour in the monosodium iodoacetate model of osteoarthritic pain. Mol Pain 2011, 7:88.
• [18]Ossipov MH, Dussor GO, Porreca F: Central modulation of pain. J Clin Invest 2010, 120:3779-3787.
• [19]Heinricher MM, Morgan MM, Tortorici V, Fields HL: Disinhibition of off-cells and antinociception produced by an opioid action within the rostral ventromedial medulla. Neuroscience 1994, 63:279-288.
• [20]Marinelli S, Vaughan CW, Schnell SA, Wessendorf MW, Christie MJ: Rostral Ventromedial Medulla Neurons That Project to the Spinal Cord Express Multiple Opioid Receptor Phenotypes. J Neurosci 2002, 22:10847-10855.
• [21]Burgess SE, Gardell LR, Ossipov MH, Malan TP, Vanderah TW, Lai J, Porreca F: Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain. J Neurosci 2002, 22:5129-5136.
• [22]Bee LA, Dickenson AH: Descending facilitation from the brainstem determines behavioural and neuronal hypersensitivity following nerve injury and efficacy of pregabalin. Pain 2008, 140:209-223.
• [23]Zhang W, Gardell S, Zhang D, Xie JY, Agnes RS, Badghisi H, Hruby VJ, Rance N, Ossipov MH, Vanderah TW, Porreca F, Lai J: Neuropathic pain is maintained by brainstem neurons co-expressing opioid and cholecystokinin receptors. Brain 2009, 132(Pt 3):778-787.
• [24]Wei F, Dubner R, Zou S, Ren K, Bai G, Wei D, Guo W: Molecular depletion of descending serotonin unmasks its novel facilitatory role in the development of persistent pain. J Neurosci 2010, 30:8624-8636.
• [25]Géranton SM, Fratto V, Tochiki KK, Hunt SP: Descending serotonergic controls regulate inflammation-induced mechanical sensitivity and methyl-CpG-binding protein 2 phosphorylation in the rat superficial dorsal horn. Mol Pain 2008, 4:35.
• [26]Rahman W, Suzuki R, Webber M, Hunt SP, Dickenson AH: Depletion of endogenous spinal 5-HT attenuates the behavioural hypersensitivity to mechanical and cooling stimuli induced by spinal nerve ligation. Pain 2006, 123:264-274.
• [27]Reynolds J, Bilsky EJ, Meng ID: Selective ablation of mu-opioid receptor expressing neurons in the rostral ventromedial medulla attenuates stress-induced mechanical hypersensitivity. Life Sci 2011, 89:313-319.
• [28]Géranton SM, Morenilla-Palao C, Hunt SP: A role for transcriptional repressor methyl-CpG-binding protein 2 and plasticity-related gene serum- and glucocorticoid-inducible kinase 1 in the induction of inflammatory pain states. J Neurosci 2007, 27:6163-6173.
• [29]Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G: Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 2000, 25:25-29.
• [30]Huang DW, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009, 4:44-57.
• [31]MacMicking J, Xie Q, Nathan C: Nitric Oxide and Macrophage Function. Annu Rev Immunol 1997, 15:323-350.
• [32]Gühring H, Görig M, Ates M, Coste O, Zeilhofer HU, Pahl A, Rehse K, Brune K: Suppressed injury-induced rise in spinal prostaglandin E2 production and reduced early thermal hyperalgesia in iNOS-deficient mice. J Neurosci 2000, 20:6714-6720.
• [33]Infante C, Díaz M, Hernández A, Constandil L, Pelissier T: Expression of nitric oxide synthase isoforms in the dorsal horn of monoarthritic rats: effects of competitive and uncompetitive N-methyl-D-aspartate antagonists. Arthritis Res Ther 2007, 9:R53.
• [34]Kuboyama K, Tsuda M, Tsutsui M, Toyohara Y, Tozaki-Saitoh H, Shimokawa H, Yanagihara N, Inoue K: Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases. Mol Pain 2011, 7:50.
• [35]Tang Q, Svensson CI, Fitzsimmons B, Webb M, Yaksh TL, Hua X-Y: Inhibition of spinal constitutive NOS-2 by 1400 W attenuates tissue injury and inflammation-induced hyperalgesia and spinal p38 activation. Eur J Neurosci 2007, 25:2964-2972.
