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      Hyperalgesia by synaptic long-term potentiation (LTP): an update

      review-article
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      Current Opinion in Pharmacology
      Elsevier Science Ltd

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          Highlights

          ► Latest insights into synaptic mechanisms of hyperalgesia including the recently discovered opioid-withdrawal LTP. ► Depiction of distinct signalling pathways for the induction and for the maintenance of LTP. ► Emerging role of glial cells for LTP at synapses of nociceptive primary afferents. ► Description of newly discovered reversal of LTP by clinically approved drugs. ► We argue that LTP at synapses of nociceptive nerve fibres is an element of a biological cascade amplifier in a nociceptive daisy chain.

          Abstract

          Long-term potentiation of synaptic strength (LTP) in nociceptive pathways shares principle features with hyperalgesia including induction protocols, pharmacological profile, neuronal and glial cell types involved and means for prevention. LTP at synapses of nociceptive nerve fibres constitutes a contemporary cellular model for pain amplification following trauma, inflammation, nerve injury or withdrawal from opioids. It provides a novel target for pain therapy. This review summarizes recent progress which has been made in unravelling the properties and functions of LTP in the nociceptive system and in identifying means for its prevention and reversal.

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          Most cited references76

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          Models and mechanisms of hyperalgesia and allodynia.

          Hyperalgesia and allodynia are frequent symptoms of disease and may be useful adaptations to protect vulnerable tissues. Both may, however, also emerge as diseases in their own right. Considerable progress has been made in developing clinically relevant animal models for identifying the most significant underlying mechanisms. This review deals with experimental models that are currently used to measure (sect. II) or to induce (sect. III) hyperalgesia and allodynia in animals. Induction and expression of hyperalgesia and allodynia are context sensitive. This is discussed in section IV. Neuronal and nonneuronal cell populations have been identified that are indispensable for the induction and/or the expression of hyperalgesia and allodynia as summarized in section V. This review focuses on highly topical spinal mechanisms of hyperalgesia and allodynia including intrinsic and synaptic plasticity, the modulation of inhibitory control (sect. VI), and neuroimmune interactions (sect. VII). The scientific use of language improves also in the field of pain research. Refined definitions of some technical terms including the new definitions of hyperalgesia and allodynia by the International Association for the Study of Pain are illustrated and annotated in section I.
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            Central mechanisms of pathological pain.

            Chronic pain is a major challenge to clinical practice and basic science. The peripheral and central neural networks that mediate nociception show extensive plasticity in pathological disease states. Disease-induced plasticity can occur at both structural and functional levels and is manifest as changes in individual molecules, synapses, cellular function and network activity. Recent work has yielded a better understanding of communication within the neural matrix of physiological pain and has also brought important advances in concepts of injury-induced hyperalgesia and tactile allodynia and how these might contribute to the complex, multidimensional state of chronic pain. This review focuses on the molecular determinants of network plasticity in the central nervous system (CNS) and discusses their relevance to the development of new therapeutic approaches.
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              Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex.

              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 (PKMζ) maintains pain-induced persistent changes in the mouse anterior cingulate cortex (ACC). Peripheral nerve injury caused activation of PKMζ in the ACC, and inhibiting PKMζ by a selective inhibitor, ζ-pseudosubstrate inhibitory peptide (ZIP), erased synaptic potentiation. Microinjection of ZIP into the ACC blocked behavioral sensitization. These results suggest that PKMζ in the ACC acts to maintain neuropathic pain. PKMζ could thus be a new therapeutic target for treating chronic pain.
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                Author and article information

                Journal
                Curr Opin Pharmacol
                Curr Opin Pharmacol
                Current Opinion in Pharmacology
                Elsevier Science Ltd
                1471-4892
                1471-4973
                February 2012
                February 2012
                : 12
                : 1
                : 18-27
                Affiliations
                Medical University of Vienna, Center for Brain Research, Department of Neurophysiology, Spitalgasse 4, A-1090 Vienna, Austria
                Article
                COPHAR988
                10.1016/j.coph.2011.10.018
                3315008
                22078436
                b1c9be16-6556-4d69-93f9-20789283f1cf
                © 2012 Elsevier Ltd.

                This document may be redistributed and reused, subject to certain conditions.

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                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine

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