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Koga, K.,Descalzi, G.,Chen, T.,Ko, H.G.,Lu, J.,Li, S.,Son, J.,Kim, T.,Kwak, C.,Huganir, Richard L.,Zhao, M.g.,Kaang, B.K.,Collingridge, Graham L.,Zhuo, M. Cell Press 2015 Neuron Vol.85 No.2
Chronic pain can lead to anxiety and anxiety can enhance the sensation of pain.@?Unfortunately, little is known about the synaptic mechanisms that mediate these re-enforcing interactions. Here we characterized two forms of long-term potentiation (LTP) in the anterior cingulate cortex (ACC); a presynaptic form (pre-LTP) that requires kainate receptors and a postsynaptic form (post-LTP) that requires N-methyl-D-aspartate receptors. Pre-LTP also involves adenylyl cyclase and protein kinase A and is expressed via a mechanism involving hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Interestingly, chronic pain and anxiety both result in selective occlusion of pre-LTP. Significantly, microinjection of the HCN blocker ZD7288 into the ACC in vivo produces both anxiolytic and analgesic effects. Our results provide a mechanism by which two forms of LTP in the ACC may converge to mediate the interaction between anxiety and chronic pain.
Fragile X Mental Retardation Protein in Learning-Related Synaptic Plasticity
Valentina Mercaldo,Giannina Descalzi,민쭈오 한국분자세포생물학회 2009 Molecules and cells Vol.28 No.6
Fragile X syndrome (FXS) is caused by a lack of the fragile X mental retardation protein (FMRP) due to silencing of the Fmr1 gene. As an RNA binding protein, FMRP is thought to contribute to synaptic plasticity by regulating plasticity-related protein synthesis and other signaling pathways. Previous studies have mostly focused on the roles of FMRP within the hippocampus - a key structure for spatial memory. However, recent studies indicate that FMRP may have a more general contribution to brain functions, in-cluding synaptic plasticity and modulation within the pre-frontal cortex. In this brief review, we will focus on recent studies reported in the prefrontal cortex, including the anterior cingulate cortex (ACC). We hypothesize that al-terations in ACC-related plasticity and synaptic modula-tion may contribute to various forms of cognitive deficits associated with FXS.
Kim, Susan S.,Descalzi, Giannina,Zhuo, Min Bentham Science Publishers Ltd 2010 CURRENT GENOMICS Vol.11 No.1
<P>Recent advances into the understanding of molecular mechanism of chronic pain have been largely developed through the use of genetic manipulations. This is in part due to the scarcity of selective pharmacological tools, which can be readily solved by creating knockout or transgenic mice. By identifying new genes that are of import, our efforts can then be aimed at studying relevant signaling pathways, and combination of pharmacological manipulations with genetic models can be used to further examine the specific mechanisms involved in chronic pain. In this review, we will examine the genetic models that are currently in use to study chronic pain in the anterior cingulate cortex: knockout mice; transgenic mice; and the strength of combining pharmacology with these genetic models.</P>
Alleviating Neuropathic Pain Hypersensitivity by Inhibiting PKM in the Anterior Cingulate Cortex
Li, X.-Y.,Ko, H.-G.,Chen, T.,Descalzi, G.,Koga, K.,Wang, H.,Kim, S. S.,Shang, Y.,Kwak, C.,Park, S.-W.,Shim, J.,Lee, K.,Collingridge, G. L.,Kaang, B.-K.,Zhuo, M. American Association for the Advancement of Scienc 2010 Science Vol.330 No.6009
<P>Synaptic plasticity is a key mechanism for chronic pain. It occurs at different levels of the central nervous system, including spinal cord and cortex. Studies have mainly focused on signaling proteins that trigger these plastic changes, whereas few have addressed the maintenance of plastic changes related to chronic pain. We found that protein kinase M zeta (PKM관) maintains pain-induced persistent changes in the mouse anterior cingulate cortex (ACC). Peripheral nerve injury caused activation of PKM관 in the ACC, and inhibiting PKM관 by a selective inhibitor, 관-pseudosubstrate inhibitory peptide (ZIP), erased synaptic potentiation. Microinjection of ZIP into the ACC blocked behavioral sensitization. These results suggest that PKM관 in the ACC acts to maintain neuropathic pain. PKM관 could thus be a new therapeutic target for treating chronic pain.</P>
An Increase in Synaptic NMDA Receptors in the Insular Cortex Contributes to Neuropathic Pain
Qiu, Shuang,Chen, Tao,Koga, Kohei,Guo, Yan-yan,Xu, Hui,Song, Qian,Wang, Jie-jie,Descalzi, Giannina,Kaang, Bong-Kiun,Luo, Jian-hong,Zhuo, Min,Zhao, Ming-gao AAAS 2013 Science signaling Vol.6 No.275
<P><B>Stopping the Pain</B></P><P>Damage to the central or peripheral nervous system can trigger the development of neuropathic pain, which can manifest as painful sensations in response to stimuli that are not normally painful. Qiu <I>et al.</I> found that mice that had developed neuropathic pain after peripheral nerve injury showed changes in synaptic plasticity and increased abundance of synaptic NMDA receptors in the insular cortex, a region of the brain that is activated by acute and chronic pain. Using pharmacological inhibitors and transgenic mice, they mimicked these changes in vitro with insular cortical slices and thus identified the signaling pathway responsible. Mice injected with NMDA receptor inhibitors showed reduced behavioral signs of neuropathic pain after peripheral nerve injury. Thus, blocking NMDA receptor function in the insular cortex may prevent the development of neuropathic pain.</P>
Identification of an Adenylyl Cyclase Inhibitor for Treating Neuropathic and Inflammatory Pain
Wang, H.,Xu, H.,Wu, L.-J.,Kim, S. S.,Chen, T.,Koga, K.,Descalzi, G.,Gong, B.,Vadakkan, K. I.,Zhang, X.,Kaang, B.-K.,Zhuo, M. American Association for the Advancement of Scienc 2011 Science Translational Medicine Vol.3 No.65
<P>Neuropathic pain, often caused by nerve injury, is commonly observed among patients with different diseases. Because its basic mechanisms are poorly understood, effective medications are limited. Previous investigations of basic pain mechanisms and drug discovery efforts have focused mainly on early sensory neurons such as dorsal root ganglion and spinal dorsal horn neurons, and few synaptic-level studies or new drugs are designed to target the injury-related cortical plasticity that accompanies neuropathic pain. Our previous work has demonstrated that calcium-stimulated adenylyl cyclase 1 (AC1) is critical for nerve injury-induced synaptic changes in the anterior cingulate cortex. Through rational drug design and chemical screening, we have identified a lead candidate AC1 inhibitor, NB001, which is relatively selective for AC1 over other adenylate cyclase isoforms. Using a variety of behavioral tests and toxicity studies, we have found that NB001, when administered intraperitoneally or orally, has an analgesic effect in animal models of neuropathic pain, without any apparent side effects. Our study thus shows that AC1 could be a productive therapeutic target for neuropathic pain and describes a new agent for the possible treatment of neuropathic pain.</P>