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Neurochemical Research

, Volume 43, Issue 8, pp 1660–1670 | Cite as

Withdrawal from spinal application of remifentanil induces long-term potentiation of c-fiber-evoked field potentials by activation of Src family kinases in spinal microglia

  • Tao Yang
  • Sujuan Du
  • Xianguo Liu
  • Xijiu Ye
  • Xuhong Wei
Original Paper

Abstract

It is well known that remifentanil, a widely used intravenous anesthesia drug, can paradoxically induce hyperalgesia. The underlying mechanisms are still not clear despite the wide investigations. The present study demonstrated that withdrawal from spinal application of remifentanil could dose-dependently induce long term potentiation (LTP) of C-fiber evoked field potentials. Remifentanil withdrawal could activate Src family kinases (SFKs) in microglia, and upregulate the expression of tumor necrosis factor alpha (TNFα) in spinal dorsal horn. Furthermore, pretreatment with either microglia inhibitor Minocycline, SFKs inhibitor PP2 or TNF αneutralization antibody could block remifentanil withdrawal induced spinal LTP, whereas supplement of recombinant rat TNFα to the spinal cord could reverse the inhibitory effect of Minocycline or PP2 on remifentanil withdrawal induced LTP. Our results suggested that TNFαrelease following SFKs activation in microglia is involved in the induction of LTP induced by remifentanil withdrawal.

Keywords

Remifentanil Long term potentiation Src-family kinase Microglia Tumor necrosis factor alpha 

