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Published in: BMC Musculoskeletal Disorders 1/2021

Open Access 01-12-2021 | Neuropathic Pain | Research article

Analysis of pain markers and epidural fibrosis caused by repeated spinal surgery in Sprague–Dawley rats

Authors: Meiling Quan, Won-Ha Hwang, Jae-Hoon Kim, Young-Yul Kim

Published in: BMC Musculoskeletal Disorders | Issue 1/2021

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Abstract

Background

Epidural fibrosis is one of the aetiologies of pain following a spinal revision surgery. It is reported that the specific members of the mitogen – activated protein kinases (MAPK) family might mediate neuropathic pain. However, roles of epidural fibrosis caused by repeated spinal surgeries and pain-related proteins in causing the post spinal surgery syndrome remain unknown. Using a rat spinal surgery epidural fibrosis and adhesion model, in this study, we evaluated and investigated the relationship between pain markers and epidural fibrosis.

Methods

Sprague–Dawley rats that underwent the spinal surgery were divided into three groups: group A (single laminectomy), group B (two repeated surgeries) and group C (three repeated surgeries). Dural thickness was measured in each experimental group, and immunohistochemical analysis and western blotting of mitogen-activated protein kinases were performed (ERK, p38 and JNK) using the spine cord.

Results

Dural thickness was 6.363 ± 1.911 μm in group A, 13.238 ± 2.123 μm in group B and 19.4 ± 2.115 μm in group C, respectively. In the western blotting, phosphorylated ERK expression gradually increased with the number of repeated surgeries, and expression in groups B (1.77-fold) and C (2.42-fold) increased as compared to expression in group A. Phosphorylated p38 showed an increasing trend with the number of repeated surgeries, and groups B (1.17-fold) and C (1.33-fold) expression increased compared with group A. However, phosphorylated JNK expression did not gradually increase with the number of repeated surgeries, and groups B (1.62-fold) and C (1.43-fold) expression increased compared with group A. Excluding phosphorylated JNK, immunohistochemical analysis revealed that phosphorylated ERK and p38 expression gradually increased with the number of repeated surgeries in the spine dorsal horn, as evidenced by western blotting.

