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Cortical LTP: A Synaptic Model for Chronic Pain

  • Min Zhuo
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1099)

Abstract

Cumulative evidence indicates that cortical synapses not only play important roles in pain perception and related emotional functions but also undergo long-term potentiation (LTP) and contribute to chronic pain. LTP is found at two key cortical regions such as the anterior cingulate cortex (ACC) and insular cortex (IC), and inhibition of cortical LTP produces analgesic effects as well as anxiolytic effects. In this chapter, I will summarize our work on ACC and IC and provide evidence for calcium-stimulated AC1 as a key molecule for cortical LTP and chronic pain.

Keywords

Anterior cingulate cortex Insular cortex Long-term potentiation NMDA AC1 

Notes

Acknowledgment

I would like to thank Melissa Lepp for the help of the citation and reading of the manuscript. This work was supported by grants from the EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health, Canada Research Chair, Canadian Institute for Health Research operating grants (CIHR66975, 84256) and project grant (PJT-148648), Azrieli Neurodevelopmental Research Program, and Brain Canada (MZ).

References

  1. 1.
    Bliss TVP, Collingridge GL, Kaang B-K, Zhuo M (2016) Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Nat Rev Neurosci 17:485–496CrossRefGoogle Scholar
  2. 2.
    Bushnell MC, Čeko M, Low LA (2013) Cognitive and emotional control of pain and its disruption in chronic pain. Nat Rev Neurosci 14:502–511CrossRefPubMedCentralGoogle Scholar
  3. 3.
    Chen T, O’Den G, Song Q, Koga K, Zhang M-M, Zhuo M (2014) Adenylyl cyclase subtype 1 is essential for late-phase long term potentiation and spatial propagation of synaptic responses in the anterior cingulate cortex of adult mice. Mol Pain 10:65PubMedPubMedCentralGoogle Scholar
  4. 4.
    Kang W-b, Yang Q, Guo Y-y, Wang L, Wang D-s, Cheng Q, X-m L, Tang J, Zhao J-N, Liu G, Zhuo M, Zhao M-G (2016) Analgesic effects of adenylyl cyclase inhibitor NB001 on bone cancer pain in a mouse model. Mol Pain 12:1744806916652409CrossRefPubMedCentralGoogle Scholar
  5. 5.
    Ko H-G et al (2018) Rapid turnover of cortical NCAM1 regulates synaptic reorganization after peripheral nerve injury. Cell Rep 22:748–759CrossRefPubMedCentralGoogle Scholar
  6. 6.
    Koga K, Descalzi G, Chen T, Ko H-G, Lu J, Li S, Son J, Kim T, Kwak C, Huganir Richard L, M-g Z, Kaang B-K, Collingridge Graham L, Zhuo M (2015a) Coexistence of two forms of LTP in ACC provides a synaptic mechanism for the interactions between anxiety and chronic pain. Neuron 85:377–389CrossRefPubMedCentralGoogle Scholar
  7. 7.
    Koga K, Liu MG, Qiu S, Song Q, O’Den G, Chen T, Zhuo M (2015b) Impaired presynaptic long-term potentiation in the anterior cingulate cortex of Fmr1 knock-out mice. J Neurosci 35:2033–2043CrossRefPubMedCentralGoogle Scholar
  8. 8.
    Li XYKH, Chen T, Descalzi G, Koga K, Wang H, Kim SS, Shang Y, Kwak C, Park SW, Shim J, Lee K, Collingridge GL, Kaang BK, Zhuo M (2010) Alleviating neuropathic pain hypersensitivity by inhibiting PKMζ in the anterior cingulate cortex. Science 330:1400–1404CrossRefGoogle Scholar
  9. 9.
    Liauw J, Wu L-J, Zhuo M (2005) Calcium-stimulated adenylyl Cyclases required for long-term potentiation in the anterior cingulate cortex. J Neurophysiol 94:878–882CrossRefGoogle Scholar
  10. 10.
    Liu M-G, Zhuo M (2014) Loss of long-term depression in the insular cortex after tail amputation in adult mice. Mol Pain 10:1–1PubMedPubMedCentralGoogle Scholar
  11. 11.
    Liu M-G, Kang SJ, Shi T-Y, Koga K, Zhang M-M, Collingridge GL, Kaang B-K, Zhuo M (2013) Long-term potentiation of synaptic transmission in the adult mouse insular cortex: multielectrode array recordings. J Neurophysiol 110:505–521CrossRefPubMedCentralGoogle Scholar
  12. 12.
