ZIPping to Pain Relief: The Role (or Not) of PKMζ in Chronicc Pain
Open Access
- 1 January 2013
- journal article
- review article
- Published by SAGE Publications in Molecular Pain
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 PKMζ, 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 PKMζ 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 PKMζ as a memory maintenance molecule. Here we critically review the evidence that PKMζ 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 PKMζ, 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.Keywords
This publication has 116 references indexed in Scilit:
- Contribution of PKMζ-dependent and independent amplification to components of experimental neuropathic painPain, 2012
- Postsynaptic signaling during plasticity of dendritic spinesTrends in Neurosciences, 2012
- Central sensitization: Implications for the diagnosis and treatment of painPain, 2011
- Spatiotemporal Dynamics of Kinase Signaling Visualized by Targeted ReportersCurrent Protocols in Chemical Biology, 2009
- Nociceptors: a phylogenetic viewJournal of Comparative Physiology A, 2009
- Critical role of nociceptor plasticity in chronic painTrends in Neurosciences, 2009
- Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural PlasticityThe Journal of Pain, 2009
- Neurotrophic factors and structural plasticity in addictionNeuropharmacology, 2008
- Role of interleukin-6 in chronic muscle hyperalgesic primingNeuroscience, 2008
- BDNF: A key regulator for protein synthesis-dependent LTP and long-term memory?Neurobiology of Learning and Memory, 2007