Notes

Acknowledgements

This work was supported by grants from the National Natural Science Foundation (Beijing, People’s Republic of China. Nos. 81200856 and 81471250); Nature Science Foundation of Guangdong Province of China (Guangzhou, People’s Republic of China. Nos. 2014A030313029), and by Scientific Research Foundation of Guangdong Province of China (Guangzhou, People’s Republic of China. No. 2016A020215035). All grants were awarded to Dr. Wei.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Yu EH, Tran DH, Lam SW, Irwin MG (2016) Remifentanil tolerance and hyperalgesia: short-term gain, long-term pain? Anaesthesia 71:1347–1362CrossRefPubMedGoogle Scholar
  2. 2.
    Yuan Y, Wang JY, Yuan F, Xie KL, Yu YH, Wang GL (2013) Glycogen synthase kinase-3beta contributes to remifentanil-induced postoperative hyperalgesia via regulating N-methyl-D-aspartate receptor trafficking. Anesth Analg 116:473–481CrossRefPubMedGoogle Scholar
  3. 3.
    Wang C, Li Y, Wang H, Xie K, Shu R, Zhang L, Hu N, Yu Y, Wang G (2015) Inhibition of DOR prevents remifentanil induced postoperative hyperalgesia through regulating the trafficking and function of spinal NMDA receptors in vivo and in vitro. Brain Res Bull 110:30–39CrossRefPubMedGoogle Scholar
  4. 4.
    Wehrfritz A, Schaefer S, Troester A, Noel N, Bessiere B, Apiou-Sbirlea G, Simonnet G, Schuettler J, Richebe P (2016) A randomized phase I trial evaluating the effects of inhaled 50–50% N2 O-O2 on remifentanil-induced hyperalgesia and allodynia in human volunteers. Eur J Pain 20:1467–1477CrossRefPubMedGoogle Scholar
  5. 5.
    Li S, Zeng J, Wan X, Yao Y, Zhao N, Yu Y, Yu C, Xia Z (2017) [EXPRESS] Enhancement of spinal dorsal horn neuron NMDA receptor phosphorylation as the mechanism of remifentanil induced hyperalgesia: Roles of PKC and CaMKII. Mol Pain 13:17448069–17723789PubMedPubMedCentralGoogle Scholar
  6. 6.
    Heinl C, Drdla-Schutting R, Xanthos DN, Sandkuhler J (2011) Distinct mechanisms underlying pronociceptive effects of opioids. J Neurosci 31:16748–16756CrossRefPubMedGoogle Scholar
  7. 7.
    Romero A, Gonzalez-Cuello A, Laorden ML, Campillo A, Vasconcelos N, Romero-Alejo E, Puig MM (2012) Effects of surgery and/or remifentanil administration on the expression of pERK1/2, c-Fos and dynorphin in the dorsal root ganglia in mice. Naunyn Schmiedebergs Arch Pharmacol 385:397–409CrossRefPubMedGoogle Scholar
  8. 8.
    Williams JT, Ingram SL, Henderson G, Chavkin C, von Zastrow M, Schulz S, Koch T, Evans CJ, Christie MJ (2013) Regulation of mu-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 65:223–254CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Sandkuhler J (2007) Understanding LTP in pain pathways. Mol Pain 3:9CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sandkuhler J, Benrath J, Brechtel C, Ruscheweyh R, Heinke B (2000) Synaptic mechanisms of hyperalgesia. Prog Brain Res 129:81–100CrossRefPubMedGoogle Scholar
  11. 11.
    Willis WD (2002) Long-term potentiation in spinothalamic neurons. Brain Res Brain Res Rev 40:202–214CrossRefPubMedGoogle Scholar
  12. 12.
    Drdla R, Gassner M, Gingl E, Sandkühler J (2009) Induction of synaptic long-term potentiation after opioid withdrawal. Science 325(5937):207–210CrossRefPubMedGoogle Scholar
  13. 13.
    Zhong Y, Zhou LJ, Ren WJ, Xin WJ, Li YY, Zhang T, Liu XG (2010) The direction of synaptic plasticity mediated by C-fibers in spinal dorsal horn is decided by Src-family kinases in microglia: the role of tumor necrosis factor-alpha. Brain Behav Immun 24:874–880CrossRefPubMedGoogle Scholar
  14. 14.
    Zhou LJ, Yang T, Wei X, Liu Y, Xin WJ, Chen Y, Pang RP, Zang Y, Li YY, Liu XG (2011) Brain-derived neurotrophic factor contributes to spinal long-term potentiation and mechanical hypersensitivity by activation of spinal microglia in rat. Brain Behav Immun 25:322–334CrossRefPubMedGoogle Scholar
  15. 15.
    Gong QJ, Li YY, Xin WJ, Zang Y, Ren WJ, Wei XH, Zhang T, Liu XG (2009) ATP induces long-term potentiation of C-fiber-evoked field potentials in spinal dorsal horn: the roles of P2 × 4 receptors and p38 MAPK in microglia. Glia 57:583–591CrossRefPubMedGoogle Scholar
  16. 16.
