Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain

Key Points

  • The anterior cingulate cortex (ACC) plays an important part in chronic pain states.

  • NMDA-receptor-dependent postsynaptic long-term potentiation (LTP) in the ACC sustains the affective component of the pain state.

  • Kainate-receptor-dependent presynaptic LTP in the ACC contributes to pain-related anxiety.

  • The mechanism for neuropathic pain is linked to the expression of LTP in the ACC.

  • Upregulation of GluN2B-containing NMDA receptors is found in chronic neuropathic pain conditions.

  • Calcium-stimulated adenylyl cyclase 1 is a potential target for future treatment of chronic pain and anxiety.

Abstract

The anterior cingulate cortex (ACC) is activated in both acute and chronic pain. In this Review, we discuss increasing evidence from rodent studies that ACC activation contributes to chronic pain states and describe several forms of synaptic plasticity that may underlie this effect. In particular, one form of long-term potentiation (LTP) in the ACC, which is triggered by the activation of NMDA receptors and expressed by an increase in AMPA-receptor function, sustains the affective component of the pain state. Another form of LTP in the ACC, which is triggered by the activation of kainate receptors and expressed by an increase in glutamate release, may contribute to pain-related anxiety.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Major sensory inputs to and outputs from the ACC.
Figure 2: Forms of long-term potentiation and long-term depression in the ACC.
Figure 3: Signalling pathways that mediate the upregulation of excitatory transmission in the ACC in rodent models of chronic pain.

References

  1. 1

    Fields, H. L. & Besson, J.-M. R. Pain Modulation (Elsevier, 1988).

    Google Scholar 

  2. 2

    Wall, P. D. Pain: The Science of Suffering (Columbia Univ. Press, 2000).

    Google Scholar 

  3. 3

    Zhuo, M. Cortical excitation and chronic pain. Trends Neurosci. 31, 199–207 (2008).

    CAS  Google Scholar 

  4. 4

    Sandkuhler, J. Understanding LTP in pain pathways. Mol. Pain 3, 9 (2007). A comprehensive review of LTP in spinal pain pathways and its contribution to chronic pain.

    PubMed  PubMed Central  Google Scholar 

  5. 5

    Zhuo, M. Long-term potentiation in the anterior cingulate cortex and chronic pain. Phil. Trans. R. Soc. B 369, 20130146 (2014).

    Google Scholar 

  6. 6

    Bushnell, M. C., Ceko, M. & Low, L. A. Cognitive and emotional control of pain and its disruption in chronic pain. Nat. Rev. Neurosci. 14, 502–511 (2013). This article reviews recent progress in human imaging studies of chronic pain and describes its negative effects on cognition and emotion.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Apkarian, A. V., Bushnell, M. C., Treede, R. D. & Zubieta, J. K. Human brain mechanisms of pain perception and regulation in health and disease. Eur. J. Pain 9, 463–484 (2005).

    Google Scholar 

  8. 8

    Talbot, J. D. et al. Multiple representations of pain in human cerebral cortex. Science 251, 1355–1358 (1991).

    CAS  Google Scholar 

  9. 9

    Craig, A. D., Reiman, E. M., Evans, A. & Bushnell, M. C. Functional imaging of an illusion of pain. Nature 384, 258–260 (1996).

    CAS  Google Scholar 

  10. 10

    Eisenberger, N. I., Lieberman, M. D. & Williams, K. D. Does rejection hurt? An fMRI study of social exclusion. Science 302, 290–292 (2003). This report shows that activity in the ACC in humans can be triggered by social exclusion.

    CAS  Google Scholar 

  11. 11

    Yoshino, A. et al. Sadness enhances the experience of pain via neural activation in the anterior cingulate cortex and amygdala: an fMRI study. Neuroimage 50, 1194–1201 (2010).

    Google Scholar 

  12. 12

    Vogt, B. A. Pain and emotion interactions in subregions of the cingulate gyrus. Nat. Rev. Neurosci. 6, 533–544 (2005). This review article provides an overview of investigations into pain and related brain functions in the context of the ACC.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Devinsky, O., Morrell, M. J. & Vogt, B. A. Contributions of anterior cingulate cortex to behaviour. Brain 118, 279–306 (1995).

    Google Scholar 

  14. 14

    Chen, T. et al. Postsynaptic potentiation of corticospinal projecting neurons in the anterior cingulate cortex after nerve injury. Mol. Pain 10, 33 (2014).

    PubMed  PubMed Central  Google Scholar 

  15. 15

    Wu, L. J., Li, X., Chen, T., Ren, M. & Zhuo, M. Characterization of intracortical synaptic connections in the mouse anterior cingulate cortex using dual patch clamp recording. Mol. Brain 2, 32 (2009).