• [36]Müller M, Carter S, Hofer MJ, Campbell IL: Review: The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity – a tale of conflict and conundrum. Neuropathol Appl Neurobiol 2010, 36:368-387.
• [37]Steain M, Gowrishankar K, Rodriguez M, Slobedman B, Abendroth A: Upregulation of CXCL10 in human dorsal root ganglia during experimental and natural varicella-zoster virus infection. J Virol 2011, 85:626-631.
• [38]Strong JA, Xie W, Coyle DE, Zhang J-M: Microarray analysis of rat sensory ganglia after local inflammation implicates novel cytokines in pain. PLoS One 2012, 7:e40779.
• [39]Cervero F, Schaible HG, Schmidt RF: Tonic descending inhibition of spinal cord neurones driven by joint afferents in normal cats and in cats with an inflamed knee joint. Exp Brain Res 1991, 83:675-678.
• [40]Danziger N, Weil-Fugazza J, Le Bars D, Bouhassira D: Stage-dependent changes in the modulation of spinal nociceptive neuronal activity during the course of inflammation. Eur J Neurosci 2001, 13:230-240.
• [41]Schaible HG, Neugebauer V, Cervero F, Schmidt RF: Changes in tonic descending inhibition of spinal neurons with articular input during the development of acute arthritis in the cat. J Neurophysiol 1991, 66:1021-1032.
• [42]Fields HL, Bry J, Hentall I, Zorman G: The activity of neurons in the rostral medulla of the rat during withdrawal from noxious heat. J Neurosci 1983, 3:2545-2552.
• [43]Zhuo M, Gebhart GF: Characterization of descending inhibition and facilitation from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat. Pain 1990, 42:337-350.
• [44]Pertovaara A: Plasticity in descending pain modulatory systems. Prog Brain Res 2000, 129:231-242.
• [45]Vanegas H: To the descending pain-control system in rats, inflammation-induced primary and secondary hyperalgesia are two different things. Neurosci Lett 2004, 361:225-228.
• [46]Latremoliere A, Woolf CJ: Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity. J Pain 2009, 10:895-926.
• [47]Costigan M, Moss A, Latremoliere A, Johnston C, Verma-Gandhu M, Herbert TA, Barrett L, Brenner GJ, Vardeh D, Woolf CJ, Fitzgerald M: T-Cell Infiltration and Signaling in the Adult Dorsal Spinal Cord Is a Major Contributor to Neuropathic Pain-Like Hypersensitivity. J Neurosci 2009, 29:14415-14422.
• [48]Griffin RS, Costigan M, Brenner GJ, Ma CHE, Scholz J, Moss A, Allchorne AJ, Stahl GL, Woolf CJ: Complement induction in spinal cord microglia results in anaphylatoxin C5a-mediated pain hypersensitivity. J Neurosci 2007, 27:8699-8708.
• [49]Yukhananov R, Kissin I: Persistent changes in spinal cord gene expression after recovery from inflammatory hyperalgesia: a preliminary study on pain memory. BMC Neurosci 2008, 9:32.
• [50]Amitai Y: Physiologic role for “inducible” nitric oxide synthase: a new form of astrocytic–neuronal interface. Glia 2010, 58:1775-1781.
• [51]Coderre TJ, Yashpal K: Intracellular messengers contributing to persistent nociception and hyperalgesia induced by L-glutamate and substance P in the rat formalin pain model. Eur J Neurosci 1994, 6:1328-1334.
• [52]Malmberg AB, Yaksh TL: Spinal nitric oxide synthesis inhibition blocks NMDA-induced thermal hyperalgesia and produces antinociception in the formalin test in rats. Pain 1993, 54:291-300.
• [53]Meller ST, Cummings CP, Traub RJ, Gebhart GF: The role of nitric oxide in the development and maintenance of the hyperalgesia produced by intraplantar injection of carrageenan in the rat. Neuroscience 1994, 60:367-374.
