Top

Published in:

Open Access 01-12-2011 | Research

The contribution of spinal glial cells to chronic pain behaviour in the monosodium iodoacetate model of osteoarthritic pain

Authors: Devi Rani Sagar, James J Burston, Gareth J Hathway, Stephen G Woodhams, Richard G Pearson, Andrew J Bennett, David A Kendall, Brigitte E Scammell, Victoria Chapman

Published in: Molecular Pain | Issue 1/2011

Abstract

Background

Clinical studies of osteoarthritis (OA) suggest central sensitization may contribute to the chronic pain experienced. This preclinical study used the monosodium iodoacetate (MIA) model of OA joint pain to investigate the potential contribution of spinal sensitization, in particular spinal glial cell activation, to pain behaviour in this model. Experimental OA was induced in the rat by the intra-articular injection of MIA and pain behaviour (change in weight bearing and distal allodynia) was assessed. Spinal cord microglia (Iba1 staining) and astrocyte (GFAP immunofluorescence) activation were measured at 7, 14 and 28 days post MIA-treatment. The effects of two known inhibitors of glial activation, nimesulide and minocycline, on pain behaviour and activation of microglia and astrocytes were assessed.

Results

Seven days following intra-articular injection of MIA, microglia in the ipsilateral spinal cord were activated (p < 0.05, compared to contralateral levels and compared to saline controls). Levels of activated microglia were significantly elevated at day 14 and 21 post MIA-injection. At day 28, microglia activation was significantly correlated with distal allodynia (p < 0.05). Ipsilateral spinal GFAP immunofluorescence was significantly (p < 0.01) increased at day 28, but not at earlier timepoints, in the MIA model, compared to saline controls. Repeated oral dosing (days 14-20) with nimesulide attenuated pain behaviour and the activation of microglia in the ipsilateral spinal cord at day 21. This dosing regimen also significantly attenuated distal allodynia (p < 0.001) and numbers of activated microglia (p < 0.05) and GFAP immunofluorescence (p < 0.001) one week later in MIA-treated rats, compared to vehicle-treated rats. Repeated administration of minocycline also significantly attenuated pain behaviour and reduced the number of activated microglia and decreased GFAP immunofluorescence in ipsilateral spinal cord of MIA treated rats.

Conclusions

Here we provide evidence for a contribution of spinal glial cells to pain behaviour, in particular distal allodynia, in this model of osteoarthritic pain. Our data suggest there is a potential role of glial cells in the central sensitization associated with OA, which may provide a novel analgesic target for the treatment of OA pain.

Available only for authorised users

Dieppe PA, Lohmander LS: Pathogenesis and management of pain in osteoarthritis. Lancet 2005, 365: 965–973. 10.1016/S0140-6736(05)71086-2PubMedCrossRef

Yusuf E, Kortekaas MC, Watt I, Huizinga TW, Kloppenburg M: Do knee abnormalities visualised on MRI explain knee pain in knee osteoarthritis? A systematic review Ann Rheum Dis 2011, 70: 60–67.PubMedCrossRef

Arendt-Nielsen L, Nie H, Laursen MB, Laursen BS, Madeleine P, Simonsen OH, et al.: Sensitization in patients with painful knee osteoarthritis. Pain 2010, 149: 573–581. 10.1016/j.pain.2010.04.003PubMedCrossRef

Gwilym SE, Keltner JR, Warnaby CE, Carr AJ, Chizh B, Chessell I, et al.: Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients. Arthritis Rheum 2009, 61: 1226–1234. 10.1002/art.24837PubMedCrossRef

Bove SE, Calcaterra SL, Brooker RM, Huber CM, Guzman RE, Juneau PL, et al.: Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. Osteoarthritis Cartilage 2003, 11: 821–830. 10.1016/S1063-4584(03)00163-8PubMedCrossRef

Combe R, Bramwell S, Field MJ: The monosodium iodoacetate model of osteoarthritis: a model of chronic nociceptive pain in rats? Neurosci Lett 2004, 370: 236–240. 10.1016/j.neulet.2004.08.023PubMedCrossRef