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Shyu, B. C. & Vogt, B. A. Short-term synaptic plasticity in the nociceptive thalamic-anterior cingulate pathway. Mol. Pain 5, 51 (2009).

    PubMed  PubMed Central  Google Scholar 

  17. 17

    Dum, R. P., Levinthal, D. J. & Strick, P. L. The spinothalamic system targets motor and sensory areas in the cerebral cortex of monkeys. J. Neurosci. 29, 14223–14235 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Kung, J. C. & Shyu, B. C. Potentiation of local field potentials in the anterior cingulate cortex evoked by the stimulation of the medial thalamic nuclei in rats. Brain Res. 953, 37–44 (2002).

    CAS  Google Scholar 

  19. 19

    Yang, J. W., Shih, H. C. & Shyu, B. C. Intracortical circuits in rat anterior cingulate cortex are activated by nociceptive inputs mediated by medial thalamus. J. Neurophysiol. 96, 3409–3422 (2006).

    Google Scholar 

  20. 20

    Delevich, K., Tucciarone, J., Huang, Z. J. & Li, B. The mediodorsal thalamus drives feedforward inhibition in the anterior cingulate cortex via parvalbumin interneurons. J. Neurosci. 35, 5743–5753 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Ma, W. & Peschanski, M. Spinal and trigeminal projections to the parabrachial nucleus in the rat: electron-microscopic evidence of a spino-ponto-amygdalian somatosensory pathway. Somatosens. Res. 5, 247–257 (1988).

    CAS  Google Scholar 

  22. 22

    Han, S., Soleiman, M. T., Soden, M. E., Zweifel, L. S. & Palmiter, R. D. Elucidating an affective pain circuit that creates a threat memory. Cell 162, 363–374 (2015). The authors show that parabrachial neurons expressing calcitonin gene-related peptide (CGRP) are crucial for relaying pain signals to the central nucleus of the amygdala.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Eto, K. et al. Inter-regional contribution of enhanced activity of the primary somatosensory cortex to the anterior cingulate cortex accelerates chronic pain behavior. J. Neurosci. 31, 7631–7636 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Bragin, E. O. et al. Cortical projections to the periaqueductal grey in the cat: a retrograde horseradish peroxidase study. Neurosci. Lett. 51, 271–275 (1984).

    CAS  Google Scholar 

  25. 25

    LeDoux, J. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).

    CAS  Google Scholar 

  26. 26

    Tovote, P., Fadok, J. P. & Luthi, A. Neuronal circuits for fear and anxiety. Nat. Rev. Neurosci. 16, 317–331 (2015). A recent review article summarizing progress in the study of neuronal mechanisms underlying anxiety and fear.

    CAS  Google Scholar 

  27. 27

    Medalla, M. & Barbas, H. The anterior cingulate cortex may enhance inhibition of lateral prefrontal cortex via m2 cholinergic receptors at dual synaptic sites. J. Neurosci. 32, 15611–15625 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Aston-Jones, G. & Cohen, J. D. Adaptive gain and the role of the locus coeruleus–norepinephrine system in optimal performance. J. Comp. Neurol. 493, 99–110 (2005).

    CAS  Google Scholar 

  29. 29

    Hickey, L. et al. Optoactivation of locus ceruleus neurons evokes bidirectional changes in thermal nociception in rats. J. Neurosci. 34, 4148–4160 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Chandler, D. J., Lamperski, C. S. & Waterhouse, B. D. Identification and distribution of projections from monoaminergic and cholinergic nuclei to functionally differentiated subregions of prefrontal cortex. Brain Res. 1522, 38–58 (2013).

    CAS  Google Scholar 

  31. 31

    Wu, L. J., Zhao, M. G., Toyoda, H., Ko, S. W. & Zhuo, M. Kainate receptor-mediated synaptic transmission in the adult anterior cingulate cortex. J. Neurophysiol. 94, 1805–1813 (2005).

    CAS  Google Scholar 

  32. 32

    Liauw, J., Wang, G. D. & Zhuo, M. NMDA receptors contribute to synaptic transmission in anterior cingulate cortex of adult mice. Sheng Li Xue Bao 55, 373–380 (2003).

    CAS  Google Scholar 

  33. 33

    Wu, L. J. et al. Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation. J. Neurosci. 25, 11107–11116 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Kang, S. J. et al. N-type voltage gated calcium channels mediate excitatory synaptic transmission in the anterior cingulate cortex of adult mice. Mol. Pain 9, 58 (2013).

