Molecular mechanisms of pain in the anterior cingulate cortex.
ABSTRACT It is well known that peripheral sensory stimuli, including pain, trigger a series of neuronal activities along the somatosensory pathways as well as the neuronal network in the high brain structures. These neuronal activities not only produce appropriate physiological responses but also induce long-term plastic changes in some of the central synapses. It is believed that long-term synaptic changes help the brain to process and store new information. Such learning is critical for animals and humans to gain new knowledge of changing environment, generate appropriate emotional responses, and avoid dangerous stimuli in the future. In the case of permanent injury, however, the brain fails to distinguish the difference between "useful" and painful stimuli. Long-term synaptic changes work against the system and at least in part contribute to chronic pain. In this short article, the possible molecular mechanisms for long-term plasticity within the anterior cingulate cortex (ACC) will be discussed and reviewed, and it is hypothesized that potentiation of excitatory responses within the ACC contributes to chronic pain and pain-related mental disorders.
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ABSTRACT: The pathogenic mechanisms underlying neuropathic pain still remain largely unknown. In this study, we investigated whether spinal BDNF contributes to dorsal horn LTP induction and neuropathic pain development by activation of GluN2B-NMDA receptors via Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) phosphorylation in rats following spinal nerve ligation (SNL). We first demonstrated that spinal BDNF participates in the development of long-lasting hyperexcitability of dorsal horn WDR neurons (i.e. central sensitization) as well as pain allodynia in both intact and SNL rats. Second, we revealed that BDNF induces spinal LTP at C-fiber synapses via functional up-regulation of GluN2B-NMDA receptors in the spinal dorsal horn, and this BDNF-mediated LTP-like state is responsible for the occlusion of spinal LTP elicited by subsequent high-frequency electrical stimulation (HFS) of the sciatic nerve in SNL rats. Finally, we validated that BDNF-evoked SHP2 phosphorylation is required for subsequent GluN2B-NMDA receptors up-regulation and spinal LTP induction, and also for pain allodynia development. Blockade of SHP2 phosphorylation in the spinal dorsal horn using a potent SHP2 protein tyrosine phosphatase inhibitor NSC-87877, or knockdown of spinal SHP2 by intrathecal delivery of SHP2 siRNA, not only prevents BDNF-mediated GluN2B-NMDA receptors activation as well as spinal LTP induction and pain allodynia elicitation in intact rats, but also reduces the SNL-evoked GluN2B-NMDA receptors up-regulation and spinal LTP occlusion, and ultimately alleviates pain allodynia in neuropathic rats. Taken together, these results suggest that the BDNF/SHP2/GluN2B-NMDA signaling cascade plays a vital role in the development of central sensitization and neuropathic pain after peripheral nerve injury. Copyright © 2014 Elsevier Inc. All rights reserved.Neurobiology of Disease 11/2014; 73C:428-451. · 5.62 Impact Factor
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ABSTRACT: One major interest in the study of transient receptor potential vanilloid type 1 (TRPV1) in sensory system is that it may serve as a drug target for treating chronic pain. While the roles of TRPV1 in peripheral nociception and sensitization have been well documented, less is known about its contribution to pain-related cortical plasticity. Here, we used 64 multi-electrode array recording to examine the potential role of TRPV1 in two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), in the anterior cingulate cortex (ACC). We found that pharmacological blockade of TRPV1 with either [(E)-3-(4-t-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide] (AMG9810, 10 muM) or N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791, 20 muM) failed to affect LTP induced by strong theta burst stimulation in the ACC of adult mice. Similarly, neither AMG9810 nor SB366791 blocked the cingulate LTD induced by low-frequency stimulation. Analysis of the results from different layers of the ACC obtained the same conclusions. Spatial distribution of LTP or LTD-showing channels among the ACC network was also unaltered by the TRPV1 antagonists. Since cortical LTP and LTD in the ACC play critical roles in chronic pain triggered by inflammation or nerve injury, our findings suggest that TRPV1 may not be a viable target for treating chronic pain, especially at the cortical level.Molecular Brain 04/2014; 7(1):27. · 4.35 Impact Factor
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ABSTRACT: To explore the involvement of synaptic plasticity in pain induced by experimental tooth movement, we evaluated the expression of protein kinase M zeta (PKMζ), an enzyme necessary for maintaining long-term potentiation (LTP) in the anterior cingulate cortex (ACC). Male Sprague-Dawley rats weighing 250-300g were used. The change of the expression of PKMζ in the ACC was measured by western blot, and the mRNA of PKMζ was detected by quantitative real-time PCR 1, 3, 7 days after experimental tooth movement. The average time spent on mouth-wiping behaviour of rats involved in pain perception was detected. After that a selective PKMζ inhibitor, called myristoylated ζ-pseudosubstrate inhibitory peptide (ZIP) was injected into ACC, and the effects of ZIP were evaluated. The mouth-wiping behaviour of rats was significantly increased 1, 3, and 7 days after experimental tooth movement. Changes in PKMζ levels were not detected on day 1 but were found to be increased 3 days following the tooth movement, and then declined to the baseline 7 days after tooth movement in the ACC. PKMζ mRNA levels were not significantly different between the experimental and sham-treated groups at the three time points. Time spent on mouth-wiping behaviour was reduced after ZIP was injected into ACC 3 days after tooth movement, and the analgesic effect last for at least 24h. PKMζ in the ACC acts to maintain the pain induced by experimental tooth movement. Increased expression of PKMζ protein is attributed to persistent translation of PKMζ mRNA. Synaptic plasticity may be involved in the development of tooth movement pain.Archives of oral biology 04/2014; 59(7):749-755. · 1.65 Impact Factor