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

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.

Plasticity of Metabotropic Glutamate Receptor-Dependent Long-Term Depression in the Anterior Cingulate Cortex after Amputation

“…Animal studies of the ACC not only confirm the importance of ACC in nociception (Vogt, 2005;Zhuo, 2008Zhuo, , 2011, but also reveal molecular mechanisms for chronic pain (Zhuo, 2006(Zhuo, , 2008. While peripheral injury triggers activity-dependent immediate early genes (Zhuo, 2006(Zhuo, , 2011 and induces long-term potentiation (LTP) of excitatory synaptic responses in the ACC neurons (Wei and Zhuo, 2001;Xu et al, 2008), inhibition or genetic deletion of key molecules required for triggering LTP produces analgesic effects in animal models of chronic pain (Wei et al, 2002;Wu et al, 2005b;Wang et al, 2011). Recently, protein kinase M (PKM) has been identified as a key enzyme required to maintain such injury-related LTP (Li et al, 2010).…”

“…Peripheral injuries, such as nerve injury or inflammation, trigger synaptic potentiation in the ACC pyramidal cells. Both presynaptic enhancement of glutamate release and postsynaptic amplification of AMPA receptor-mediated responses contribute to the potentiation (Xu et al, 2008;Zhuo, 2008;Li et al, 2010). For peripheral amputation, LTPlike potentiation has been reported in rats under anesthesia in vivo (Wei and Zhuo, 2001).…”

Initial Phase of Neuropathic Pain within a Few Hours after Nerve Injury in Mice

“…2C). It has been reported that peripheral nerve injury triggers long-term potentiation in the anterior cingulate cortex (Xu et al, 2008). Therefore, we investigated the fluorescence responses in the cortical areas medial to the response center.…”

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

“…the ratio of the second peak amplitude over the first peak amplitude induced by paired pulse stimulation). Analysis of PPRs is a classic approach to determine the transmitter release probability from presynaptic terminals (27,(41)(42)(43)(44). A decrease of PPR indicates an increased probability of neurotransmitter release from presynaptic terminals.…”