Presynaptic and Postsynaptic Amplifications of Neuropathic Pain in the Anterior Cingulate Cortex

Overview

Journal J Neurosci

Specialty Neurology

Date 2008 Jul 18

PMID 18632948

Citations 197

Authors

Hui Xu

Long-Jun Wu

Hansen Wang

Xuehan Zhang

Kunjumon I Vadakkan

Susan S Kim

Hendrik W Steenland

Min Zhuo

Affiliations

Soon will be listed here.

Abstract

Neuropathic pain is caused by a primary lesion or dysfunction in the nervous system. Investigations have mainly focused on the spinal mechanisms of neuropathic pain, and less is known about cortical changes in neuropathic pain. Here, we report that peripheral nerve injury triggered long-term changes in excitatory synaptic transmission in layer II/III neurons within the anterior cingulate cortex (ACC). Both the presynaptic release probability of glutamate and postsynaptic glutamate AMPA receptor-mediated responses were enhanced after injury using the mouse peripheral nerve injury model. Western blot showed upregulated phosphorylation of GluR1 in the ACC after nerve injury. Finally, we found that both presynaptic and postsynaptic changes after nerve injury were absent in genetic mice lacking calcium-stimulated adenylyl cyclase 1 (AC1). Our studies therefore provide direct integrative evidence for both long-term presynaptic and postsynaptic changes in cortical synapses after nerve injury, and that AC1 is critical for such long-term changes. AC1 thus may serve as a potential therapeutic target for treating neuropathic pain.

Citing Articles

Improvement in the Cognitive Function in Chronic Pain: Therapeutic Potential of the Endocannabinoid System.

Karimi-Haghighi S, Shaygan M Mol Neurobiol. 2025; .

PMID: 40059255 DOI: 10.1007/s12035-025-04814-8.

mGluR5-mediated astrocytes hyperactivity in the anterior cingulate cortex contributes to neuropathic pain in male mice.

Shen W, Chen F, Tang Y, Zhao Y, Zhu L, Xiang L Commun Biol. 2025; 8(1):266.

PMID: 39979531 PMC: 11842833. DOI: 10.1038/s42003-025-07733-5.

DNMT3a Downregulation Ttriggered Upregulation of GABA Receptor in the mPFC Promotes Paclitaxel-Induced Pain and Anxiety in Male Mice.

Tian L, Li X, Zhao Y, Yi H, Liu X, Yao R Adv Sci (Weinh). 2024; 12(5):e2407387.

PMID: 39679872 PMC: 11791956. DOI: 10.1002/advs.202407387.

Whole-brain mapping of afferents to the anterior cingulate cortex in adult mice.

Xue M, Chen Q, Shi W, Zhou Z, Li X, Xu F Mol Pain. 2024; 20:17448069241300990.

PMID: 39614717 PMC: 11607754. DOI: 10.1177/17448069241300990.

Deconstruction the feedforward inhibition changes in the layer III of anterior cingulate cortex after peripheral nerve injury.

Lian Y, Cao X, Wu C, Pei C, Liu L, Zhang C Commun Biol. 2024; 7(1):1237.

PMID: 39354145 PMC: 11445484. DOI: 10.1038/s42003-024-06849-4.

References

Esteban J, Shi S, Wilson C, Nuriya M, Huganir R, Malinow R . PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nat Neurosci. 2003; 6(2):136-43. DOI: 10.1038/nn997. View

Coull J, Boudreau D, Bachand K, Prescott S, Nault F, Sik A . Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature. 2003; 424(6951):938-42. DOI: 10.1038/nature01868. View

Tsvetkov E, Shin R, Bolshakov V . Glutamate uptake determines pathway specificity of long-term potentiation in the neural circuitry of fear conditioning. Neuron. 2004; 41(1):139-51. DOI: 10.1016/s0896-6273(03)00800-6. View

