The Contribution of Spinal Glial Cells to Chronic Pain Behaviour in the Monosodium Iodoacetate Model of Osteoarthritic Pain

Sagar, Devi Rani; Burston, James J.; Hathway, Gareth J.; Woodhams, Stephen G; Pearson, Roberta; Bennett, Andrew J.; Kendall, David A.; Scammell, Brigitte E.; Chapman, Victoria

doi:10.1186/1744-8069-7-88

Cited by 110 publications

(149 citation statements)

References 51 publications

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“…The mechanisms by which 17(R)‐HDoHE inhibits astrogliosis may arise as a result of direct effects (although there is little evidence to date) or indirect effects on the spinal signaling pathways that lead to astrogliosis. In particular, activated microglia in the spinal cord play a fundamental role in the development of chronic pain mechanisms and are known to be activated 14–28 days following induction of the MIA model of OA 25, coinciding with the increase in expression of ALX in the ipsilateral spinal cord reported herein.…”

Section: Discussionsupporting

confidence: 59%

“…We previously demonstrated a significant increase in GFAP immunofluorescence, indicative of astrogliosis and a marker of central sensitization, in the ipsilateral dorsal horn of the spinal cord at later time points in the model of MIA‐induced OA pain 25. In the current study, repeated treatment with 17(R)‐HDoHE from day 14 onward resulted in significant blockade of spinal astrogliosis in the model of MIA‐induced OA pain at the later time point (day 28 after induction of the model), and spinal GFAP expression at this time was correlated with pain behavior.…”

Section: Discussionmentioning

confidence: 96%

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Targeting the D Series Resolvin Receptor System for the Treatment of Osteoarthritis Pain

Huang

Burston

et al. 2017

Arthritis & Rheumatology

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ObjectivePain is a major symptom of osteoarthritis (OA); currently available analgesics either do not provide adequate pain relief or are associated with serious side effects. The aim of this study was to investigate the therapeutic potential of targeting the resolvin receptor system to modify OA pain and pathology.MethodsGene expression of 2 resolvin receptors (ALX and ChemR23) was quantified in synovium and medial tibial plateau specimens obtained from patients with OA at the time of joint replacement surgery. Two models of OA joint pain were used for the mechanistic studies. Gene expression in the joint and central nervous system was quantified. The effects of exogenous administration of the D series resolvin precursor 17(R)‐hydroxy‐docosahexaenoic acid (17[R]‐HDoHE) on pain behavior, joint pathology, spinal microglia, and astroglyosis were quantified. Plasma levels of relevant lipids, resolvin D2, 17(R)‐HDoHE, and arachidonic acid, were determined in rats, using liquid chromatography tandem mass spectrometry.ResultsThere was a positive correlation between resolvin receptor and interleukin‐6 (IL‐6) expression in human OA synovial and medial tibial plateau tissue. In rats, synovial expression of ALX was positively correlated with expression of IL‐1β, tumor necrosis factor, and cyclooxygenase 2. Treatment with 17(R)‐HDoHE reversed established pain behavior (but not joint pathology) in 2 models of OA pain. This was associated with a significant elevation in the plasma levels of resolvin D2 and a significant reduction in astrogliosis in the spinal cord in the monosodium iodoacetate–induced OA rat model.ConclusionOur preclinical data demonstrate the robust analgesic effects of activation of the D series resolvin pathways in 2 different animal models of OA. Our data support a predominant central mechanism of action in clinically relevant models of OA pain.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 96%

Targeting the D Series Resolvin Receptor System for the Treatment of Osteoarthritis Pain

Huang

Burston

et al. 2017

Arthritis & Rheumatology

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“…CXCL12/CXCR4 signaling facilitates pain hyperalgesia by mediating glial-glial interaction and MAPKs activation in bone cancer rats It is becoming clear that, through producing and releasing several chemokines, the activated glial cells not only enhance neuronal sensitization (Guo et al 2007) but also facilitate glial activation in return (Sagar et al 2011). Such positive feedback loops, which compose of glial-glial interactions, depend on both perseverant release of chemokines from glial cells and persistent activation of chemokine receptors on themselves or others (Miyoshi et al 2008).…”