    PubMed  PubMed Central  Google Scholar 

  35. 35

    Wu, L. J., Xu, H., Ren, M. & Zhuo, M. Genetic and pharmacological studies of GluR5 modulation of inhibitory synaptic transmission in the anterior cingulate cortex of adult mice. Dev. Neurobiol. 67, 146–157 (2007).

    CAS  Google Scholar 

  36. 36

    Gronbladh, A., Johansson, J., Nyberg, F. & Hallberg, M. Recombinant human growth hormone affects the density and functionality of GABAB receptors in the male rat brain. Neuroendocrinology 97, 203–211 (2013).

    Google Scholar 

  37. 37

    Scheperjans, F., Grefkes, C., Palomero-Gallagher, N., Schleicher, A. & Zilles, K. Subdivisions of human parietal area 5 revealed by quantitative receptor autoradiography: a parietal region between motor, somatosensory, and cingulate cortical areas. Neuroimage 25, 975–992 (2005).

    Google Scholar 

  38. 38

    Koga, K. et al. In vivo whole-cell patch-clamp recording of sensory synaptic responses of cingulate pyramidal neurons to noxious mechanical stimuli in adult mice. Mol. Pain 6, 62 (2010).

    PubMed  PubMed Central  Google Scholar 

  39. 39

    Yamamura, H. et al. Morphological and electrophysiological properties of ACCx nociceptive neurons in rats. Brain Res. 735, 83–92 (1996).

    CAS  Google Scholar 

  40. 40

    Hutchison, W. D., Davis, K. D., Lozano, A. M., Tasker, R. R. & Dostrovsky, J. O. Pain-related neurons in the human cingulate cortex. Nat. Neurosci. 2, 403–405 (1999).

    CAS  Google Scholar 

  41. 41

    Iwata, K. et al. Anterior cingulate cortical neuronal activity during perception of noxious thermal stimuli in monkeys. J. Neurophysiol. 94, 1980–1991 (2005).

    Google Scholar 

  42. 42

    Kang, S. J. et al. Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC. Mol. Brain 8, 81 (2015). Optogenetic activation of ACC pyramidal neurons leads to a reduction in the mechanical threshold for pain — an effect that is occluded in mice with inflammatory pain.

    PubMed  PubMed Central  Google Scholar 

  43. 43

    Johansen, J. P. & Fields, H. L. Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal. Nat. Neurosci. 7, 398–403 (2004). Using a rodent behavioural aversive model, this study demonstrates that chemical activation of ACC can lead to the formation of aversive memory.

    CAS  Google Scholar 

  44. 44

    Johansen, J. P., Fields, H. L. & Manning, B. H. The affective component of pain in rodents: direct evidence for a contribution of the anterior cingulate cortex. Proc. Natl Acad. Sci. USA 98, 8077–8082 (2001).

    CAS  Google Scholar 

  45. 45

    Qu, C. et al. Lesion of the rostral anterior cingulate cortex eliminates the aversiveness of spontaneous neuropathic pain following partial or complete axotomy. Pain 152, 1641–1648 (2011).

    PubMed  PubMed Central  Google Scholar 

  46. 46

    Gao, Y. J., Ren, W. H., Zhang, Y. Q. & Zhao, Z. Q. Contributions of the anterior cingulate cortex and amygdala to pain- and fear-conditioned place avoidance in rats. Pain 110, 343–353 (2004).

    Google Scholar 

  47. 47

    LaGraize, S. C. & Fuchs, P. N. GABAA but not GABAB receptors in the rostral anterior cingulate cortex selectively modulate pain-induced escape/avoidance behavior. Exp. Neurol. 204, 182–194 (2007).

    CAS  Google Scholar 

  48. 48

    Barthas, F. et al. The anterior cingulate cortex is a critical hub for pain-induced depression. Biol. Psychiatry 77, 236–245 (2015).

    Google Scholar 

  49. 49

    Donahue, R. R., LaGraize, S. C. & Fuchs, P. N. Electrolytic lesion of the anterior cingulate cortex decreases inflammatory, but not neuropathic nociceptive behavior in rats. Brain Res. 897, 131–138 (2001).

    CAS  Google Scholar 

  50. 50

    Gu, L. et al. Pain inhibition by optogenetic activation of specific anterior cingulate cortical neurons. PLoS ONE 10, e0117746 (2015).

    PubMed  PubMed Central  Google Scholar 

  51. 51

    Bliss, T. V. & Collingridge, G. L. Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide. Mol. Brain 6, 5 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

    CAS  Google Scholar 

  53. 53

    Sandkuhler, J. & Gruber-Schoffnegger, D. Hyperalgesia by synaptic long-term potentiation (LTP): an update. Curr. Opin. Pharmacol. 12, 18–27 (2012).

