Erasing injury-related cortical synaptic potentiation as a new treatment for chronic pain

Department of Physiology, Faculty of Medicine, Center for the Study of Pain, University of Toronto, Medical Science Building, Room no. 3342, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada.
Journal of Molecular Medicine (Impact Factor: 5.11). 05/2011; 89(9):847-55. DOI: 10.1007/s00109-011-0768-9
Source: PubMed


Synaptic plasticity in the spinal cord and the cortex is believed to be important for the amplification of painful information in chronic pain conditions. The investigation of molecular mechanism responsible for maintaining injury-related plastic changes, such as through the study of long-term potentiation in these structures, provides potential novel targets for designing new medicine for chronic pain. Recent studies using integrative neurobiological approaches demonstrate that protein kinase M zeta (PKMζ) maintains pain-induced persistent changes in the anterior cingulate cortex (ACC), and inhibiting PKMζ by ζ-pseudosubstrate inhibitory peptide produces analgesic effects in animal models of chronic pain. We propose that targeting PKMζ, or its up- or downstream signaling proteins, in the ACC may provide novel clinical treatment for chronic pain.

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Available from: Xiangyao Li, Oct 06, 2014
    • "targeted areas such as hippocampus (spatial memory), insular cortex (taste memory), nucleus accumbens (addiction), and amygdala (fear memory) (Pastalkova 2006; Shema et al. 2007; Serrano et al. 2008; Li et al. 2011; Shabashov et al. 2011; Crespo et al. 2012; Kwapis et al. 2012). Thus, it is plausible that a molecular switch, based on persistent activation of one or both aPKCs, plays an important role in maintaining L-LTP and memory. "
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    ABSTRACT: Memories that last a lifetime are thought to be stored, at least in part, as persistent enhancement of the strength of particular synapses. The synaptic mechanism of these persistent changes, late long-term potentiation (L-LTP), depends on the state and number of specific synaptic proteins. Synaptic proteins, however, have limited dwell times due to molecular turnover and diffusion, leading to a fundamental question: how can this transient molecular machinery store memories lasting a lifetime? Because the persistent changes in efficacy are synapse-specific, the underlying molecular mechanisms must to a degree reside locally in synapses. Extensive experimental evidence points to atypical protein kinase C (aPKC) isoforms as key components involved in memory maintenance. Furthermore, it is evident that establishing long-term memory requires new protein synthesis. However, a comprehensive model has not been developed describing how these components work to preserve synaptic efficacies over time. We propose a molecular model that can account for key empirical properties of L-LTP, including its protein synthesis dependence, dependence on aPKCs, and synapse-specificity. Simulations and empirical data suggest that either of the two aPKC subtypes in hippocampal neurons, PKMζ and PKCι/λ, can maintain L-LTP, making the system more robust. Given genetic compensation at the level of synthesis of these PKC subtypes as in knockout mice, this system is able to maintain L-LTP and memory when one of the pathways is eliminated. © 2015 Jalil et al.; Published by Cold Spring Harbor Laboratory Press.
    No preview · Article · Jun 2015 · Learning & memory (Cold Spring Harbor, N.Y.)
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    • "Some researchers have reported protein kinase (PK) M zeta at the level of the ACC as a potential treatment target for tonic pain conditions.26,27 PKM zeta is an enzyme that is responsible for maintaining long-term memories in the brain, specifically the late phase of long-term potentiation (LTP).28,29 "
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    ABSTRACT: Pain is an intricate phenomenon composed of not only sensory-discriminative aspects but also of emotional, cognitive, motivational, and affective components. There has been ample evidence for the existence of an extensive cortical network associated with pain processing over the last few decades. This network includes the anterior cingulate cortex, forebrain, insular cortex, ventrolateral orbital cortex, somatosensory cortex, occipital cortex, retrosplenial cortex, motor cortex, and prefrontal cortex. Diverse neurotransmitters participate in the cortical circuits associated with pain processing, including glutamate, gamma-aminobutyric acid, dopamine, and opioids. This work examines recent rodent studies about cortical modulation of pain, mainly at a molecular level.
    Full-text · Article · Sep 2013 · Journal of Pain Research
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    • "These findings yield important insights into how a chronic pain state is maintained and shed light on how the presence of ongoing afferent discharge may differentially regulate plasticity in the CNS. They also suggest that PKMζ may be a key molecular mechanism for pain plasticity in the CNS [31]. However, recent studies have raised serious questions about the specific role of PKMζ in learning and memory and late-LTP maintenance [34,35]. "
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    ABSTRACT: Chronic pain remains a significant clinical problem despite substantial advances in our understanding of how persistent nociceptor stimulation drives plasticity in the CNS. A major theme that has emerged in this area of work is the strong similarity between plasticity involved in learning and memory in CNS regions such as cortex and hippocampus with mechanisms underlying chronic pain development and maintenance in the spinal dorsal horn and other CNS areas such as anterior cingulate cortex (ACC). We, and others have recently implicated an atypical PKC (aPKC), called PKMzeta, in the maintenance of pain plasticity based on biochemical assays and the use of a peptide pseudosubstrate inhibitor called ZIP. These studies indicate remarkable parallels between the potential role of PKMzeta as a key molecule for the maintenance of long-term memory and long-term potentiation (LTP) and the maintenance of a chronic pain state. On the other hand, very recent studies have disputed the specificity of ZIP and called into question the role of PKMzeta as a memory maintenance molecule. Here we critically review the evidence that PKMzeta might represent a new target for the reversal of certain chronic pain states. Furthermore, we consider whether ZIP might have other aPKC or even non-aPKC targets and the significance of such off-target effects for evaluating maintenance mechanisms of chronic pain. We conclude that, current controversies aside, utilization of ZIP as a tool to interrogate maintenance mechanisms of chronic pain and further investigations into the potential role of PKMzeta, and other aPKCs, in pain plasticity are likely to lead to further insights with the potential to unravel the enigma that is the disease of chronic pain.
    Full-text · Article · Feb 2013 · Molecular Pain
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