Guzman RE, Evans MG, Bove S, Morenko B, Kilgore K: Mono-iodoacetate-induced histologic changes in subchondral bone and articular cartilage of rat femorotibial joints: an animal model of osteoarthritis. Toxicol Pathol 2003, 31: 619–624.PubMedCrossRef

Janusz MJ, Hookfin EB, Heitmeyer SA, Woessner JF, Freemont AJ, Hoyland JA, et al.: Moderation of iodoacetate-induced experimental osteoarthritis in rats by matrix metalloproteinase inhibitors. Osteoarthritis Cartilage 2001, 9: 751–760. 10.1053/joca.2001.0472PubMedCrossRef

Fernihough J, Gentry C, Malcangio M, Fox A, Rediske J, Pellas T, et al.: Pain related behaviour in two models of osteoarthritis in the rat knee. Pain 2004, 112: 83–93. 10.1016/j.pain.2004.08.004PubMedCrossRef

10.

Sagar DR, Staniaszek LE, Okine BN, Woodhams S, Norris LM, et al.: Tonic modulation of spinal hyperexcitability by the endocannabinoid receptor system in a rat model of osteoarthritis pain. Arthritis Rheum 2010, 62: 3666–3676. 10.1002/art.27698PubMedCentralPubMedCrossRef

11.

Hendiani JA, Westlund KN, Lawand N, Goel N, Lisse J, McNearney T: Mechanical sensation and pain thresholds in patients with chronic arthropathies. J Pain 2003, 4: 203–211. 10.1016/S1526-5900(03)00557-1PubMedCrossRef

12.

Woolf CJ, Salter MW: Plasticity and pain: role of the dorsal horn. In Wall and Melzack's Textbook of Pain. Volume 5. 5th edition. Edited by: SB McMahon, M Koltzenburg. London: Elsevier; 2006:91–105.CrossRef

13.

Ren K, Dubner R: Enhanced descending modulation of nociception in rats with persistent hindpaw inflammation. J Neurophysiol 1996, 76: 3025–3037.PubMed

14.

Colburn RW, DeLeo JA, Rickman AJ, Yeager MP, Kwon P, Hickey WF: Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J Neuroimmunol 1997, 79: 163–175. 10.1016/S0165-5728(97)00119-7PubMedCrossRef

15.

Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y: BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005, 438: 1017–1021. 10.1038/nature04223PubMedCrossRef

16.

Zhuang ZY, Gerner P, Woolf CJ, Ji RR: ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 2005, 114: 149–159. 10.1016/j.pain.2004.12.022PubMedCrossRef

17.

Gao YJ, Ji RR: Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther 2010, 126: 56–68. 10.1016/j.pharmthera.2010.01.002PubMedCentralPubMedCrossRef

18.

Garrison CJ, Dougherty PM, Kajander KC, Carlton SM: Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res 1991, 565: 1–7. 10.1016/0006-8993(91)91729-KPubMedCrossRef

19.

Raghavendra V, Tanga F, DeLeo JA: Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 2003, 306: 624–630. 10.1124/jpet.103.052407PubMedCrossRef

20.

Ivanavicius SP, Ball AD, Heapy CG, Westwood FR, Murray F, Read SJ: Structural pathology in a rodent model of osteoarthritis is associated with neuropathic pain: increased expression of ATF-3 and pharmacological characterisation. Pain 2007, 128: 272–282. 10.1016/j.pain.2006.12.022PubMedCrossRef

21.

Orita S, Ishikawa T, Miyagi M, Ochiai N, Inoue G, Eguchi Y, Kamoda H, Arai G, Toyone T, Aoki Y, Kubo T, Takahashi K, Ohtori S: Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain. BMC Musculoskelet Disord 2011, 12: 134. 10.1186/1471-2474-12-134PubMedCentralPubMedCrossRef

22.

Lee Y, Pai M, Brederson JD, Wilcox D, Hsieh G, Jarvis MF, Bitner RS: Monosodium iodoacetate-induced joint pain is associated with increased phosphorylation of mitogen activated protein kinases in the rat spinal cord. Mol Pain 2011, 7: 39. 10.1186/1744-8069-7-39PubMedCentralPubMedCrossRef

23.