    PubMed  PubMed Central  Google Scholar 

  54. 54

    Li, X. Y. et al. Alleviating neuropathic pain hypersensitivity by inhibiting PKMζ in the anterior cingulate cortex. Science 330, 1400–1404 (2010). This paper demonstrates that NMDAR-mediated LTP of AMPAR function in the ACC contributes to behavioural sensitization in an animal model of neuropathic pain.

    CAS  Google Scholar 

  55. 55

    Chen, T. et al. 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, 65 (2014). In this paper, the authors identify an essential role for AC1 in the expression of late LTP in the ACC.

    PubMed  PubMed Central  Google Scholar 

  56. 56

    Liauw, J., Wu, L. J. & Zhuo, M. Calcium-stimulated adenylyl cyclases required for long-term potentiation in the anterior cingulate cortex. J. Neurophysiol. 94, 878–882 (2005).

    CAS  Google Scholar 

  57. 57

    Zhao, M. G. et al. Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory. Neuron 47, 859–872 (2005).

    CAS  Google Scholar 

  58. 58

    Volianskis, A. et al. Different NMDA receptor subtypes mediate induction of long-term potentiation and two forms of short-term potentiation at CA1 synapses in rat hippocampus in vitro. J. Physiol. 591, 955–972 (2013).

    CAS  Google Scholar 

  59. 59

    Koga, K. et al. Coexistence of two forms of LTP in ACC provides a synaptic mechanism for the interactions between anxiety and chronic pain. Neuron 85, 377–389 (2015). This article reports that both pre- and postsynaptic LTP coexist in ACC synapses, contributing to pain-induced anxiety and behavioural sensitization, respectively.

    CAS  Google Scholar 

  60. 60

    Bortolotto, Z. A. et al. Kainate receptors are involved in synaptic plasticity. Nature 402, 297–301 (1999).

    CAS  Google Scholar 

  61. 61

    Jane, D. E., Lodge, D. & Collingridge, G. L. Kainate receptors: pharmacology, function and therapeutic potential. Neuropharmacology 56, 90–113 (2009). The paper demonstrates that GluK1-containing kainate receptors can mediate the induction of NMDAR-independent LTP in the CNS.

    CAS  Google Scholar 

  62. 62

    Shin, R. M. et al. Hierarchical order of coexisting pre- and postsynaptic forms of long-term potentiation at synapses in amygdala. Proc. Natl Acad. Sci. USA 107, 19073–19078 (2010).

    CAS  Google Scholar 

  63. 63

    Alford, S., Frenguelli, B. G., Schofield, J. G. & Collingridge, G. L. Characterization of Ca2+ signals induced in hippocampal CA1 neurones by the synaptic activation of NMDA receptors. J. Physiol. 469, 693–716 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Bliss, T., Collingridge, G. & Morris, R. in The Hippocampus Book (eds Andersen, P., Morris, R., Amaral, D., Bliss, T. & O'Keefe, J.) 343–474 (Oxford Univ. Press, 2007).

    Google Scholar 

  65. 65

    Wei, F. et al. Calmodulin regulates synaptic plasticity in the anterior cingulate cortex and behavioral responses: a microelectroporation study in adult rodents. J. Neurosci. 23, 8402–8409 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Xia, Z. & Storm, D. R. Calmodulin-regulated adenylyl cyclases and neuromodulation. Curr. Opin. Neurobiol. 7, 391–396 (1997).

    CAS  Google Scholar 

  67. 67

    Wei, F. et al. Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron 36, 713–726 (2002).

    CAS  Google Scholar 

  68. 68

    Wang, H. et al. Identification of an adenylyl cyclase inhibitor for treating neuropathic and inflammatory pain. Sci. Transl. Med. 3, 65ra63 (2011).

    Google Scholar 

  69. 69

    Wei, F. et al. Calcium calmodulin-dependent protein kinase IV is required for fear memory. Nat. Neurosci. 5, 573–579 (2002).

    CAS  Google Scholar 

  70. 70

    Jones, M. W. et al. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat. Neurosci. 4, 289–296 (2001).

    CAS  Google Scholar 

  71. 71

    Ko, S. W. et al. Transcription factor Egr-1 is required for long-term fear memory and anxiety. Sheng Li Xue Bao 57, 421–432 (2005).

    CAS  Google Scholar 

  72. 72

    Zalfa, F. et al. The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell 112, 317–327 (2003).

    CAS  Google Scholar 

  73. 73

    Zhao, M. G. et al. Deficits in trace fear memory and long-term potentiation in a mouse model for fragile X syndrome. J. Neurosci. 25, 7385–7392 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Toyoda, H. et al. Requirement of extracellular signal-regulated kinase/mitogen-activated protein kinase for long-term potentiation in adult mouse anterior cingulate cortex. Mol. Pain 3, 36 (2007).