    Lu J-S, Yue F, Liu X, Chen T, Zhuo M (2016) Characterization of the anterior cingulate cortex in adult tree shrew. Mol Pain 12:1744806916684515CrossRefPubMedCentralGoogle Scholar
  13. 13.
    Qiu S, Zhang M, Liu Y, Guo Y, Zhao H, Song Q, Zhao M, Huganir RL, Luo J, Xu H, Zhuo M (2014) GluA1 phosphorylation contributes to postsynaptic amplification of neuropathic pain in the insular cortex. J Neurosci 34:13505–13515CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Qiu SCT, Koga K, Guo YY, Xu H, Song Q, Wang JJ, Descalzi G, Kaang BK, Luo JH, Zhuo M, Zhao MG (2013) An increase in synaptic NMDA receptors in the insular cortex contributes to neuropathic pain. Sci Signal 6:ra34–ra34CrossRefGoogle Scholar
  15. 15.
    Song Q, Zheng H-W, Li X-H, Huganir RL, Kuner T, Zhuo M, Chen T (2017) Selective phosphorylation of AMPA receptor contributes to the network of long-term potentiation in the anterior cingulate cortex. J Neurosci 37:8534–8548CrossRefGoogle Scholar
  16. 16.
    Tang J, Ko S, Ding H-K, Qiu C-S, Calejesan AA, Zhuo M (2005) Pavlovian fear memory induced by activation in the anterior cingulate cortex. Mol Pain 1:6–6CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Wang H, Xu H, Wu L-J, Kim SS, Chen T, Koga K, Descalzi G, Gong B, Vadakkan KI, Zhang X, Kaang B-K, Zhuo M (2011) Identification of an adenylyl cyclase inhibitor for treating neuropathic and inflammatory pain. Sci Transl Med 3:65ra63–65ra63Google Scholar
  18. 18.
    Wei F, Zhuo M (2001) Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetised rat. J Physiol 532:823–833CrossRefPubMedCentralGoogle Scholar
  19. 19.
    Wei F, Li P, Zhuo M (1999) Loss of synaptic depression in mammalian anterior cingulate cortex after amputation. J Neurosci 19:9346–9354CrossRefGoogle Scholar
  20. 20.
    Wei FQC, Kim SJ, Muglia L, Maas JW Jr, Pineda VV, Xu HM, Chen ZF, Storm DR, Muglia LJ, Zhuo M (2002) Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron 36:713–726CrossRefGoogle Scholar
  21. 21.
    Xu H, Wu LJ, Wang H, Zhang X, Vadakkan KI, Kim SS, Steenland HW, Zhuo M (2008) Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex. J Neurosci 28:7445–7453CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Yamanaka M, Matsuura T, Pan H, Zhuo M (2017) Calcium-stimulated adenylyl cyclase subtype 1 (AC1) contributes to LTP in the insular cortex of adult mice. Heliyon 3:e00338CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Zhang M-M, Liu S-B, Chen T, Koga K, Zhang T, Li Y-Q, Zhuo M (2014) Effects of NB001 and gabapentin on irritable bowel syndrome-induced behavioral anxiety and spontaneous pain. Mol Brain 7:47–47CrossRefPubMedCentralGoogle Scholar
  24. 24.
    Zhuo M (2002) Glutamate receptors and persistent pain: targeting forebrain NR2B subunits. Drug Discov Today 7:259–267CrossRefPubMedCentralGoogle Scholar
  25. 25.
    Zhuo M (2008) Cortical excitation and chronic pain. Trends Neurosci 31:199–207CrossRefGoogle Scholar
  26. 26.
    Zhuo M (2011) Cortical plasticity as a new endpoint measurement for chronic pain. Mol Pain 7:54–54CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Zhuo M (2012) Targeting neuronal adenylyl cyclase for the treatment of chronic pain. Drug Discov Today 17:573–582CrossRefPubMedCentralGoogle Scholar
  28. 28.
    Zhuo M (2014) Long-term potentiation in the anterior cingulate cortex and chronic pain. Philos Trans R Soc B: Biol Sci 369:20130146CrossRefGoogle Scholar
  29. 29.
    Zhuo M (2016a) Neural mechanisms underlying anxiety-chronic pain interactions. Trends Neurosci 39:136–145CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Zhuo M (2016b) Contribution of synaptic plasticity in the insular cortex to chronic pain. Neuroscience 338:220–229CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of Physiology, Faculty of Medicine, Centre for the Study of PainUniversity of Toronto, Medical Sciences BuildingTorontoCanada

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