Conclusions

Repeated spinal surgeries may increase dural thickness and expression of phosphorylated ERK and p38 in the spinal dorsal horn, and it suggests that the neuropathic pain is likely induced by epidural fibrosis and that the pain increases with the number of repeated surgeries.
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Literature
1.
go back to reference Farrokhi MR, Vasei M, Fareghbal S, Farrokhi N. The effect of methylene blue on peridural fibrosis formation after laminectomy in rats: an experimental novel study. Spine J. 2011;11:147–52.CrossRef Farrokhi MR, Vasei M, Fareghbal S, Farrokhi N. The effect of methylene blue on peridural fibrosis formation after laminectomy in rats: an experimental novel study. Spine J. 2011;11:147–52.CrossRef
2.
go back to reference Fiume D, Sherkat S, Callovini GM, Parziale G, Gazzeri G. Treatment of the failed back surgery syndrome due to lumbo-sacral epidural fibrosis. Acta Neurochir Suppl. 1995;64:116–8.CrossRef Fiume D, Sherkat S, Callovini GM, Parziale G, Gazzeri G. Treatment of the failed back surgery syndrome due to lumbo-sacral epidural fibrosis. Acta Neurochir Suppl. 1995;64:116–8.CrossRef
3.
go back to reference Richter HP, Kast E, Tomczak R, Besenfelder W, Gaus W. Results of applying ADCON-L gel after lumbar discectomy: the German ADCON-L study. J Neurosurg. 2001;95:179–89.PubMed Richter HP, Kast E, Tomczak R, Besenfelder W, Gaus W. Results of applying ADCON-L gel after lumbar discectomy: the German ADCON-L study. J Neurosurg. 2001;95:179–89.PubMed
4.
go back to reference Burton CV. Lumbosacral arachnoiditis. Spine (Phila Pa 1976). 1978;3:24–30.CrossRef Burton CV. Lumbosacral arachnoiditis. Spine (Phila Pa 1976). 1978;3:24–30.CrossRef
5.
go back to reference Karanci T, Kelten B, Karaoglan A, Cinar N, Midi A, Antar V, et al. Effects of 4% icodextrin on experimental spinal epidural fibrosis. Turk Neurosurg. 2017;27:265–71.PubMed Karanci T, Kelten B, Karaoglan A, Cinar N, Midi A, Antar V, et al. Effects of 4% icodextrin on experimental spinal epidural fibrosis. Turk Neurosurg. 2017;27:265–71.PubMed
6.
go back to reference Hayek SM, Helm S, Benyamin RM, Singh V, Bryce DA, Smith HS. Effectiveness of spinal endoscopic adhesiolysis in post lumbar surgery syndrome: a systematic review. Pain Physician. 2009;12:419–35.PubMed Hayek SM, Helm S, Benyamin RM, Singh V, Bryce DA, Smith HS. Effectiveness of spinal endoscopic adhesiolysis in post lumbar surgery syndrome: a systematic review. Pain Physician. 2009;12:419–35.PubMed
7.
go back to reference Turkoglu E, Tuncer C, Dinc C, Serbes G, Oktay M, Sekerci Z. The effect of etanercept on spinal epidural fibrosis in a postlaminectomy rat model. Turk Neurosurg. 2014;24:506–11.PubMed Turkoglu E, Tuncer C, Dinc C, Serbes G, Oktay M, Sekerci Z. The effect of etanercept on spinal epidural fibrosis in a postlaminectomy rat model. Turk Neurosurg. 2014;24:506–11.PubMed
8.
go back to reference Ozturk Y, Bozkurt I, Yaman ME, Guvenc Y, Tolunay T, Bayram P, et al. Histopathologic analysis of Tamoxifen on epidural fibrosis. World Neurosurg. 2018;111:e941–8.CrossRef Ozturk Y, Bozkurt I, Yaman ME, Guvenc Y, Tolunay T, Bayram P, et al. Histopathologic analysis of Tamoxifen on epidural fibrosis. World Neurosurg. 2018;111:e941–8.CrossRef
9.
go back to reference Tuncer C, Subasi C, Dinc C, Turkogly E, Er U. The preventative effect of α-Tocopherol on spinal epidural fibrosis after laminectomy in a rat model. Turk Neurosurg. 2019;29:72–6.PubMed Tuncer C, Subasi C, Dinc C, Turkogly E, Er U. The preventative effect of α-Tocopherol on spinal epidural fibrosis after laminectomy in a rat model. Turk Neurosurg. 2019;29:72–6.PubMed
10.
go back to reference Ma W, Quirion R. The ERK/MAPK pathway, as a target for the treatment of neuropathic pain. Expert Opin Ther Targets. 2005;9:699–713.CrossRef Ma W, Quirion R. The ERK/MAPK pathway, as a target for the treatment of neuropathic pain. Expert Opin Ther Targets. 2005;9:699–713.CrossRef
11.
go back to reference Obata K, Noguchi K. MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci. 2004;74:2643–53.CrossRef Obata K, Noguchi K. MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci. 2004;74:2643–53.CrossRef
12.
go back to reference Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;75:50–83.CrossRef Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;75:50–83.CrossRef
13.
go back to reference Lewis TS, Shapiro PS, Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res. 1998;74:49–139.CrossRef Lewis TS, Shapiro PS, Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res. 1998;74:49–139.CrossRef
14.
go back to reference Peng G, Han M, Du Y, Lin A, Yu L, Zhang Y, et al. SIP30 is regulated by ERK in peripheral nerve injury-induced neuropathic pain. J Biol Chem. 2009;284:30138–47.CrossRef Peng G, Han M, Du Y, Lin A, Yu L, Zhang Y, et al. SIP30 is regulated by ERK in peripheral nerve injury-induced neuropathic pain. J Biol Chem. 2009;284:30138–47.CrossRef
15.
go back to reference Ji RR, Strichartz G. Cell signaling and the genesis of neuropathic pain. Sci STKE. 2004;2004:reE14.PubMed Ji RR, Strichartz G. Cell signaling and the genesis of neuropathic pain. Sci STKE. 2004;2004:reE14.PubMed
16.
go back to reference Ji RR, Woolf CJ. Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis. 2001;8:1–10.CrossRef Ji RR, Woolf CJ. Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis. 2001;8:1–10.CrossRef
17.
go back to reference Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, et al. A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci. 2006;26:3551–60.CrossRef Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, et al. A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci. 2006;26:3551–60.CrossRef
18.
go back to reference Cemil B, Tun K, Kaptanoglu E, Kaymaz F, Cevirgen B, Comert A, et al. Use of pimecrolimus to prevent epidural fibrosis in a postlaminectomy rat model. J Neurosurg Spine. 2009;11:758–63.CrossRef Cemil B, Tun K, Kaptanoglu E, Kaymaz F, Cevirgen B, Comert A, et al. Use of pimecrolimus to prevent epidural fibrosis in a postlaminectomy rat model. J Neurosurg Spine. 2009;11:758–63.CrossRef
19.
go back to reference Ozdemir O, Calisaneller T, Sonmez E, Kiyici H, Caner H, Altinors N. Topical use of colchicine to prevent spinal epidural fibrosis in rats. Neurol Res. 2010;32:1117–20.CrossRef Ozdemir O, Calisaneller T, Sonmez E, Kiyici H, Caner H, Altinors N. Topical use of colchicine to prevent spinal epidural fibrosis in rats. Neurol Res. 2010;32:1117–20.CrossRef
20.
go back to reference Nakashima H, Kanemura T, Satake K, Ito K, Ishikawa Y, Ouchida J, et al. Indirect decompression using lateral lumbar Interbody fusion for restenosis after an initial decompression surgery. ASJ. 2020;14(3):305–11.PubMed Nakashima H, Kanemura T, Satake K, Ito K, Ishikawa Y, Ouchida J, et al. Indirect decompression using lateral lumbar Interbody fusion for restenosis after an initial decompression surgery. ASJ. 2020;14(3):305–11.PubMed
21.
go back to reference Alkalay RN, Kim DH, Urry DW, Xu J, Parker TM, Glazer PA. Prevention of postlaminectomy epidural fibrosis using bioelastic materials. Spine (Phila Pa 1976). 2003;28:1659–65. Alkalay RN, Kim DH, Urry DW, Xu J, Parker TM, Glazer PA. Prevention of postlaminectomy epidural fibrosis using bioelastic materials. Spine (Phila Pa 1976). 2003;28:1659–65.
22.
go back to reference Kurt G, Celik B, Cemil B, Doğulu F, Baykaner MK, Ceviker N. A comparison of the effectiveness of waxed paper and Gore-Tex on the minimally invasive epidural fibrosis model. J Spinal Disord Tech. 2009;22:49–51.CrossRef Kurt G, Celik B, Cemil B, Doğulu F, Baykaner MK, Ceviker N. A comparison of the effectiveness of waxed paper and Gore-Tex on the minimally invasive epidural fibrosis model. J Spinal Disord Tech. 2009;22:49–51.CrossRef
23.
go back to reference Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats b partial sciatic nerve injury. Pain. 1990;43:205–18.CrossRef Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats b partial sciatic nerve injury. Pain. 1990;43:205–18.CrossRef
24.
go back to reference Crown ED, Ye Z, Johnson KM, Xu GY, McAdoo DJ, Hulsebosch CE. Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury. Exp Neurol. 2006;199:397–407.CrossRef Crown ED, Ye Z, Johnson KM, Xu GY, McAdoo DJ, Hulsebosch CE. Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury. Exp Neurol. 2006;199:397–407.CrossRef
25.
go back to reference Crown ED, Ye Z, Johnson KM, Xu GY, McAdoo DJ, Westlund KN, et al. Upregulation of the phosphorylated form of CREB in spinothalamic tract cells following spinal cord injury: relation to central neuropathic pain. Neurosci Lett. 2005;384:139–44.CrossRef Crown ED, Ye Z, Johnson KM, Xu GY, McAdoo DJ, Westlund KN, et al. Upregulation of the phosphorylated form of CREB in spinothalamic tract cells following spinal cord injury: relation to central neuropathic pain. Neurosci Lett. 2005;384:139–44.CrossRef
26.
go back to reference Yu CG, Yezierski RP. Activation of the ERK1/2 signaling cascade by excitotoxic spinal cord injury. Brain Res Mol Brain Res. 2005;138:244–55.CrossRef Yu CG, Yezierski RP. Activation of the ERK1/2 signaling cascade by excitotoxic spinal cord injury. Brain Res Mol Brain Res. 2005;138:244–55.CrossRef
27.
go back to reference Ji RR. Peripheral and central mechanisms of inflammatory pain, with emphasis on MAP kinases. Curr Drug Targets Inflamm Allergy. 2004;3:299–303.CrossRef Ji RR. Peripheral and central mechanisms of inflammatory pain, with emphasis on MAP kinases. Curr Drug Targets Inflamm Allergy. 2004;3:299–303.CrossRef
28.
go back to reference Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 2003;26:696–705.CrossRef Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 2003;26:696–705.CrossRef
29.
go back to reference Zhao P, Waxman SG, Hains BC. Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury. J Neurosci. 2007;27:2357–68.CrossRef Zhao P, Waxman SG, Hains BC. Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury. J Neurosci. 2007;27:2357–68.CrossRef
30.
go back to reference Zhuang ZY, Gerner P, Woolf C, 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;114:149–59.CrossRef Zhuang ZY, Gerner P, Woolf C, 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;114:149–59.CrossRef
31.
go back to reference Kondo M, Shibuta I. Exreacellular signal-regulated kinases (ERK) 1 and 2 as a key molecule in pain research. J Oral Sci. 2020;62:147–9.CrossRef Kondo M, Shibuta I. Exreacellular signal-regulated kinases (ERK) 1 and 2 as a key molecule in pain research. J Oral Sci. 2020;62:147–9.CrossRef
32.
go back to reference 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;23:4017–22.CrossRef 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;23:4017–22.CrossRef
34.
go back to reference Choi DC, Lee JY, Lim EJ, Baik HH, Oh TH, Yune TY. Inhibition of ROS-induced p38MAPK and ERK activation in microglia by acupuncture relieves neuropathic pain after spinal cord injury in rats. Exp Neurol. 2012;236:268–82.CrossRef Choi DC, Lee JY, Lim EJ, Baik HH, Oh TH, Yune TY. Inhibition of ROS-induced p38MAPK and ERK activation in microglia by acupuncture relieves neuropathic pain after spinal cord injury in rats. Exp Neurol. 2012;236:268–82.CrossRef
35.
go back to reference Kim SY, Bae JC, Kim JY, Lee HL, Lee KM, Kim DS, et al. Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury. NeuroReport. 2002;13:2483–6.CrossRef Kim SY, Bae JC, Kim JY, Lee HL, Lee KM, Kim DS, et al. Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury. NeuroReport. 2002;13:2483–6.CrossRef
36.
go back to reference Song XS, Xu YB, Cao JL, He JH, Zhang LC, Zeng YM. cAMP response-element binding protein participates in the phosphorylated extracellular signal-regulate kinase mediated neuropathic pain. Sheng Li Xue Bao. 2005;57:139–46.PubMed Song XS, Xu YB, Cao JL, He JH, Zhang LC, Zeng YM. cAMP response-element binding protein participates in the phosphorylated extracellular signal-regulate kinase mediated neuropathic pain. Sheng Li Xue Bao. 2005;57:139–46.PubMed
37.
go back to reference Zhang FE, Cao JL, Zhang LC, Zeng YM. Activation of p38 mitogen-activated protein kinase in spinal cord contributes to chronic constriction injury-induced neuropathic pain. Sheng Li Xue Bao. 2005;57:545–51.PubMed Zhang FE, Cao JL, Zhang LC, Zeng YM. Activation of p38 mitogen-activated protein kinase in spinal cord contributes to chronic constriction injury-induced neuropathic pain. Sheng Li Xue Bao. 2005;57:545–51.PubMed
Metadata
Title
Analysis of pain markers and epidural fibrosis caused by repeated spinal surgery in Sprague–Dawley rats
Authors
Meiling Quan
Won-Ha Hwang
Jae-Hoon Kim
Young-Yul Kim
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2021
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-020-03920-z

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