    PubMed  PubMed Central  Google Scholar 

  75. 75

    Nicoll, R. A. & Schmitz, D. Synaptic plasticity at hippocampal mossy fibre synapses. Nat. Rev. Neurosci. 6, 863–876 (2005).

    CAS  Google Scholar 

  76. 76

    Koga, K. et al. Impaired presynaptic long-term potentiation in the anterior cingulate cortex of Fmr1 knock-out mice. J. Neurosci. 35, 2033–2043 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267 (2000).

    CAS  Google Scholar 

  78. 78

    Passafaro, M., Piech, V. & Sheng, M. Subunit-specific temporal and spatial patterns of AMPA receptor exocytosis in hippocampal neurons. Nat. Neurosci. 4, 917–926 (2001).

    CAS  Google Scholar 

  79. 79

    Toyoda, H., Wu, L. J., Zhao, M. G., Xu, H. & Zhuo, M. Time-dependent postsynaptic AMPA GluR1 receptor recruitment in the cingulate synaptic potentiation. Dev. Neurobiol. 67, 498–509 (2007).

    CAS  Google Scholar 

  80. 80

    Toyoda, H. et al. Roles of the AMPA receptor subunit GluA1 but not GluA2 in synaptic potentiation and activation of ERK in the anterior cingulate cortex. Mol. Pain 5, 46 (2009).

    PubMed  PubMed Central  Google Scholar 

  81. 81

    Plant, K. et al. Transient incorporation of native GluR2-lacking AMPA receptors during hippocampal long-term potentiation. Nat. Neurosci. 9, 602–604 (2006).

    CAS  Google Scholar 

  82. 82

    Park, P. et al. Calcium-permeable AMPA receptors mediate the induction of the protein kinase A-dependent component of long-term potentiation in the hippocampus. J. Neurosci. 36, 622–631 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Sacktor, T. C. Memory maintenance by PKMζ — an evolutionary perspective. Mol. Brain 5, 31 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Yao, Y. et al. PKMζ maintains late long-term potentiation by N-ethylmaleimide-sensitive factor/GluR2-dependent trafficking of postsynaptic AMPA receptors. J. Neurosci. 28, 7820–7827 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Volk, L. J., Bachman, J. L., Johnson, R., Yu, Y. & Huganir, R. L. PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory. Nature 493, 420–423 (2013).

    CAS  Google Scholar 

  86. 86

    Lee, A. M. et al. Prkcz null mice show normal learning and memory. Nature 493, 416–419 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Tsokas, P. et al. Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice. eLife 5, e14846 (2016).

    PubMed  PubMed Central  Google Scholar 

  88. 88

    Mellor, J., Nicoll, R. A. & Schmitz, D. Mediation of hippocampal mossy fiber long-term potentiation by presynaptic Ih channels. Science 295, 143–147 (2002).

    CAS  Google Scholar 

  89. 89

    Chevaleyre, V. & Castillo, P. E. Assessing the role of Ih channels in synaptic transmission and mossy fiber LTP. Proc. Natl Acad. Sci. USA 99, 9538–9543 (2002).

    CAS  Google Scholar 

  90. 90

    Collingridge, G. L., Peineau, S., Howland, J. G. & Wang, Y. T. Long-term depression in the CNS. Nat. Rev. Neurosci. 11, 459–473 (2010).

    CAS  Google Scholar 

  91. 91

    Wei, F., Li, P. & Zhuo, M. Loss of synaptic depression in mammalian anterior cingulate cortex after amputation. J. Neurosci. 19, 9346–9354 (1999).

    CAS  Google Scholar 

  92. 92

    Kang, S. J. et al. Plasticity of metabotropic glutamate receptor-dependent long-term depression in the anterior cingulate cortex after amputation. J. Neurosci. 32, 11318–11329 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Toyoda, H., Zhao, M. G. & Zhuo, M. Roles of NMDA receptor NR2A and NR2B subtypes for long-term depression in the anterior cingulate cortex. Eur. J. Neurosci. 22, 485–494 (2005).

    Google Scholar 

  94. 94

    Toyoda, H. et al. Long-term depression requires postsynaptic AMPA GluR2 receptor in adult mouse cingulate cortex. J. Cell. Physiol. 211, 336–343 (2007).

    CAS  Google Scholar 

  95. 95

    Wei, F. & Zhuo, M. Activation of Erk in the anterior cingulate cortex during the induction and expression of chronic pain. Mol. Pain 4, 28 (2008).