Section: R E T R a C T E Dmentioning

confidence: 99%

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Liu

Zhang

et al. 2015

Journal of Neurochemistry

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The activation of MAPK pathways in spinal cord and subsequent production of proinflammatory cytokines in glial cells contribute to the development of spinal central sensitization, the basic mechanism underlying bone cancer pain (BCP). Our previous study showed that spinal CXCL12 from astrocytes mediates BCP generation by binding to CXCR4 in both astrocyters and microglia. Here, we verified that CXCL12/CXCR4 signaling contributed to BCP through a MAPK-mediated mechanism. In na€ ıve rats, a single intrathecal administration of CXCL12 considerably induced pain hyperalgesia and phosphorylation expression of spinal MAPK members (including extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase), which could be partially prevented by pre-treatment with CXCR4 inhibitor AMD3100. This CXCL12-induced hyperalgesia was also reduced by MAPK inhibitors. In bone cancer rats, tumor cell inoculation into the tibial cavity caused prominent and persistent pain hyperalgesia, and associated with up-regulation of CXCL12 and CXCR4, activation of glial cells, phosphorylation of MAPKs, and production of proinflammatory cytokines in the spinal cord. These tumor cell inoculation-induced behavioral and neurochemical alterations were all suppressed by blocking CXCL12/CXCR4 signaling or MAPK pathways. Taken together, these results demonstrate that spinal MAPK pathways mediated CXCL12/CXCR4-induced pain hypersensitivity in bone cancer rats, which could be druggable targets for alleviating BCP and glia-derived neuroinflammation. Keywords: astrocytes, bone cancer pain, chemokine, mitogenactivated protein kinase, microglia, neuroinflammation. Bone cancer pain (BCP) caused by primary tumors or bone metastases is the most common source of moderate and severe cancer pain, which not only makes patients less confident to receive therapeutic plan but also discourages tumor-burdened people from desiring to live (Knopp et al. 2011). With effective treatment strategies depending on a better understanding of BCP, intensive studies of underlying pathogenic mechanisms of BCP and development of novel analgesic targets are highly anticipated in the basic and clinical research communities.Following local inoculation of primary or metastatic bone tumor in the bone microenvironment, cellular and neurochemical alterations take place abundantly in the spinal cord, triggering hyperalgesic behaviors (Medhurst et al. 2002). In this complex pathophysiologic process, glial cells (especially astrocytes and microglia) react and release various proinflammatory cytokines, including tumor necrosis factor a (TNF-a), interleukin 1b (IL-1b) and IL-6, which enhance central sensitization and thus evoking pain hypersensitivity (Falk and Dickenson 2014). Indeed, inhibiting functional activation of astrocytes and microglia at the spinal level is sufficient to suppress BCP and these glia-derived mediators Moreover, numerous studies have shown that all three MAPK members are prone to be phosphorylated following the activation of certain GPCRs, especially che...

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“…The same model causes reduced nociceptive thresholds in the biceps femoris which neurophysiologically represents a spinal mechanism (Kelly et al, 2013). The monoiodoacetate (MIA) model also seems capable of activating spinal glial cells which may contribute to the development and maintenance of CS (Sagar et al, 2011).…”

Section: Osteoarthritis (Oa) Painmentioning

confidence: 99%

Assessment and manifestation of central sensitisation across different chronic pain conditions

Arendt-Nielsen

Morlion

Perrot

et al. 2017

European Journal of Pain

452

445

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Different neuroplastic processes can occur along the nociceptive pathways and may be important in the transition from acute to chronic pain and for diagnosis and development of optimal management strategies. The neuroplastic processes may result in gain (sensitisation) or loss (desensitisation) of function in relation to the incoming nociceptive signals. Such processes play important roles in chronic pain, and although the clinical manifestations differ across condition processes, they share some common mechanistic features. The fundamental understanding and quantitative assessment of particularly some of the central sensitisation mechanisms can be translated from preclinical studies into the clinic. The clinical perspectives are implementation of such novel information into diagnostics, mechanistic phenotyping, prevention, personalised treatment, and drug development. The aims of this paper are to introduce and discuss (1) some common fundamental central pain mechanisms, (2) how they may translate into the clinical signs and symptoms across different chronic pain conditions, (3) how to evaluate gain and loss of function using quantitative pain assessment tools, and (4) the implications for optimising prevention and management of pain. The chronic pain conditions selected for the paper are neuropathic pain in general, musculoskeletal pain (chronic low back pain and osteoarthritic pain in particular), and visceral pain (irritable bowel syndrome in particular). The translational mechanisms addressed are local and widespread sensitisation, central summation, and descending pain modulation. Significance Central sensitisation is an important manifestation involved in many different chronic pain conditions. Central sensitisation can be different to assess and evaluate as the manifestations vary from pain condition to pain condition. Understanding central sensitisation may promote better profiling and diagnosis of pain patients and development of new regimes for mechanism based therapy. Some of the mechanisms underlying central sensitisation can be translated from animals to humans providing new options in development of therapies and profiling drugs under development.

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The Contribution of Spinal Glial Cells to Chronic Pain Behaviour in the Monosodium Iodoacetate Model of Osteoarthritic Pain

Cited by 110 publications

References 51 publications

Targeting the D Series Resolvin Receptor System for the Treatment of Osteoarthritis Pain

Targeting the D Series Resolvin Receptor System for the Treatment of Osteoarthritis Pain

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Assessment and manifestation of central sensitisation across different chronic pain conditions

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