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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Fields, H. L. & Besson, J.-M. R. Pain Modulation (Elsevier, 1988).
Wall, P. D. Pain: The Science of Suffering (Columbia Univ. Press, 2000).
Zhuo, M. Cortical excitation and chronic pain. Trends Neurosci. 31, 199–207 (2008).
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.
Zhuo, M. Long-term potentiation in the anterior cingulate cortex and chronic pain. Phil. Trans. R. Soc. B 369, 20130146 (2014).
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.
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).
Talbot, J. D. et al. Multiple representations of pain in human cerebral cortex. Science 251, 1355–1358 (1991).
Craig, A. D., Reiman, E. M., Evans, A. & Bushnell, M. C. Functional imaging of an illusion of pain. Nature 384, 258–260 (1996).
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.
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).
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.
Devinsky, O., Morrell, M. J. & Vogt, B. A. Contributions of anterior cingulate cortex to behaviour. Brain 118, 279–306 (1995).
Chen, T. et al. Postsynaptic potentiation of corticospinal projecting neurons in the anterior cingulate cortex after nerve injury. Mol. Pain 10, 33 (2014).
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).
Shyu, B. C. & Vogt, B. A. Short-term synaptic plasticity in the nociceptive thalamic-anterior cingulate pathway. Mol. Pain 5, 51 (2009).
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).
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).
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).
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).
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).
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.
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).
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).
LeDoux, J. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).
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.
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).
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).
Hickey, L. et al. Optoactivation of locus ceruleus neurons evokes bidirectional changes in thermal nociception in rats. J. Neurosci. 34, 4148–4160 (2014).
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).
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).
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).
Wu, L. J. et al. Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation. J. Neurosci. 25, 11107–11116 (2005).
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).
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).
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).
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).
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).
Yamamura, H. et al. Morphological and electrophysiological properties of ACCx nociceptive neurons in rats. Brain Res. 735, 83–92 (1996).
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).
Iwata, K. et al. Anterior cingulate cortical neuronal activity during perception of noxious thermal stimuli in monkeys. J. Neurophysiol. 94, 1980–1991 (2005).
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.
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.
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).
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).
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).
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).
Barthas, F. et al. The anterior cingulate cortex is a critical hub for pain-induced depression. Biol. Psychiatry 77, 236–245 (2015).
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).
Gu, L. et al. Pain inhibition by optogenetic activation of specific anterior cingulate cortical neurons. PLoS ONE 10, e0117746 (2015).
Bliss, T. V. & Collingridge, G. L. Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide. Mol. Brain 6, 5 (2013).
Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).
Sandkuhler, J. & Gruber-Schoffnegger, D. Hyperalgesia by synaptic long-term potentiation (LTP): an update. Curr. Opin. Pharmacol. 12, 18–27 (2012).
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.
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.
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).
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).
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).
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.
Bortolotto, Z. A. et al. Kainate receptors are involved in synaptic plasticity. Nature 402, 297–301 (1999).
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.
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).
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).
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).
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).
Xia, Z. & Storm, D. R. Calmodulin-regulated adenylyl cyclases and neuromodulation. Curr. Opin. Neurobiol. 7, 391–396 (1997).
Wei, F. et al. Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron 36, 713–726 (2002).
Wang, H. et al. Identification of an adenylyl cyclase inhibitor for treating neuropathic and inflammatory pain. Sci. Transl. Med. 3, 65ra63 (2011).
Wei, F. et al. Calcium calmodulin-dependent protein kinase IV is required for fear memory. Nat. Neurosci. 5, 573–579 (2002).
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).
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).
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).
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).
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).
Nicoll, R. A. & Schmitz, D. Synaptic plasticity at hippocampal mossy fibre synapses. Nat. Rev. Neurosci. 6, 863–876 (2005).
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).
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).
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).
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).
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).
Plant, K. et al. Transient incorporation of native GluR2-lacking AMPA receptors during hippocampal long-term potentiation. Nat. Neurosci. 9, 602–604 (2006).
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).
Sacktor, T. C. Memory maintenance by PKMζ — an evolutionary perspective. Mol. Brain 5, 31 (2012).
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).
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).
Lee, A. M. et al. Prkcz null mice show normal learning and memory. Nature 493, 416–419 (2013).
Tsokas, P. et al. Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice. eLife 5, e14846 (2016).