    PubMed  PubMed Central  Google Scholar 

  96. 96

    Wu, M. F., Pang, Z. P., Zhuo, M. & Xu, Z. C. Prolonged membrane potential depolarization in cingulate pyramidal cells after digit amputation in adult rats. Mol. Pain 1, 23 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Wei, F. & Zhuo, M. Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetised rat. J. Physiol. 532, 823–833 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Chiou, C. S., Huang, C. C., Liang, Y. C., Tsai, Y. C. & Hsu, K. S. Impairment of long-term depression in the anterior cingulate cortex of mice with bone cancer pain. Pain 153, 2097–2108 (2012). This paper demonstrates that LTD in the ACC is impaired in an animal model of cancer pain.

    Google Scholar 

  99. 99

    Xu, H. et al. Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex. J. Neurosci. 28, 7445–7453 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Zhao, M. G. et al. Enhanced presynaptic neurotransmitter release in the anterior cingulate cortex of mice with chronic pain. J. Neurosci. 26, 8923–8930 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Bie, B., Brown, D. L. & Naguib, M. Increased synaptic GluR1 subunits in the anterior cingulate cortex of rats with peripheral inflammation. Eur. J. Pharmacol. 653, 26–31 (2011).

    CAS  Google Scholar 

  102. 102

    Chen, T. et al. Postsynaptic insertion of AMPA receptor onto cortical pyramidal neurons in the anterior cingulate cortex after peripheral nerve injury. Mol. Brain 7, 76 (2014).

    PubMed  PubMed Central  Google Scholar 

  103. 103

    Hartmann, B. et al. The AMPA receptor subunits GluR-A and GluR-B reciprocally modulate spinal synaptic plasticity and inflammatory pain. Neuron 44, 637–650 (2004).

    CAS  Google Scholar 

  104. 104

    Yang, J. X. et al. Caveolin-1 in the anterior cingulate cortex modulates chronic neuropathic pain via regulation of NMDA receptor 2B subunit. J. Neurosci. 35, 36–52 (2015). This paper provides insights into the mechanisms by which NMDAR-mediated functions are upregulated in the ACC during neuropathic pain.

    PubMed  PubMed Central  Google Scholar 

  105. 105

    Metz, A. E., Yau, H. J., Centeno, M. V., Apkarian, A. V. & Martina, M. Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain. Proc. Natl Acad. Sci. USA 106, 2423–2428 (2009).

    CAS  Google Scholar 

  106. 106

    Qiu, S. et al. An increase in synaptic NMDA receptors in the insular cortex contributes to neuropathic pain. Sci. Signal. 6, ra34 (2013).

    Google Scholar 

  107. 107

    Niikura, K. et al. Enhancement of glutamatergic transmission in the cingulate cortex in response to mild noxious stimuli under a neuropathic pain-like state. Synapse 65, 424–432 (2011).

    CAS  Google Scholar 

  108. 108

    Cao, X. Y. et al. Characterization of intrinsic properties of cingulate pyramidal neurons in adult mice after nerve injury. Mol. Pain 5, 73 (2009).

    PubMed  PubMed Central  Google Scholar 

  109. 109

    Li, X. Y. et al. Long-term temporal imprecision of information coding in the anterior cingulate cortex of mice with peripheral inflammation or nerve injury. J. Neurosci. 34, 10675–10687 (2014).

    PubMed  PubMed Central  Google Scholar 

  110. 110

    Zhang, M. M. et al. Effects of NB001 and gabapentin on irritable bowel syndrome-induced behavioral anxiety and spontaneous pain. Mol. Brain 7, 47 (2014).

    PubMed  PubMed Central  Google Scholar 

  111. 111

    Zhuo, M. Targeting neuronal adenylyl cyclase for the treatment of chronic pain. Drug Discov. Today 17, 573–582 (2012).

    CAS  Google Scholar 

  112. 112

    Descalzi, G., Fukushima, H., Suzuki, A., Kida, S. & Zhuo, M. Genetic enhancement of neuropathic and inflammatory pain by forebrain upregulation of CREB-mediated transcription. Mol. Pain 8, 90 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Wu, L. J. et al. Enhancement of presynaptic glutamate release and persistent inflammatory pain by increasing neuronal cAMP in the anterior cingulate cortex. Mol. Pain 4, 40 (2008).

    PubMed  PubMed Central  Google Scholar 

  114. 114

    Rumpel, S., LeDoux, J., Zador, A. & Malinow, R. Postsynaptic receptor trafficking underlying a form of associative learning. Science 308, 83–88 (2005).

    CAS  Google Scholar 

  115. 115

    Tang, J. et al. Pavlovian fear memory induced by activation in the anterior cingulate cortex. Mol. Pain 1, 6 (2005).