    Ye L, Xiao L, Yang SY, Duan JJ, Chen Y, Cui Y (2017) Cathepsin S in the spinal microglia contributes to remifentanil-induced hyperalgesia in rats. Neuroscience 344:265–275CrossRefPubMedGoogle Scholar
  17. 17.
    Thomas SM, Brugge JS (1997) Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 13:513–609CrossRefPubMedGoogle Scholar
  18. 18.
    Zhang L, Zhao H, Qiu Y, Loh HH, Law PY (2009) Src phosphorylation of micro-receptor is responsible for the receptor switching from an inhibitory to a stimulatory signal. J Biol Chem 284:1990–2000CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Walwyn W, Evans CJ, Hales TG (2007) Beta-arrestin2 and c-Src regulate the constitutive activity and recycling of mu opioid receptors in dorsal root ganglion neurons. J Neurosci 27:5092–5104CrossRefPubMedGoogle Scholar
  20. 20.
    Liu XG, Sandkuhler J (1998) Activation of spinal N-methyl-D-aspartate or neurokinin receptors induces long-term potentiation of spinal C-fibre-evoked potentials. Neuroscience 86:1209–1216CrossRefPubMedGoogle Scholar
  21. 21.
    Taniguchi S, Nakazawa T, Tanimura A, Kiyama Y, Tezuka T, Watabe AM, Katayama N, Yokoyama K, Inoue T, Izumi-Nakaseko H, Kakuta S, Sudo K, Iwakura Y, Umemori H, Murphy NP, Hashimoto K, Kano M, Manabe T, Yamamoto T (2009) Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour. EMBO J 28:3717–3729CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Li S, Cai J, Feng ZB, Jin ZR, Liu BH, Zhao HY, Jing HB, Wei TJ, Yang GN, Liu LY, Cui YJ, Xing GG (2017) BDNF contributes to spinal long-term potentiation and mechanical hypersensitivity via Fyn-mediated phosphorylation of NMDA receptor GluN2B subunit at tyrosine 1472 in rats following spinal nerve ligation. Neurochem Res 42:2712–2729Google Scholar
  23. 23.
    Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110CrossRefPubMedGoogle Scholar
  24. 24.
    Wei XH, Yang T, Wu Q, Xin WJ, Wu JL, Wang YQ, Zang Y, Wang J, Li YY, Liu XG (2012) Peri-sciatic administration of recombinant rat IL-1beta induces mechanical allodynia by activation of src-family kinases in spinal microglia in rats. Exp Neurol 234:389–397CrossRefPubMedGoogle Scholar
  25. 25.
    Koo CH, Yoon S, Kim BR, Cho YJ, Kim TK, Jeon Y, Seo JH (2017) Intraoperative naloxone reduces remifentanil-induced postoperative hyperalgesia but not pain: a randomized controlled trial. Br J Anaesth 119:1161–1168CrossRefGoogle Scholar
  26. 26.
    Lahtinen P, Kokki H, Hynynen M (2008) Remifentanil infusion does not induce opioid tolerance after cardiac surgery. Jof Cardiothorac Vasc Anesth 22:225–229CrossRefGoogle Scholar
  27. 27.
    Ishii H, Petrenko AB, Kohno T, Baba H (2013) No evidence for the development of acute analgesic tolerance during and hyperalgesia after prolonged remifentanil administration in mice. Mol Pain 9:11CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Gruber-Schoffnegger D, Drdla-Schutting R, Honigsperger C, Wunderbaldinger G, Gassner M, Sandkuhler J (2013) Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-alpha and IL-1beta is mediated by glial cells. J Neurosci 33:6540–6551CrossRefPubMedGoogle Scholar
  29. 29.
    Kim SH, Stoicea N, Soghomonyan S, Bergese SD (2015) Remifentanil-acute opioid tolerance and opioid-induced hyperalgesia: a systematic review. Am J Ther 22:e62–e74CrossRefPubMedGoogle Scholar
  30. 30.
    Beck H, Schröck H, Sandkühler J (1995) Controlled superfusion of the rat spinal cord for studying non-synaptic transmission: an autoradiographic analysis. J Neurosci Methods 58:193–202CrossRefPubMedGoogle Scholar
  31. 31.
    Stroumpos C, Manolaraki M, Paspatis GA (2010) Remifentanil, a different opioid: potential clinical applications and safety aspects. Expert Opin Drug Saf 9:355–364CrossRefPubMedGoogle Scholar
  32. 32.
    Chu LF, D’Arcy N, Brady C, Zamora AK, Young CA, Kim JE, Clemenson AM, Angst MS, Clark JD (2012) Analgesic tolerance without demonstrable opioid-induced hyperalgesia: a double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain. Pain 153:1583–1592CrossRefPubMedGoogle Scholar
  33. 33.
