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A Role for Transmembrane Protein 16C/Slack Impairment in Excitatory Nociceptive Synaptic Plasticity in the Pathogenesis of Remifentanil-induced Hyperalgesia in Rats

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Abstract

Remifentanil is widely used to control intraoperative pain. However, its analgesic effect is limited by the generation of postoperative hyperalgesia. In this study, we investigated whether the impairment of transmembrane protein 16C (TMEM16C)/Slack is required for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) activation in remifentanil-induced postoperative hyperalgesia. Remifentanil anesthesia reduced the paw withdrawal threshold from 2 h to 48 h postoperatively, with a decrease in the expression of TMEM16C and Slack in the dorsal root ganglia (DRG) and spinal cord. Knockdown of TMEM16C in the DRG reduced the expression of Slack and elevated the basal peripheral sensitivity and AMPAR expression and function. Overexpression of TMEM16C in the DRG impaired remifentanil-induced ERK1/2 phosphorylation and behavioral hyperalgesia. AMPAR-mediated current and neuronal excitability were downregulated by TMEM16C overexpression in the spinal cord. Taken together, these findings suggest that TMEM16C/Slack regulation of excitatory synaptic plasticity via GluA1-containing AMPARs is critical in the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats.

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References

  1. Zhang L, Shu R, Zhao Q, Li Y, Yu Y, Wang G. Preoperative butorphanol and flurbiprofen axetil therapy attenuates remifentanil-induced hyperalgesia after laparoscopic gynaecological surgery: a randomized double-blind controlled trial. Br J Anaesth 2016, 117: 504–511.

    Article  CAS  PubMed  Google Scholar 

  2. Shu RC, Zhang LL, Wang CY, Li N, Wang HY, Xie KL. Spinal peroxynitrite contributes to remifentanil-induced postoperative hyperalgesia via enhancement of divalent metal transporter 1 without iron-responsive element-mediated iron accumulation in rats. Anesthesiology 2015, 122: 908–920.

    Article  CAS  PubMed  Google Scholar 

  3. Gong G, Hu L, Qin F, Yin L, Yi X, Yuan L, Wu W. Spinal WNT pathway contributes to remifentanil induced hyperalgesia through regulating fractalkine and CX3CR1 in rats. Neurosci lett 2016, 633: 21–27.

    Article  CAS  PubMed  Google Scholar 

  4. Yu EHY, Tran DHD, Lam SW, Irwin MG. Remifentanil tolerance and hyperalgesia: short-term gain, long-term pain?. Anaesthesia 2016, 71: 1347–1362.

    Article  CAS  PubMed  Google Scholar 

  5. Kim SH, Stoicea N, Soghomonyan S, Bergese SD. Intraoperative use of remifentanil and opioid induced hyperalgesia/acute opioid tolerance: systematic review. Front Pharmacol 2014, 5: 108.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Stoicea N, Russell D, Weidner G, Durda M, Joseph NC, Yu J, Bergese SD. Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin. Front Pharmacol 2015, 6: 104.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Fletcher D, Martinez V. Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Br J Anaesth 2014, 112: 991–1004.

    Article  CAS  PubMed  Google Scholar 

  8. de Hoogd S, Ahlers SJGM, van Dongen EPA, van de Garde EMW, Hamilton-Ter Brake TAT, Dahan A, et al. Is intraoperative remifentanil associated with acute or chronic postoperative pain after prolonged surgery? An update of the literature. Clin J Pain 2016, 32: 726–735.

    Article  PubMed  Google Scholar 

  9. Araldi D, Ferrari LF, Levine JD. Repeated Mu-opioid exposure induces a novel form of the hyperalgesic priming model for transition to chronic pain. J Neurosci 2015, 35: 12502–12517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Henley JM, Barker EA, Glebov OO. Routes, destinations and delays: recent advances in AMPA receptor trafficking. Trends Neurosci 2011, 34: 258–268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tao YX. Dorsal horn alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking in inflammatory pain. Anesthesiology 2010, 112: 1259–1265.

    Article  CAS  PubMed  Google Scholar 

  12. Hu R, Li L, Li D, Tan W, Wan L, Zhu C, et al. Downregulation of Cdh1 signalling in spinal dorsal horn contributes to the maintenance of mechanical allodynia after nerve injury in rats. Mol Pain 2016, 12: 1744806916647376.

    PubMed  PubMed Central  Google Scholar 

  13. Kopach O, Krotov V, Belan P, Voitenko N. Inflammatory-induced changes in synaptic drive and postsynaptic AMPARs in lamina II dorsal horn neurons are cell-type specific. Pain 2015, 156: 428–438.