    PubMed  PubMed Central  Google Scholar 

  116. 116

    Steenland, H. W., Li, X. Y. & Zhuo, M. Predicting aversive events and terminating fear in the mouse anterior cingulate cortex during trace fear conditioning. J. Neurosci. 32, 1082–1095 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Bonin, R. P. & De Koninck, Y. A spinal analog of memory reconsolidation enables reversal of hyperalgesia. Nat. Neurosci. 17, 1043–1045 (2014). This study demonstrates that memory-like reconsolidation events take place in spinal nociceptive pathways.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Bonin, R. P. & De Koninck, Y. Reconsolidation and the regulation of plasticity: moving beyond memory. Trends Neurosci. 38, 336–344 (2015).

    CAS  Google Scholar 

  119. 119

    Bissiere, S. et al. The rostral anterior cingulate cortex modulates the efficiency of amygdala-dependent fear learning. Biol. Psychiatry 63, 821–831 (2008).

    Google Scholar 

  120. 120

    Jeon, D. et al. Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC. Nat. Neurosci. 13, 482–488 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Descalzi, G. et al. Rapid synaptic potentiation within the anterior cingulate cortex mediates trace fear learning. Mol. Brain 5, 6 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Knight, D. C., Cheng, D. T., Smith, C. N., Stein, E. A. & Helmstetter, F. J. Neural substrates mediating human delay and trace fear conditioning. J. Neurosci. 24, 218–228 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Frankland, P. W., Bontempi, B., Talton, L. E., Kaczmarek, L. & Silva, A. J. The involvement of the anterior cingulate cortex in remote contextual fear memory. Science 304, 881–883 (2004). This study identifies an important role for the ACC in remote fear memory.

    CAS  Google Scholar 

  124. 124

    Ploghaus, A. et al. Exacerbation of pain by anxiety is associated with activity in a hippocampal network. J. Neurosci. 21, 9896–9903 (2001).

    CAS  Google Scholar 

  125. 125

    Kain, Z. N., Mayes, L. C., Caldwell-Andrews, A. A., Karas, D. E. & McClain, B. C. Preoperative anxiety, postoperative pain, and behavioral recovery in young children undergoing surgery. Pediatrics 118, 651–658 (2006).

    Google Scholar 

  126. 126

    Myers, B. & Greenwood-Van Meerveld, B. Role of anxiety in the pathophysiology of irritable bowel syndrome: importance of the amygdala. Front. Neurosci. 3, 47 (2009).

    PubMed  PubMed Central  Google Scholar 

  127. 127

    Wise, R. G. et al. The anxiolytic effects of midazolam during anticipation to pain revealed using fMRI. Magn. Reson. Imag. 25, 801–810 (2007).

    CAS  Google Scholar 

  128. 128

    Osuch, E. A. et al. Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients. Biol. Psychiatry 48, 1020–1023 (2000).

    CAS  Google Scholar 

  129. 129

    Hubbard, C. S. et al. Behavioral, metabolic and functional brain changes in a rat model of chronic neuropathic pain: a longitudinal MRI study. Neuroimage 107, 333–344 (2015).

    Google Scholar 

  130. 130

    Robbins, M., DeBerry, J. & Ness, T. Chronic psychological stress enhances nociceptive processing in the urinary bladder in high-anxiety rats. Physiol. Behav. 91, 544–550 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Gabbott, P. L., Warner, T. A., Jays, P. R., Salway, P. & Busby, S. J. Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers. J. Comp. Neurol. 492, 145–177 (2005).

    Google Scholar 

  132. 132

    Cassell, M. D. & Wright, D. J. Topography of projections from the medial prefrontal cortex to the amygdala in the rat. Brain Res. Bull. 17, 321–333 (1986).

    CAS  Google Scholar 

  133. 133

    Buchanan, S. L., Thompson, R. H., Maxwell, B. L. & Powell, D. A. Efferent connections of the medial prefrontal cortex in the rabbit. Exp. Brain Res. 100, 469–483 (1994).

    CAS  Google Scholar 

  134. 134

    Kim, S. S. et al. Neurabin in the anterior cingulate cortex regulates anxiety-like behavior in adult mice. Mol. Brain 4, 6 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Ruscheweyh, R., Wilder-Smith, O., Drdla, R., Liu, X. G. & Sandkuhler, J. Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy. Mol. Pain 7, 20 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Sandkuhler, J. & Liu, X. Induction of long-term potentiation at spinal synapses by noxious stimulation or nerve injury. Eur. J. Neurosci. 10, 2476–2480 (1998).

    CAS  Google Scholar 

  137. 137

    Ikeda, H. et al. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 312, 1659–1662 (2006).