Gao YJ, Xu ZZ, Liu YC, Wen YR, Decosterd I, Ji RR: The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition. Pain 2010, 148: 309–319. 10.1016/j.pain.2009.11.017PubMedCentralPubMedCrossRef

24.

Fernihough J, Gentry C, Bevan S, Winter J: Regulation of calcitonin gene-related peptide and TRPV1 in a rat model of osteoarthritis. Neurosci Lett 2005, 388: 75–80. 10.1016/j.neulet.2005.06.044PubMedCrossRef

25.

Seybold VS, Jia YP, Abrahams LG: Cyclo-oxygenase-2 contributes to central sensitization in rats with peripheral inflammation. Pain 2003, 105: 47–55. 10.1016/S0304-3959(03)00254-9PubMedCrossRef

26.

Vardeh D, Wang D, Costigan M, Lazarus M, Saper CB, Woolf CJ, et al.: COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice. J Clin Invest 2009, 119: 287–294.PubMedCentralPubMed

27.

Prochazkova M, Zanvit P, Dolezal T, Prokesova L, Krsiak M: Increased gene expression and production of spinal cyclooxygenase 1 and 2 during experimental osteoarthritis pain. Physiol Res 2009, 58: 419–425.PubMed

28.

McMahon SB, Cafferty WB, Marchand F: Immune and glial cell factors as pain mediators and modulators. Exp Neurol 2005, 192: 444–462. 10.1016/j.expneurol.2004.11.001PubMedCrossRef

29.

Jin SX, Zhuang ZY, Woolf CJ, Ji RR: p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci 2003, 23: 4017–4022.PubMed

30.

Raghavendra V, Tanga FY, DeLeo JA: Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. Eur J Neurosci 2004, 20: 467–473. 10.1111/j.1460-9568.2004.03514.xPubMedCrossRef

31.

Calvo M, Zhu N, Tsantoulas C, Ma Z, Grist J, Loeb JA, et al.: Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury. J Neurosci 2010, 30: 5437–5450. 10.1523/JNEUROSCI.5169-09.2010PubMedCentralPubMedCrossRef

32.

Scali C, Prosperi C, Vannucchi MG, Pepeu G, Casamenti F: Brain inflammatory reaction in an animal model of neuronal degeneration and its modulation by an anti-inflammatory drug: implication in Alzheimer's disease. Eur J Neurosci 2000, 12: 1900–1912. 10.1046/j.1460-9568.2000.00075.xPubMedCrossRef

33.

Wakita H, Tomimoto H, Akiguchi I, Lin JX, Miyamoto K, Oka N: A cyclooxygenase-2 inhibitor attenuates white matter damage in chronic cerebral ischemia. Neuroreport 1999, 10: 1461–1465. 10.1097/00001756-199905140-00013PubMedCrossRef

34.

Bernareggi A, Rainsford KD: Pharmacokinetics of Nimesulide. In Nimesulide - Actions and Uses. Edited by: KD Rainsford. Switzerland: Birkhäuser Basel; 2005:63–120.CrossRef

35.

Kim TH, Kim HI, Kim J, Park M, Song JH: Effects of minocycline on Na(+) currents in rat dorsal root ganglion neurons. Brain Res 2011, 1370: 34–42.PubMedCrossRef

36.

Mika J, Rojewska E, Makuch W, Przewlocka B: Minocycline reduces the injury-induced expression of prodynorphin and pronociceptin in the dorsal root ganglion in a rat model of neuropathic pain. Neuroscience 2010, 165: 1420–8. 10.1016/j.neuroscience.2009.11.064PubMedCrossRef

37.

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: 1086–92. 10.1016/j.neuroscience.2008.01.065PubMedCentralPubMedCrossRef

38.

Hartung HP, Schafer B, Heininger K, Toyka KV: Recombinant interleukin-1 beta stimulates eicosanoid production in rat primary culture astrocytes. Brain Res 1989, 489: 113–119. 10.1016/0006-8993(89)90013-9PubMedCrossRef

39.

