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Synaptic Plasticity and Central Sensitization: Author Reply

      Dr Sandkühler raises several relevant and interesting points regarding our review on activity-dependent central sensitization and synaptic plasticity, and we are happy to clarify our approach to, and understanding of, synaptic plasticity in the dorsal horn, particularly the relationship between central sensitization and long-term potentiation (LTP). The definition of LTP needs to be addressed, we believe, in the context of the type of preparation (in vivo or in vitro), nature of the neurons (cerebellum, neocortex, hippocampus, dorsal horn), the synaptic changes that occur (homo- or heterosynaptic, pre- or postsynaptic), duration of changes (short term or persistent), molecular mechanisms (signal transduction pathways engaged, transcription independent or dependent), and the biological function of the circuits involved (learning, memory, or pain). For our review,
      • Latremoliere A.
      • Woolf C.J.
      Central sensitization: A generator of pain hypersensitivity by central neural plasticity.
      we focused on the relationship between the different forms of activity-dependent synaptic plasticity reported in the dorsal horn of the spinal cord, including those that have been called LTP, and central sensitization. We thought it was particularly relevant to address the phenomenon of central sensitization as a defense mechanism specific to nociception, one that contributes to maintaining the integrity of the organism by producing pain hypersensitivity following a conditioning nociceptive afferent barrage, and, in this way, protecting an organism from further damage. This is an evolutionary conserved process, with prominent central sensitization-like behavior in Aplysia and other invertebrates;
      • Antonov I.
      • Kandel E.R.
      • Hawkins R.D.
      The contribution of facilitation of monosynaptic PSPs to dishabituation and sensitization of the Aplysia siphon withdrawal reflex.
      • Woolf C.J.
      • Walters E.T.
      Common patterns of plasticity contributing to nociceptive sensitization in mammals and Aplysia.
      and while it shares general mechanistic aspects with several forms of synaptic plasticity in other systems, there are also, we argue, some important differences that make central sensitization unique. At a conceptual level, for example, we believe that there is a major difference between the input-specific synaptic potentiation that constitutes classic LTP in cortical neurons
      • Collingridge G.L.
      • Isaac J.T.
      • Wang Y.T.
      Receptor trafficking and synaptic plasticity.
      • Malenka R.C.
      • Bear M.F.
      LTP and LTD: An embarrassment of riches.
      • Malenka R.C.
      • Nicoll R.A.
      Long-term potentiation–a decade of progress?.
      and the more generalized heightened excitability in nociceptive pathways that underlies central sensitization.
      • Thompson S.W.
      • Woolf C.J.
      • Sivilotti L.G.
      Small-caliber afferent inputs produce a heterosynaptic facilitation of the synaptic responses evoked by primary afferent A-fibers in the neonatal rat spinal cord in vitro.
      • Woolf C.J.
      Evidence for a central component of post-injury pain hypersensitivity.
      Memory, which is widely considered dependent on hippocampal LTP,
      • Collingridge G.L.
      • Isaac J.T.
      • Wang Y.T.
      Receptor trafficking and synaptic plasticity.
      • Madison D.V.
      • Malenka R.C.
      • Nicoll R.A.
      Mechanisms underlying long-term potentiation of synaptic transmission.
      • Malenka R.C.
      • Bear M.F.
      LTP and LTD: An embarrassment of riches.
      • Malenka R.C.
      • Nicoll R.A.
      Long-term potentiation–a decade of progress?.
      • Neves G.
      • Cooke S.F.
      • Bliss T.V.
      Synaptic plasticity, memory and the hippocampus: A neural network approach to causality.
      is a convergent neural operation where the storage of defined information is the consequence of coincident temporal and spatial association between specific stimuli. In contrast, central sensitization represents a divergent neural operation, one where a conditioning nociceptive input triggers diffuse changes such that other unstimulated synaptic inputs can now generate pain. For example, nociceptive stimulation of deep tissue, like muscle, results in an enlargement and reduction in threshold of the cutaneous receptive field of dorsal horn neurons, to an extent and duration that is even greater than when a nociceptive input is generated from the skin.
      • Wall P.D.
      • Woolf C.J.
      Muscle but not cutaneous C-afferent input produces prolonged increases in the excitability of the flexion reflex in the rat.
      If central sensitization were entirely maintained by LTP, it would not have this fundamental feature, which characterizes it.
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      Linked Article

      • Central Sensitization Versus Synaptic Long-Term Potentiation (LTP): A Critical Comment
        The Journal of PainVol. 11Issue 8
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          I read with interest the chapter, “Activity-Dependent Central Sensitization and Synaptic Plasticity,” in the recent review article by Latrémolière and Woolf11 in The Journal of Pain. I noticed a number of issues in that chapter which deserve some discussion. These include the concept of synaptic long-term potentiation in pain pathways and its relation to the more general phrase “central sensitization.”
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