    CAS  Google Scholar 

  138. 138

    Guilbaud, G., Benoist, J. M., Jazat, F. & Gautron, M. Neuronal responsiveness in the ventrobasal thalamic complex of rats with an experimental peripheral mononeuropathy. J. Neurophysiol. 64, 1537–1554 (1990).

    CAS  Google Scholar 

  139. 139

    Zhao, P., Waxman, S. G. & Hains, B. C. Sodium channel expression in the ventral posterolateral nucleus of the thalamus after peripheral nerve injury. Mol. Pain 2, 27 (2006).

    PubMed  PubMed Central  Google Scholar 

  140. 140

    Guilbaud, G., Kayser, V., Benoist, J. M. & Gautron, M. Modifications in the responsiveness of rat ventrobasal thalamic neurons at different stages of carrageenin-produced inflammation. Brain Res. 385, 86–98 (1986).

    CAS  Google Scholar 

  141. 141

    Neugebauer, V., Li, W., Bird, G. C., Bhave, G. & Gereau, R. W. Synaptic plasticity in the amygdala in a model of arthritic pain: differential roles of metabotropic glutamate receptors 1 and 5. J. Neurosci. 23, 52–63 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Ikeda, R., Takahashi, Y., Inoue, K. & Kato, F. NMDA receptor-independent synaptic plasticity in the central amygdala in the rat model of neuropathic pain. Pain 127, 161–172 (2007).

    CAS  Google Scholar 

  143. 143

    Nakao, A., Takahashi, Y., Nagase, M., Ikeda, R. & Kato, F. Role of capsaicin-sensitive C-fiber afferents in neuropathic pain-induced synaptic potentiation in the nociceptive amygdala. Mol. Pain 8, 51 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Liu, M. G. et al. Long-term depression of synaptic transmission in the adult mouse insular cortex in vitro. Eur. J. Neurosci. 38, 3128–3145 (2013).

    Google Scholar 

  145. 145

    Liu, M. G. et al. Long-term potentiation of synaptic transmission in the adult mouse insular cortex: multielectrode array recordings. J. Neurophysiol. 110, 505–521 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Qiu, S. et al. GluA1 phosphorylation contributes to postsynaptic amplification of neuropathic pain in the insular cortex. J. Neurosci. 34, 13505–13515 (2014).

    PubMed  PubMed Central  Google Scholar 

  147. 147

    Liu, M. G. & Zhuo, M. No requirement of TRPV1 in long-term potentiation or long-term depression in the anterior cingulate cortex. Mol. Brain 7, 27 (2014).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work is supported by grants from Xi'an Jiaotong University, China. M.Z. is supported by grants from the EJLB Fondation-CIHR (Canadian Institutes of Health Research) Michael Smith Chair in Neurosciences and Mental Health, the Canada Research Chair, the Canadian Institute for Health Research (MOP-258523), the Natural Sciences and Engineering Research Council of Canada (RGPIN 402555), the Azrieli Neurodevelopmental Research Program and Brain Canada. B.-K.K. is supported by the National Honor Scientist Program (NRF 2012R1A3A1050385) in Korea. G.C. is supported by grants from the UK Medical Research Council, the UK Biotechnology and Biological Sciences Research Council and the European Research Council.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Tim V. P. Bliss, Graham L. Collingridge, Bong-Kiun Kaang or Min Zhuo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Acute pain

Pain that is associated with a noxious stimulus and that does not persist when the noxious stimulus is removed.

Fear memory

A type of associative memory in which a fear response is triggered by a context or a neutral stimulus that was previously associated with an aversive event.

Anxiety

An affective state reflecting a feeling of unease, worry or fear.

Chronic pain

Long-lasting pain that is associated with a chronic disease, or an aberrant type of pain that persists beyond recovery from disease or injury.

Neuropathic pain

A type of chronic pain caused by a lesion or disease of the peripheral nervous system or the CNS.

Fear conditioning

A behavioural task in which an animal learns to associate a neutral stimulus (for example, a tone) with an aversive event (for example, a footshock). See the glossary definition for 'fear memory'.

Trace fear conditioning

A form of fear conditioning in which a time interval is interposed between the conditioned stimulus and the unconditioned stimulus.

Affective component of the pain state

The feeling of unpleasantness that is associated with pain.

Allodynia

An abnormal type of pain that is caused by a stimulus that typically does not evoke pain.

Hyperalgesia

A condition in which the level of pain arising from a particular painful stimulus is greater than would normally arise from that stimulus.

Central sensitization

Increased responsiveness of nociceptive neurons in the CNS to their normal or subthreshold afferent input.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bliss, T., Collingridge, G., Kaang, BK. et al. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Nat Rev Neurosci 17, 485–496 (2016). https://doi.org/10.1038/nrn.2016.68

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing