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Resolvin D2 Relieving Radicular Pain is Associated with Regulation of Inflammatory Mediators, Akt/GSK-3β Signal Pathway and GPR18

Neurochemical Research volume 43, pages 2384–2392 (2018)Cite this article

Abstract

Neuroinflammation induced by protruded nucleus pulposus (NP) has been shown to play a significant role in facilitation of radicular pain. Resolvin D2 (RvD2), a novel member of resolvin family, exhibits potent anti-inflammatory, pro-resolving and antinociceptive effects. But the effect of RvD2 in radicular pain remains unknown. The radicular pain rat models were induced by application of NP to L5 dorsal root ganglion. Each animal received intrathecal injections of vehicle or RvD2 (10 ng µl−1 or 100 ng µl−1). Mechanical thresholds were determined by measuring the paw withdrawal threshold for 7 days. The expressions of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor-β1 (TGF-β1) in ipsilateral lumbar segment of rat spinal dorsal horns were measured by using ELISA and real time-PCR. Western blot was used to measure the expressions of phosphorylated Akt (p-Akt) and phosphorylated glycogen synthase kinase 3 beta (p-GSK-3β). The expressions and distributions of RvD2 receptor, G-protein-coupled receptor 18 (GPR18), were also explored in the spinal cord of rats by using double-label immunofluorescence. RvD2 treatment caused significant reductions in the intensity of mechanical hypersensitivity and spinal expressions of TNF-α and IL-6. Meanwhile, RvD2 increased the expressions of TGF-β1 and regulated Akt/GSK-3β signaling. Furthermore, immunofluorescence showed that GPR18 colocalized with neurons and astrocytes in spinal cord. The results suggested that RvD2 might attenuate mechanical allodynia via regulating the expressions of inflammatory mediators and activation of Akt/GSK-3β signal pathway. RvD2 might offer a hopeful method for radicular pain therapy.

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References

  1. Manchikanti L, Hirsch JA (2015) Clinical management of radicular pain. Expert Rev Neurother 15(6):681–693

    CAS  Article  Google Scholar 

  2. Yabuki S, Igarashi T, Kikuchi S (2000) Application of nucleus pulposus to the nerve root simultaneously reduces blood flow in dorsal root ganglion and corresponding hindpaw in the rat. Spine (Phila Pa 1976) 25(12):1471–1476

    CAS  Article  Google Scholar 

  3. Cuellar JM, Borges PM, Cuellar VG et al (2013) Cytokine expression in the epidural space: a model of noncompressive disc herniation-induced inflammation. Spine (Phila Pa 1976) 38(1):17–23

    Article  Google Scholar 

  4. Park HW, Ahn SH, Kim SJ et al (2011) Changes in spinal cord expression of fractalkine and its receptor in a rat model of disc herniation by autologous nucleus pulposus. Spine (Phila Pa 1976) 36(12):E753–E760

    Article  Google Scholar 

  5. Botz B, Bolcskei K, Helyes Z (2017) Challenges to develop novel anti-inflammatory and analgesic drugs. Wiley Interdiscip Rev 9(3):e1427

    Google Scholar 

  6. Serhan CN (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature 510(7503):92–101

    CAS  Article  Google Scholar 

  7. Ji RR, Xu ZZ, Strichartz G, Serhan CN (2011) Emerging roles of resolvins in the resolution of inflammation and pain. Trends Neurosci 34(11):599–609

    CAS  Article  Google Scholar 

  8. Park CK, Xu ZZ, Liu T et al (2011) Resolvin D2 is a potent endogenous inhibitor for transient receptor potential subtype V1/A1, inflammatory pain, and spinal cord synaptic plasticity in mice: distinct roles of resolvin D1, D2, and E1. J Neurosci 31(50):18433–18438

    CAS  Article  Google Scholar 

  9. Liu ZH, Miao GS, Wang JN et al (2016) Resolvin D1 inhibits mechanical hypersensitivity in sciatica by modulating the expression of nuclear factor-kappaB, phospho-extracellular signal-regulated kinase, and pro- and antiinflammatory cytokines in the spinal cord and dorsal root ganglion. Anesthesiology 124(4):934–944

    CAS  Article  Google Scholar 

  10. Chiang N, Dalli J, Colas RA, Serhan CN (2015) Identification of resolvin D2 receptor mediating resolution of infections and organ protection. J Exp Med 212(8):1203–1217

    CAS  Article  Google Scholar 

  11. Hou Y, Wang L, Gao J et al (2016) A modified procedure for lumbar intrathecal catheterization in rats. Neurol Res 38(8):725–732

    Article  Google Scholar 

  12. Zhang JJ, Song W, Luo WY et al (2011) Autologous nucleus pulposus transplantation to lumbar 5 dorsal root ganglion after epineurium dissection in rats: a modified model of non-compressive lumbar herniated intervertebral disc. Chin Med J (Engl) 124(13):2009–2014

    Google Scholar 

  13. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63

    CAS  Article  Google Scholar 

  14. Cuellar JM, Montesano PX, Antognini JF, Carstens E (2005) Application of nucleus pulposus to L5 dorsal root ganglion in rats enhances nociceptive dorsal horn neuronal windup. J Neurophysiol 94(1):35–48

    CAS  Article  Google Scholar 

  15. Ellis A, Bennett DL (2013) Neuroinflammation and the generation of neuropathic pain. Br J Anaesth 111(1):26–37

    CAS  Article  Google Scholar 

  16. Freire MO, Van Dyke TE (2013) Natural resolution of inflammation. Periodontol 2000 63(1):149–164

    Article  Google Scholar 

  17. Serhan CN, Chiang N, Dalli J (2015) The resolution code of acute inflammation: novel pro-resolving lipid mediators in resolution. Semin Immunol 27(3):200–215

    CAS  Article  Google Scholar 

  18. Tian Y, Zhang Y, Zhang R, Qiao S, Fan J (2015) Resolvin D2 recovers neural injury by suppressing inflammatory mediators expression in lipopolysaccharide-induced Parkinson’s disease rat model. Biochem Biophys Res Commun 460(3):799–805

    CAS  Article  Google Scholar 

  19. Akagi D, Chen M, Toy R, Chatterjee A, Conte MS (2015) Systemic delivery of proresolving lipid mediators resolvin D2 and maresin 1 attenuates intimal hyperplasia in mice. Faseb J 29(6):2504–2513

    CAS  Article  Google Scholar 

  20. Hernangomez M, Klusakova I, Joukal M et al.(2016) CD200R1 agonist attenuates glial activation, inflammatory reactions, and hypersensitivity immediately after its intrathecal application in a rat neuropathic pain model, J Neuroinflamm 13:1

    Article  Google Scholar 

  21. Sacerdote P, Franchi S, Moretti S et al (2013) Cytokine modulation is necessary for efficacious treatment of experimental neuropathic pain. J Neuroimmune Pharmacol 8(1):202–211

    Article  Google Scholar 

  22. Youn DH, Wang H, Jeong SJ (2008) Exogenous tumor necrosis factor-alpha rapidly alters synaptic and sensory transmission in the adult rat spinal cord dorsal horn. J Neurosci Res 86(13):2867–2875

    CAS  Article  Google Scholar 

  23. Svensson CI, Schafers M, Jones TL, Powell H, Sorkin LS (2005) Spinal blockade of TNF blocks spinal nerve ligation-induced increases in spinal P-p38. Neurosci Lett 379(3):209–213

    CAS  Article  Google Scholar 

  24. Zhou YQ, Liu Z, Liu ZH et al (2016) Interleukin-6: an emerging regulator of pathological pain. J Neuroinflamm 13(1):141

    Article  Google Scholar 

  25. Brenn D, Richter F, Schaible HG (2007) 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 56(1):351–359

    CAS  Article  Google Scholar 

  26. Echeverry S, Shi XQ, Haw A et al (2009) Transforming growth factor-beta1 impairs neuropathic pain through pleiotropic effects. Mol Pain 5:16

    Article  Google Scholar 

  27. Chen NF, Huang SY, Chen WF et al (2013) TGF-beta1 attenuates spinal neuroinflammation and the excitatory amino acid system in rats with neuropathic pain. J Pain 14(12):1671–1685

    CAS  Article  Google Scholar 

  28. Golpich M, Amini E, Hemmati F et al (2015) Glycogen synthase kinase-3 beta (GSK-3beta) signaling: Implications for Parkinson’s disease. Pharmacol Res 97:16–26

    CAS  Article  Google Scholar 

  29. Azoulay-Alfaguter I, Elya R, Avrahami L, Katz A, Eldar-Finkelman H (2015) Combined regulation of mTORC1 and lysosomal acidification by GSK-3 suppresses autophagy and contributes to cancer cell growth. Oncogene 34(35):4613–4623

    CAS  Article  Google Scholar 

  30. Gao M, Yan X, Weng HR (2013) Inhibition of glycogen synthase kinase 3beta activity with lithium prevents and attenuates paclitaxel-induced neuropathic pain. Neuroscience 254:301–311

    CAS  Article  Google Scholar 

  31. Weng HR, Gao M, Maixner DW (2014) Glycogen synthase kinase 3 beta regulates glial glutamate transporter protein expression in the spinal dorsal horn in rats with neuropathic pain. Exp Neurol 252:18–27

    CAS  Article  Google Scholar 

  32. Martins DF, Rosa AO, Gadotti VM et al (2011) The antinociceptive effects of AR-A014418, a selective inhibitor of glycogen synthase kinase-3 beta, in mice. J Pain 12(3):315–322

    CAS  Article  Google Scholar 

  33. Wang H, Kumar A, Lamont RJ, Scott DA (2014) GSK3beta and the control of infectious bacterial diseases. Trends Microbiol 22(4):208–217

    CAS  Article  Google Scholar 

  34. Green HF, Nolan YM (2012) GSK-3 mediates the release of IL-1beta, TNF-alpha and IL-10 from cortical glia. Neurochem Int 61(5):666–671

    CAS  Article  Google Scholar 

  35. Beurel E, Jope RS (2009) Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain. J Neuroinflamm 6:9

    Article  Google Scholar 

  36. Maekawa T, Hosur K, Abe T et al (2015) Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3beta-C/EBPbeta pathway. Nat Commun 6:8272

    Article  Google Scholar 

  37. Yoo S, Lim JY, Hwang SW (2013) Resolvins: endogenously-generated potent painkilling substances and their therapeutic perspectives. Curr Neuropharmacol 11(6):664–676

    CAS  Article  Google Scholar 

  38. Zhang MJ, Sansbury BE, Hellmann J et al (2016) Resolvin D2 enhances postischemic revascularization while resolving inflammation. Circulation 134(9):666–680

    CAS  Article  Google Scholar 

  39. Pascoal LB, Bombassaro B, Ramalho AF et al (2017) Resolvin RvD2 reduces hypothalamic inflammation and rescues mice from diet-induced obesity. J Neuroinflamm 14(1):5

    Article  Google Scholar 

  40. Rajaraman G, Simcocks A, Hryciw DH, Hutchinson DS, McAinch AJ (2016) G protein coupled receptor 18: a potential role for endocannabinoid signaling in metabolic dysfunction. Mol Nutr Food Res 60(1):92–102

    CAS  Article  Google Scholar 

  41. Malek N, Kostrzewa M, Makuch W et al (2016) The multiplicity of spinal AA-5-HT anti-nociceptive action in a rat model of neuropathic pain. Pharmacol Res 111:251–263

    CAS  Article  Google Scholar 

  42. Hesselink JM, Chiosi F, Costagliola C (2016) Resolvins and aliamides: lipid autacoids in ophthalmology—what promise do they hold? Drug Des Devel Ther 10:3133–3141

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 81271232 and 81772443), Provincial Natural Science Foundation of Jiangxi Province, China (Grant No. 20171BAB205037).

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Affiliations

  1. Department of Pain Management, Shandong Provincial Hospital affiliated to Shandong University, 324 Jingwu Road, Jinan, 250021, Shandong, People’s Republic of China

    Lan-yu Zhang, Zhi-hua Liu, Shuang Wen, Cong-xian Yang, Zhi-jian Fu & Tao Sun

  2. Department of Pain Management, Ganzhou People’s Hospital, Ganzhou, Jiangxi, China

    Qing Zhu

Authors
  1. Lan-yu Zhang
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  2. Zhi-hua Liu
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  3. Qing Zhu
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  4. Shuang Wen
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  5. Cong-xian Yang
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  6. Zhi-jian Fu
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  7. Tao Sun
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Contributions

Lan-yu Zhang was responsible for carrying out the major part of the study, the statistical analyses and writing the manuscript. Zhi-hua Liu helped conducting the animal models and injecting the drugs. Qing Zhu conducted behavioral tests. Shuang Wen carried out part of the ELISA and Western blot study. Cong-xian Yang was in charge of real-time polymerase chain reaction and the immunofluorescence study. Zhi-jian Fu revised the manuscript. Tao Sun conceived and designed the study. All authors read and approved the final manuscript.

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Correspondence to Tao Sun.

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Zhang, Ly., Liu, Zh., Zhu, Q. et al. Resolvin D2 Relieving Radicular Pain is Associated with Regulation of Inflammatory Mediators, Akt/GSK-3β Signal Pathway and GPR18. Neurochem Res 43, 2384–2392 (2018). https://doi.org/10.1007/s11064-018-2666-9

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  • DOI: https://doi.org/10.1007/s11064-018-2666-9

Keywords

  • Radicular pain
  • RvD2
  • GSK-3β
  • Akt
  • GPR18