    Article  CAS  PubMed  Google Scholar 

  14. Luo C, Kuner T, Kuner R. Synaptic plasticity in pathological pain. Trends Neurosci 2014, 37: 343–355.

    Article  CAS  PubMed  Google Scholar 

  15. Li YZ, Tang XH, Wang CY, Hu N, Xie KL, Wang HY, et al. Glycogen synthase kinase-3β inhibition prevents remifentanil-induced postoperative hyperalgesia via regulating the expression and function of AMPA receptors. Anesth Analg 2014, 119: 978–987.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang L, Guo S, Zhao Q, Li Y, Song C, Wang C, et al. Spinal protein kinase Mζ regulates α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking and dendritic spine plasticity via kalirin-7 in the pathogenesis of remifentanil-induced postincisional hyperalgesia in rats. Anesthesiology 2018, 129: 173–186.

    Article  CAS  PubMed  Google Scholar 

  17. Bhattacharjee A, Kaczmarek LK. For K+ channels, Na+ is the new Ca2+. Trends Neurosci 2005, 28: 422–428.

    Article  CAS  PubMed  Google Scholar 

  18. Tamsett TJ, Picchione KE, Bhattacharjee A. NAD+ activates KNa channels in dorsal root ganglion neurons. J Neurosci 2009, 29: 5127–5134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nuwer MO, Picchione KE, Bhattacharjee A. PKA-induced internalization of slack KNa channels produces dorsal root ganglion neuron hyperexcitability. J Neurosci 2010, 30: 14165–14172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Huang F, Wang X, Ostertag EM, Nuwal T, Huang B, Jan YN, et al. TMEM16C facilitates Na+-activated K+ currents in rat sensory neurons and regulates pain processing. Nat Neurosci 2013, 16: 1284–1290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Franceschetti S, Lavazza T, Curia G, Aracri P, Panzica F, Sancini G, et al. Na+-activated K+ current contributes to postexcitatory hyperpolarization in neocortical intrinsically bursting neurons. J Neurophysiol 2003, 89: 2101–2111.

    Article  CAS  PubMed  Google Scholar 

  22. Wallén P, Robertson B, Cangiano L, Löw P, Bhattacharjee A, Kaczmarek LK, et al. Sodium-dependent potassium channels of a Slack-like subtype contribute to the slow afterhyperpolarization in lamprey spinal neurons. J Physiol 2007, 585: 75–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Martinez-Espinosa PL, Wu J, Yang C, Gonzalez-Perez V, Zhou H, Liang H, et al. Knockout of Slo2.2 enhances itch, abolishes KNa current, and increases action potential firing frequency in DRG neurons. Elife 2015, 4: e10013.

  24. Evely KM, Pryce KD, Bausch AE, Lukowski R, Ruth P, Haj-Dahmane S, et al. Slack K(Na) channels influence dorsal horn synapses and nociceptive behavior. Mol Pain 2017, 13: 1744806917714342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nanou E, El Manira A. A postsynaptic negative feedback mediated by coupling between AMPA receptors and Na+-activated K+ channels in spinal cord neurones. Eur J Neurosci 2007, 25: 445–450.

    Article  PubMed  Google Scholar 

  26. Gadotti VM, Zamponi GW. TMEM16C cuts pain no SLACK. Nat Neurosci 2013, 16: 1165–1166.

    Article  CAS  PubMed  Google Scholar 

  27. Yuan Y, Wang JY, Yuan F, Xie KL, Yu YH, Wang GL. Glycogen synthase kinase-3β contributes to remifentanil-induced postoperative hyperalgesia via regulating N-methyl-D-aspartate receptor trafficking. Anesth Analg 2013, 116: 473–481.

    Article  CAS  PubMed  Google Scholar 

  28. Kumar P, Wu H, McBride JL, Jung KE, Kim MH, Davidson BL, et al. Transvascular delivery of small interfering RNA to the central nervous system. Nature 2007, 448: 39–43.

    Article  CAS  PubMed  Google Scholar 

  29. Berta T, Park CK, Xu ZZ, Xie RG, Liu T, Lü N, et al. Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion. J Clin Invest 2014, 124: 1173–1186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhao X, Tang Z, Zhang H, Atianjoh FE, Zhao JY, Liang L, et al. A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons. Nat Neurosci 2013, 16: 1024–1031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li Z, Gu X, Sun L, Wu S, Liang L, Cao J, et al. Dorsal root ganglion myeloid zinc finger protein 1 contributes to neuropathic pain after peripheral nerve trauma. Pain 2015, 156: 711–721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. Lin JS, Lai EM. Protein-protein interactions: Co-immunoprecipitation. Methods Mol Biol 2017, 1615: 211–219.