Blair H, Schafe G, Bauer E, Rodrigues S, LeDoux J . Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning. Learn Mem. 2001; 8(5):229-42. DOI: 10.1101/lm.30901. View

Kaas J . Plasticity of sensory and motor maps in adult mammals. Annu Rev Neurosci. 1991; 14:137-67. DOI: 10.1146/annurev.ne.14.030191.001033. View

Vadakkan K, Wang H, Ko S, Zastepa E, Petrovic M, Sluka K . Genetic reduction of chronic muscle pain in mice lacking calcium/calmodulin-stimulated adenylyl cyclases. Mol Pain. 2006; 2:7. PMC: 1395303. DOI: 10.1186/1744-8069-2-7. View

Hessler N, Shirke A, Malinow R . The probability of transmitter release at a mammalian central synapse. Nature. 1993; 366(6455):569-72. DOI: 10.1038/366569a0. View

Zhao M, Toyoda H, Lee Y, Wu L, Ko S, Zhang X . Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory. Neuron. 2005; 47(6):859-72. DOI: 10.1016/j.neuron.2005.08.014. View

Foster T, McNaughton B . Long-term enhancement of CA1 synaptic transmission is due to increased quantal size, not quantal content. Hippocampus. 1991; 1(1):79-91. DOI: 10.1002/hipo.450010108. View

10.

Sandkuhler J . Understanding LTP in pain pathways. Mol Pain. 2007; 3:9. PMC: 1852298. DOI: 10.1186/1744-8069-3-9. View

11.

Boucher T, McMahon S . Neurotrophic factors and neuropathic pain. Curr Opin Pharmacol. 2001; 1(1):66-72. DOI: 10.1016/s1471-4892(01)00010-8. View

12.

Sommer B, Kohler M, Sprengel R, Seeburg P . RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell. 1991; 67(1):11-9. DOI: 10.1016/0092-8674(91)90568-j. View

13.

Derkach V, Oh M, Guire E, Soderling T . Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat Rev Neurosci. 2007; 8(2):101-13. DOI: 10.1038/nrn2055. View

14.

Wei F, Vadakkan K, Toyoda H, Wu L, Zhao M, Xu H . Calcium calmodulin-stimulated adenylyl cyclases contribute to activation of extracellular signal-regulated kinase in spinal dorsal horn neurons in adult rats and mice. J Neurosci. 2006; 26(3):851-61. PMC: 6675366. DOI: 10.1523/JNEUROSCI.3292-05.2006. View

15.

Bolshakov V, Golan H, Kandel E, Siegelbaum S . Recruitment of new sites of synaptic transmission during the cAMP-dependent late phase of LTP at CA3-CA1 synapses in the hippocampus. Neuron. 1997; 19(3):635-51. DOI: 10.1016/s0896-6273(00)80377-3. View

16.

Toyoda H, Wu L, Zhao M, Xu H, Zhuo M . Time-dependent postsynaptic AMPA GluR1 receptor recruitment in the cingulate synaptic potentiation. Dev Neurobiol. 2007; 67(4):498-509. DOI: 10.1002/dneu.20380. View

17.

Buonomano D, Merzenich M . Cortical plasticity: from synapses to maps. Annu Rev Neurosci. 1998; 21:149-86. DOI: 10.1146/annurev.neuro.21.1.149. View

18.

Rainville P, Duncan G, Price D, Carrier B, Bushnell M . Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science. 1997; 277(5328):968-71. DOI: 10.1126/science.277.5328.968. View

19.

Casey K . Forebrain mechanisms of nociception and pain: analysis through imaging. Proc Natl Acad Sci U S A. 1999; 96(14):7668-74. PMC: 33599. DOI: 10.1073/pnas.96.14.7668. View

20.

LeDoux J . The emotional brain, fear, and the amygdala. Cell Mol Neurobiol. 2003; 23(4-5):727-38. PMC: 11530156. DOI: 10.1023/a:1025048802629. View