• [54]Moore PK, Oluyomi AO, Babbedge RC, Wallace P, Hart SL: L-NG-nitro arginine methyl ester exhibits antinociceptive activity in the mouse. Br J Pharmacol 1991, 102:198-202.
• [55]Wu J, Fang L, Lin Q, Willis WD: Nitric oxide synthase in spinal cord central sensitization following intradermal injection of capsaicin. Pain 2001, 94:47-58.
• [56]Rivat C, Becker C, Blugeot A, Zeau B, Mauborgne A, Pohl M, Benoliel J-J: Chronic stress induces transient spinal neuroinflammation, triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia. Pain 2010, 150:358-368.
• [57]Fernandez EJ, Lolis E: Structure, Function, and Inhibition of Chemokines. Annu Rev Pharmacol Toxicol 2002, 42:469-499.
• [58]Robertson B, Xu XJ, Hao JX, Wiesenfeld-Hallin Z, Mhlanga J, Grant G, Kristensson K: Interferon-gamma receptors in nociceptive pathways: role in neuropathic pain-related behaviour. Neuroreport 1997, 8:1311-1316.
• [59]Xu XJ, Hao JX, Olsson T, Kristensson K, van der Meide PH, Wiesenfeld-Hallin Z: Intrathecal interferon-gamma facilitates the spinal nociceptive flexor reflex in the rat. Neurosci Lett 1994, 182:263-266.
• [60]Vikman K, Robertson B, Grant G, Liljeborg A, Kristensson K: Interferon-gamma receptors are expressed at synapses in the rat superficial dorsal horn and lateral spinal nucleus. J Neurocytol 1998, 27:749-759.
• [61]Vikman KS, Duggan AW, Siddall PJ: Interferon-gamma induced disruption of GABAergic inhibition in the spinal dorsal horn in vivo. Pain 2007, 133:18-28.
• [62]Vinet J, De Jong EK, Boddeke HWGM, Stanulovic V, Brouwer N, Granic I, Eisel ULM, Liem RSB, Biber K: Expression of CXCL10 in cultured cortical neurons. J Neurochem 2010, 112:703-714.
• [63]Cho J, Nelson TE, Bajova H, Gruol DL: Chronic CXCL10 alters neuronal properties in rat hippocampal culture. J Neuroimmunol 2009, 207:92-100.
• [64]Adler M, Geller E, Chen X, Rogers T: Viewing chemokines as a third major system of communication in the brain. AAPS J 2005, 7:E865-E870.
• [65]Laragione T, Brenner M, Sherry B, Gulko PS: CXCL10 and its receptor CXCR3 regulate synovial fibroblast invasion in rheumatoid arthritis. Arthritis Rheum 2011, 63:3274-3283.
• [66]Yoshida S, Arakawa F, Higuchi F, Ishibashi Y, Goto M, Sugita Y, Nomura Y, Niino D, Shimizu K, Aoki R, Hashikawa K, Kimura Y, Yasuda K, Tashiro K, Kuhara S, Nagata K, Ohshima K: Gene expression analysis of rheumatoid arthritis synovial lining regions by cDNA microarray combined with laser microdissection: up-regulation of inflammation-associated STAT1, IRF1, CXCL9, CXCL10, and CCL5. Scand J Rheumatol 2012, 41:170-179.
• [67]Jenh C-H, Cox MA, Cui L, Reich E-P, Sullivan L, Chen S-C, Kinsley D, Qian S, Kim SH, Rosenblum S, Kozlowski J, Fine JS, Zavodny PJ, Lundell D: A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection. BMC Immunol 2012, 13:2.
• [68]Paxinos G, Watson C, Pennisi M, Topple A: Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods 1985, 13:139-143.
• [69]Bourquin A-F, Süveges M, Pertin M, Gilliard N, Sardy S, Davison AC, Spahn DR, Decosterd I: Assessment and analysis of mechanical allodynia-like behavior induced by spared nerve injury (SNI) in the mouse. Pain 2006, 122:14.e1-14.e14.
• [70]Géranton SM, Jiménez-Díaz L, Torsney C, Tochiki KK, Stuart SA, Leith JL, Lumb BM, Hunt SP: A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states. J Neurosci 2009, 29:15017-15027.