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      Increased local expressions of CX3CL1 and CCL2 are related to clinical severity in lumbar disk herniation patients with sciatic pain

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          Chemokines have been identified to be involved in the modulation of pain through both peripheral and central mechanisms. However, the role of chemokines in lumbar disk herniation (LDH) with sciatic pain remains unknown.


          The current study was performed to explore the expression of two most commonly studied chemokines CX3CL1 and CCL2 and assess their associations with clinical severity in LDH patients with sciatic pain.


          The soft tissues around nerve root (STANR), annulus fibrosus (AF), and nucleus pulposus (NP) biopsies were obtained from 36 LDH patients with chronic sciatic pain and 10 scoliosis patients (painless controls). The serum and local expressions of CX3CL1 and CCL2 were determined using enzyme-linked immunosorbent assay and Western blot analysis, respectively. The visual analog scale (VAS) scores for low back pain and lower extremity pain and Japanese Orthopaedic Association (JOA) scores were recorded on the day of hospital admission to evaluate the clinical severity. LDH patients with sciatic pain were divided into severe pain (SP) group (VAS ≥7; n=18) and mild-to-moderate pain (M-MP) group (VAS <7; n=18) for lower extremity pain.


          Local expressions instead of CX3CL1 and CCL2 in STANR, AF, and NP were significantly higher in the SP group than in M-MP compared with scoliosis painless group. Expressions of both CX3CL1 and CCL2 in STANR and AF were positively correlated with VAS scores for lower extremity and for low back pain, respectively. In addition, CX3CL1 and CCL2 expressions in STANR were negatively associated with JOA scores. There were no significant differences of serum CX3CL1 and CCL2 levels among SP group, M-MP group, and scoliosis painless group.


          Both CX3CL1 and CCL2 may play important roles in maintaining pain in LDH patients. Local blockade of CX3CL1 and CCL2 in LDH patients with persistent pain deserves further intensive study.

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          Most cited references 29

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          Role of cytokines in intervertebral disc degeneration: pain and disc content.

          Degeneration of the intervertebral discs (IVDs) is a major contributor to back, neck and radicular pain. IVD degeneration is characterized by increases in levels of the proinflammatory cytokines TNF, IL-1α, IL-1β, IL-6 and IL-17 secreted by the IVD cells; these cytokines promote extracellular matrix degradation, chemokine production and changes in IVD cell phenotype. The resulting imbalance in catabolic and anabolic responses leads to the degeneration of IVD tissues, as well as disc herniation and radicular pain. The release of chemokines from degenerating discs promotes the infiltration and activation of immune cells, further amplifying the inflammatory cascade. Leukocyte migration into the IVD is accompanied by the appearance of microvasculature tissue and nerve fibres. Furthermore, neurogenic factors, generated by both disc and immune cells, induce expression of pain-associated cation channels in the dorsal root ganglion. Depolarization of these ion channels is likely to promote discogenic and radicular pain, and reinforce the cytokine-mediated degenerative cascade. Taken together, an enhanced understanding of the contribution of cytokines and immune cells to these catabolic, angiogenic and nociceptive processes could provide new targets for the treatment of symptomatic disc disease. In this Review, the role of key inflammatory cytokines during each of the individual phases of degenerative disc disease, as well as the outcomes of major clinical studies aimed at blocking cytokine function, are discussed.
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            Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain.

             Ji Zhang (corresponding) ,  Xiang Shi,  Stefania Echeverry (2007)
            Neuropathic pain resulting from damage to or dysfunction of peripheral nerves is not well understood and difficult to treat. Although CNS hyperexcitability is a critical component, recent findings challenge the neuron-centric view of neuropathic pain etiology and pathology. Indeed, glial cells were shown to play an active role in the initiation and maintenance of pain hypersensitivity. However, the origins of these cells and the triggers that induce their activation have yet to be elucidated. Here we show that, after peripheral nerve injury induced by a partial ligation on the sciatic nerve, in addition to activation of microglia resident to the CNS, hematogenous macrophage/monocyte infiltrate the spinal cord, proliferate, and differentiate into microglia. Signaling from chemokine monocyte chemoattractant protein-1 (MCP-1, CCL2) to its receptor CCR2 is critical in the spinal microglial activation. Indeed, intrathecal injection of MCP-1 caused activation of microglia in wild-type but not in CCR2-deficient mice. Furthermore, treatment with an MCP-1 neutralizing antibody prevented bone marrow-derived microglia (BMDM) infiltration into the spinal cord after nerve injury. In addition, using selective knock-out of CCR2 in resident microglia or BMDM, we found that, although total CCR2 knock-out mice did not develop microglial activation or mechanical allodynia, CCR2 expression in either resident microglia or BMDM is sufficient for the development of mechanical allodynia. Thus, to effectively relieve neuropathic pain, both CNS resident microglia and blood-borne macrophages need to be targeted. These findings also open the door for a novel therapeutic strategy: to take advantage of the natural ability of bone marrow-derived cells to infiltrate selectively affected CNS regions by using these cells as vehicle for targeted drug delivery to inhibit hypersensitivity and chronic pain.
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              Risk factors in low-back pain. An epidemiological survey.


                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                17 January 2017
                : 10
                : 157-165
                [1 ]Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha
                [2 ]Department of Spine Surgery, Chenzhou No. 1 People’s Hospital, Chenzhou
                [3 ]Department of Neurosurgery, Nanhua Hospital Affiliated to Nanhua University, Hengyang
                [4 ]Department of Orthopedics, Chenzhou No. 1 People’s Hospital, Chenzhou, Hunan, People’s Republic of China
                Author notes
                Correspondence: Xi-Yang Wang, Department of Spine Surgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, Hunan 410008, People’s Republic of China, Tel +86 731 8432 8888, Email wxyorthoxy@ 123456163.com
                © 2017 Peng et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Anesthesiology & Pain management

                ccl2, lumbar disk herniation, cx3cl1, sciatic pain


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