    Article  PubMed  CAS  Google Scholar 

  34. Zhao JY, Liang L, Gu X, Li Z, Wu S, Sun L, et al. DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons. Nat Commun 2017, 8: 14712.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Liang L, Gu X, Zhao JY, Wu S, Miao X, Xiao J, et al. G9a participates in nerve injury-induced Kcna2 downregulation in primary sensory neurons. Sci Rep 2016, 6: 37704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Xie RG, Gao YJ, Park CK, Lu N, Luo C, Wang WT, et al. Spinal CCL2 promotes central sensitization, long-term potentiation, and inflammatory pain via CCR2: Further insights into molecular, synaptic, and cellular mechanisms. Neurosci Bull 2018, 34: 13–21.

    Article  CAS  PubMed  Google Scholar 

  37. Turovskaya MV, Gaidin SG, Vedunova MV, Babaev AA, Turovsky EA. BDNF overexpression enhances the preconditioning effect of brief episodes of hypoxia, promoting survival of GABAergic neurons. Neurosci Bull 2020, 36: 733–760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Picollo A, Malvezzi M, Accardi A. TMEM16 proteins: unknown structure and confusing functions. J Mol Biol 2015, 427: 94–105.

    Article  CAS  PubMed  Google Scholar 

  39. Ran C, Fourier C, Arafa D, Liesecke F, Sjöstrand C, Waldenlind E, et al. Anoctamin 3: a possible link between cluster headache and Ca2+ signaling. Brain Sci 2019, 9: 184.

    Article  CAS  PubMed Central  Google Scholar 

  40. Lu R, Bausch AE, Kallenborn-Gerhardt W, Stoetzer C, Debruin N, Ruth P, et al. Slack channels expressed in sensory neurons control neuropathic pain in mice. J Neurosci 2015, 35: 1125–1135.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Abrahamsen B, Zhao J, Asante CO, Cendan CM, Marsh S, Martinez-Barbera JP, et al. The cell and molecular basis of mechanical, cold, and inflammatory pain. Science 2008, 321: 702–705.

    Article  CAS  PubMed  Google Scholar 

  42. Pryce KD, Powell R, Agwa D, Evely KM, Sheehan GD, Nip A, et al. Magi-1 scaffolds Na(V)1.8 and Slack K(Na) channels in dorsal root ganglion neurons regulating excitability and pain. FASEB J 2019, 33: 7315–7330.

  43. Gururaj S, Evely KM, Pryce KD, Li J, Qu J, Bhattacharjee A. Protein kinase A-induced internalization of Slack channels from the neuronal membrane occurs by adaptor protein-2/clathrin-mediated endocytosis. J Biol Chem 2017, 293: 19304.

    Article  Google Scholar 

  44. Budelli G, Hage TA, Wei A, Rojas P, Jong JY, O’Malley K, Salkoff L. Na+-activated K+ channels express a large delayed outward current in neurons during normal physiology. Nat Neurosci 2009, 12: 745–750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fimiani C, Goina E, Su Q, Gao G, Mallamaci A. RNA activation of haploinsufficient Foxg1 gene in murine neocortex. Sci Rep 2016, 6: 39311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dryer SE. Na+-activated K+ channels: a new family of large-conductance ion channels. Trends Neurosci 1994, 17: 155–160.

    Article  CAS  PubMed  Google Scholar 

  47. Nanou E, El Manira A. Mechanisms of modulation of AMPA-induced Na+-activated K+ current by mGluR1. J Neurophysiol 2010, 103: 441–445.

    Article  CAS  PubMed  Google Scholar 

  48. Nanou E, Kyriakatos A, Bhattacharjee A, Kaczmarek LK, Paratcha G, El Manira A. Na+-mediated coupling between AMPA receptors and KNa channels shapes synaptic transmission. Proc Natl Acad Sci USA 2008, 105: 20941–20946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kaczmarek LK. Slack, Slick and sodium-activated potassium channels. ISRN Neurosci 2013, 2013: 354262.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82071243, 81801107, 81772043, and 81400908), Tianjin Natural Science Foundation (20JCYBJC00460) and Young Elite Scientists Sponsorship Program by Tianjin Municipality, China (TJSQNTJ-2020-10).

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  1. Yize Li and Linlin Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin Research Institute of Anesthesiology, Tianjin, 300052, China

    Yize Li, Linlin Zhang, Jing Li, Chunyan Wang, Yi Chen, Yuan Yuan, Keliang Xie, Guolin Wang & Yonghao Yu

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Li, Y., Zhang, L., Li, J. et al. A Role for Transmembrane Protein 16C/Slack Impairment in Excitatory Nociceptive Synaptic Plasticity in the Pathogenesis of Remifentanil-induced Hyperalgesia in Rats. Neurosci. Bull. 37, 669–683 (2021). https://doi.org/10.1007/s12264-021-00652-5

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