ZIPping to pain relief: the role (or not) of PKMzeta in chronic pain
AffiliationDepartment of Pharmacology, The University of Arizona School of Medicine, Arizona, USA
Department of Cellular and Molecular Medicine, The University of Arizona School of Medicine, Arizona, USA
Bio5 Institute, The University of Arizona School of Medicine, Arizona, USA
Graduate Interdisciplinary Program in Neuroscience, The University of Arizona School of Medicine, Arizona, USA
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CitationPrice and Ghosh Molecular Pain 2013, 9:6 http://www.molecularpain.com/content/9/1/6
Rights© 2013 Price and Ghosh; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
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AbstractChronic 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.
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