Mellor, J., Nicoll, R. A. & Schmitz, D. Mediation of hippocampal mossy fiber long-term potentiation by presynaptic Ih channels. Science 295, 143–147 (2002).
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).
Collingridge, G. L., Peineau, S., Howland, J. G. & Wang, Y. T. Long-term depression in the CNS. Nat. Rev. Neurosci. 11, 459–473 (2010).
Wei, F., Li, P. & Zhuo, M. Loss of synaptic depression in mammalian anterior cingulate cortex after amputation. J. Neurosci. 19, 9346–9354 (1999).
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).
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).
Toyoda, H. et al. Long-term depression requires postsynaptic AMPA GluR2 receptor in adult mouse cingulate cortex. J. Cell. Physiol. 211, 336–343 (2007).
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).
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).
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).
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.
Xu, H. et al. Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex. J. Neurosci. 28, 7445–7453 (2008).
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).
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).
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).
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).
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.
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).
Qiu, S. et al. An increase in synaptic NMDA receptors in the insular cortex contributes to neuropathic pain. Sci. Signal. 6, ra34 (2013).
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).
Cao, X. Y. et al. Characterization of intrinsic properties of cingulate pyramidal neurons in adult mice after nerve injury. Mol. Pain 5, 73 (2009).
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).
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).
Zhuo, M. Targeting neuronal adenylyl cyclase for the treatment of chronic pain. Drug Discov. Today 17, 573–582 (2012).
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).
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).
Rumpel, S., LeDoux, J., Zador, A. & Malinow, R. Postsynaptic receptor trafficking underlying a form of associative learning. Science 308, 83–88 (2005).
Tang, J. et al. Pavlovian fear memory induced by activation in the anterior cingulate cortex. Mol. Pain 1, 6 (2005).
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).
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.
Bonin, R. P. & De Koninck, Y. Reconsolidation and the regulation of plasticity: moving beyond memory. Trends Neurosci. 38, 336–344 (2015).
Bissiere, S. et al. The rostral anterior cingulate cortex modulates the efficiency of amygdala-dependent fear learning. Biol. Psychiatry 63, 821–831 (2008).
Jeon, D. et al. Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC. Nat. Neurosci. 13, 482–488 (2010).
Descalzi, G. et al. Rapid synaptic potentiation within the anterior cingulate cortex mediates trace fear learning. Mol. Brain 5, 6 (2012).
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).
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.
Ploghaus, A. et al. Exacerbation of pain by anxiety is associated with activity in a hippocampal network. J. Neurosci. 21, 9896–9903 (2001).
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).
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).
Wise, R. G. et al. The anxiolytic effects of midazolam during anticipation to pain revealed using fMRI. Magn. Reson. Imag. 25, 801–810 (2007).
Osuch, E. A. et al. Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients. Biol. Psychiatry 48, 1020–1023 (2000).
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).
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).
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).
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).
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).
Kim, S. S. et al. Neurabin in the anterior cingulate cortex regulates anxiety-like behavior in adult mice. Mol. Brain 4, 6 (2011).
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).
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).
Ikeda, H. et al. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 312, 1659–1662 (2006).
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).
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).
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).
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).
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).
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).
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).
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).
Qiu, S. et al. GluA1 phosphorylation contributes to postsynaptic amplification of neuropathic pain in the insular cortex. J. Neurosci. 34, 13505–13515 (2014).
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).
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.
The authors declare no competing financial interests.
- 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.
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.
An abnormal type of pain that is caused by a stimulus that typically does not evoke pain.
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.
About this article
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
Antibiotics-induced intestinal dysbacteriosis caused behavioral alternations and neuronal activation in different brain regions in mice
Molecular Brain (2021)
Conditional knock out of transcription factor CTCF in excitatory neurons induces cognitive deficiency
Molecular Brain (2021)
NMDA GluN2C/2D receptors contribute to synaptic regulation and plasticity in the anterior cingulate cortex of adult mice
Molecular Brain (2021)
Multiple synaptic connections into a single cortical pyramidal cell or interneuron in the anterior cingulate cortex of adult mice
Molecular Brain (2021)
Repeated oxytocin prevents central sensitization by regulating synaptic plasticity via oxytocin receptor in a chronic migraine mouse model
The Journal of Headache and Pain (2021)