    Kronschlager MT, Drdla-Schutting R, Gassner M, Honsek SD, Teuchmann HL, Sandkuhler J (2016) Gliogenic LTP spreads widely in nociceptive pathways. Science 354:1144–1148CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ying YL, Wei XH, Xu XB, She SZ, Zhou LJ, Lv J, Li D, Zheng B, Liu XG (2014) Over-expression of P2 × 7 receptors in spinal glial cells contributes to the development of chronic postsurgical pain induced by skin/muscle incision and retraction (SMIR) in rats. Exp Neurol 261:836–843CrossRefPubMedGoogle Scholar
  35. 35.
    Li YY, Wei XH, Lu ZH, Chen JS, Huang QD, Gong QJ (2013) Src/p38 MAPK pathway in spinal microglia is involved in mechanical allodynia induced by peri-sciatic administration of recombinant rat TNF-alpha. Brain Res Bull 96:54–61CrossRefPubMedGoogle Scholar
  36. 36.
    Liu XJ, Gingrich JR, Vargas-Caballero M, Dong YN, Sengar A, Beggs S, Wang SH, Ding HK, Frankland PW, Salter MW (2008) Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex. Nat Med 14:1325–1332CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Yang HB, Yang X, Cao J, Li S, Liu YN, Suo ZW, Cui HB, Guo Z, Hu XD (2011) cAMP-dependent protein kinase activated Fyn in spinal dorsal horn to regulate NMDA receptor function during inflammatory pain. J Neurochem 116:93–104CrossRefPubMedGoogle Scholar
  38. 38.
    Huang Y, Li Y, Zhong X, Hu Y, Liu P, Zhao Y, Deng Z, Liu X, Liu S, Zhong Y (2017) Src-family kinases activation in spinal microglia contributes to central sensitization and chronic pain after lumbar disc herniation. Mol Pain 13:1744806917733637PubMedPubMedCentralGoogle Scholar
  39. 39.
    Zhang L, Berta T, Xu ZZ, Liu T, Park JY, Ji RR (2011) TNF-alpha contributes to spinal cord synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2. Pain 152:419–427CrossRefPubMedGoogle Scholar
  40. 40.
    Zhang L, Tetrault J, Wang W, Loh HH, Law PY (2006) Short- and long-term regulation of adenylyl cyclase activity by delta-opioid receptor are mediated by Galphai2 in neuroblastoma N2A cells. Mol Pharmacol 69:1810–1819CrossRefPubMedGoogle Scholar
  41. 41.
    Zhang L, Loh HH, Law PY (2013) A novel noncanonical signaling pathway for the mu-opioid receptor. Mol Pharmacol 84:844–853CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Nestler EJ (1997) Molecular mechanisms of opiate and cocaine addiction. Curr Opin Neurobiol 7:713–719CrossRefPubMedGoogle Scholar
  43. 43.
    Nogales E (2000) Structural insights into microtubule function. Annu Rev Biochem 69:277–302CrossRefPubMedGoogle Scholar
  44. 44.
    Palazzo A, Ackerman B, Gundersen GG (2003) Cell biology: tubulin acetylation and cell motility. Nature 421:230CrossRefPubMedGoogle Scholar
  45. 45.
    Tsai RY, Cheng YC, Wong CS (2015) (+)-Naloxone inhibits morphine-induced chemotaxis via prevention of heat shock protein 90 cleavage in microglia. J Formos Med Assoc 114:446–455CrossRefPubMedGoogle Scholar
  46. 46.
    Chen SX, Liao GJ, Yao PW, Wang SK, Li YY, Zeng WA, Liu XG, Zang Y (2018) Calpain-2 regulates TNF-alpha expression associated with neuropathic pain following motor nerve injury. Neuroscience 376:142–151CrossRefPubMedGoogle Scholar
  47. 47.
    Chen SX, Wang SK, Yao PW, Liao GJ, Na XD, Li YY, Zeng WA, Liu XG, Zang Y (2018) Early CALP2 expression and microglial activation are potential inducers of spinal IL-6 up-regulation and bilateral pain following motor nerve injury. J Neurochem 145:154–169CrossRefPubMedGoogle Scholar
  48. 48.
    Li YZ, Tang XH, Wang CY, Hu N, Xie KL, Wang HY, Yu YH, Wang GL (2014) Glycogen synthase kinase-3beta inhibition prevents remifentanil-induced postoperative hyperalgesia via regulating the expression and function of AMPA receptors. Anesth Analg 119:978–987CrossRefPubMedGoogle Scholar
  49. 49.
    Sun Y, Zhang W, Liu Y, Liu X, Ma Z, Gu X (2014) Intrathecal injection of JWH015 attenuates remifentanil-induced postoperative hyperalgesia by inhibiting activation of spinal glia in a rat model. Anesth Analg 118:841–853CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Anesthesiology, SunYat-SenMemorial HospitalSunYat-Sen UniversityGuangzhouPeople’s Republic of China
  2. 2.Department of Physiology and Pain Research Center, Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouPeople’s Republic of China
  3. 3.Guangdong Provincial Key Laboratory of Brain Function and DiseaseGuangzhouPeople’s Republic of China

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