Katsuura G, Gottschall PE, Dahl RR, Arimura A: Interleukin-1 beta increases prostaglandin E2 in rat astrocyte cultures: modulatory effect of neuropeptides. Endocrinology 1989, 124: 3125–3127. 10.1210/endo-124-6-3125PubMedCrossRef

40.

Milligan ED, Watkins LR: Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 2009, 10: 23–36. 10.1038/nrn2533PubMedCentralPubMedCrossRef

41.

Clarke KA, Heitmeyer SA, Smith AG, Taiwo YO: Gait analysis in a rat model of osteoarthrosis. Physiol Behav 1997, 62: 951–954. 10.1016/S0031-9384(97)00022-XPubMedCrossRef

42.

Pomonis JD, Boulet JM, Gottshall SL, Phillips S, Sellers R, Bunton T, et al.: Development and pharmacological characterization of a rat model of osteoarthritis pain. Pain 2005, 114: 339–346. 10.1016/j.pain.2004.11.008PubMedCrossRef

43.

Clayton N, Marshall FH, Bountra C, O'Shaughnessy CT: CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain 2002, 96: 253–260. 10.1016/S0304-3959(01)00454-7PubMedCrossRef

44.

Elmes SJ, Winyard LA, Medhurst SJ, Clayton NM, Wilson AW, Kendall DA, et al.: Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat. Pain 2005, 118: 327–335. 10.1016/j.pain.2005.09.005PubMedCrossRef

45.

Hathway GJ, Vega-Avelaira D, Moss A, Ingram R, Fitzgerald M: Brief, low frequency stimulation of rat peripheral C-fibres evokes prolonged microglial-induced central sensitization in adults but not in neonates. Pain 2009, 144: 110–118. 10.1016/j.pain.2009.03.022PubMedCentralPubMedCrossRef

46.

Pekny M, Pekna M: Astrocyte intermediate filaments in CNS pathologies and regeneration. J Pathol 2004, 204: 428–437. 10.1002/path.1645PubMedCrossRef

47.

Erhuma A, Salter AM, Sculley DV, Langley-Evans SC, Bennett AJ: Prenatal exposure to a low-protein diet programs disordered regulation of lipid metabolism in the aging rat. Am J Physiol Endocrinol Metab 2007, 292: E1702–1714. 10.1152/ajpendo.00605.2006PubMedCentralPubMedCrossRef

48.

Tanga FY, Raghavendra V, DeLeo JA: Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem Int 2004, 45: 397–407. 10.1016/j.neuint.2003.06.002PubMedCrossRef

49.

Shafer LM, Slice LW: Anisomycin induces COX-2 mRNA expression through p38(MAPK) and CREB independent of small GTPases in intestinal epithelial cells. Biochim Biophys Acta 2005, 1745: 393–400. 10.1016/j.bbamcr.2005.07.002PubMedCrossRef

Title: The contribution of spinal glial cells to chronic pain behaviour in the monosodium iodoacetate model of osteoarthritic pain
Authors: Devi Rani Sagar
James J Burston
Gareth J Hathway
Stephen G Woodhams
Richard G Pearson
Andrew J Bennett
David A Kendall
Brigitte E Scammell
Victoria Chapman
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2011
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-7-88

At a glance: The STEP trials

Springer Medicine

The contribution of spinal glial cells to chronic pain behaviour in the monosodium iodoacetate model of osteoarthritic pain

Abstract

Background

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2011

Visceral hyperalgesia induced by forebrain-specific suppression of native Kv7/KCNQ/M-current in mice

EP1 receptor within the ventrolateral periaqueductal grey controls thermonociception and rostral ventromedial medulla cell activity in healthy and neuropathic rat

Nav1.7 is the predominant sodium channel in rodent olfactory sensory neurons

On the possible role of ERK, p38 and CaMKII in the regulation of CGRP expression in morphine-tolerant rats

Ensemble encoding of nociceptive stimulus intensity in the rat medial and lateral pain systems

Resveratrol inhibits Cdk5 activity through regulation of p35 expression