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: 4.74). 05/2011; 89(9):847-55. DOI: 10.1007/s00109-011-0768-9
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Xiangyao Li, Oct 06, 2014
  • Source
    [Show abstract] [Hide abstract]
    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.
    Journal of Pain Research 09/2013; 6:713-725. DOI:10.2147/JPR.S45958
  • Source
    [Show abstract] [Hide abstract]
    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.
    Molecular Pain 02/2013; 9(1):6. DOI:10.1186/1744-8069-9-6 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Animal models of chronic pain are widely used to investigate basic mechanisms of chronic pain and to evaluate potential novel drugs for treating chronic pain. Among the different criteria used to measure chronic pain, behavioral responses are commonly used as the end point measurements. However, not all chronic pain conditions can be easily measured by behavioral responses such as the headache, phantom pain and pain related to spinal cord injury. Here I propose that cortical indexes, that indicate neuronal plastic changes in pain-related cortical areas, can be used as endpoint measurements for chronic pain. Such cortical indexes are not only useful for those chronic pain conditions where a suitable animal model is lacking, but also serve as additional screening methods for potential drugs to treat chronic pain in humans. These cortical indexes are activity-dependent immediate early genes, electrophysiological identified plastic changes and biochemical assays of signaling proteins. It can be used to evaluate novel analgesic compounds that may act at peripheral or spinal sites. I hope that these new cortical endpoint measurements will facilitate our search for new, and more effective, pain medicines, and help to reduce false lead drug targets.
    Molecular Pain 07/2011; 7:54. DOI:10.1186/1744-8069-7-54 · 3.53 Impact Factor