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      Pain hypersensitivity mechanisms at a glance

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          Abstract

          There are two basic categories of pain: physiological pain, which serves an important protective function, and pathological pain, which can have a major negative impact on quality of life in the context of human disease. Major progress has been made in understanding the molecular mechanisms that drive sensory transduction, amplification and conduction in peripheral pain-sensing neurons, communication of sensory inputs to spinal second-order neurons, and the eventual modulation of sensory signals by spinal and descending circuits. This poster article endeavors to provide an overview of how molecular and cellular mechanisms underlying nociception in a physiological context undergo plasticity in pathophysiological states, leading to pain hypersensitivity and chronic pain.

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          Most cited references56

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          Neuronal plasticity: increasing the gain in pain.

          We describe those sensations that are unpleasant, intense, or distressing as painful. Pain is not homogeneous, however, and comprises three categories: physiological, inflammatory, and neuropathic pain. Multiple mechanisms contribute, each of which is subject to or an expression of neural plasticity-the capacity of neurons to change their function, chemical profile, or structure. Here, we develop a conceptual framework for the contribution of plasticity in primary sensory and dorsal horn neurons to the pathogenesis of pain, identifying distinct forms of plasticity, which we term activation, modulation, and modification, that by increasing gain, elicit pain hypersensitivity.
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            The menthol receptor TRPM8 is the principal detector of environmental cold.

            Sensory nerve fibres can detect changes in temperature over a remarkably wide range, a process that has been proposed to involve direct activation of thermosensitive excitatory transient receptor potential (TRP) ion channels. One such channel--TRP melastatin 8 (TRPM8) or cold and menthol receptor 1 (CMR1)--is activated by chemical cooling agents (such as menthol) or when ambient temperatures drop below approximately 26 degrees C, suggesting that it mediates the detection of cold thermal stimuli by primary afferent sensory neurons. However, some studies have questioned the contribution of TRPM8 to cold detection or proposed that other excitatory or inhibitory channels are more critical to this sensory modality in vivo. Here we show that cultured sensory neurons and intact sensory nerve fibres from TRPM8-deficient mice exhibit profoundly diminished responses to cold. These animals also show clear behavioural deficits in their ability to discriminate between cold and warm surfaces, or to respond to evaporative cooling. At the same time, TRPM8 mutant mice are not completely insensitive to cold as they avoid contact with surfaces below 10 degrees C, albeit with reduced efficiency. Thus, our findings demonstrate an essential and predominant role for TRPM8 in thermosensation over a wide range of cold temperatures, validating the hypothesis that TRP channels are the principal sensors of thermal stimuli in the peripheral nervous system.
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              Central sensitization and LTP: do pain and memory share similar mechanisms?

              Synaptic plasticity is fundamental to many neurobiological functions, including memory and pain. Central sensitization refers to the increased synaptic efficacy established in somatosensory neurons in the dorsal horn of the spinal cord following intense peripheral noxious stimuli, tissue injury or nerve damage. This heightened synaptic transmission leads to a reduction in pain threshold, an amplification of pain responses and a spread of pain sensitivity to non-injured areas. In the cortex, LTP - a long-lasting highly localized increase in synaptic strength - is a synaptic substrate for memory and learning. Analysis of the molecular mechanisms underlying the generation and maintenance of central sensitization and LTP indicates that, although there are differences between the synaptic plasticity contributing to memory and pain, there are also striking similarities.
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                Author and article information

                Journal
                Dis Model Mech
                Dis Model Mech
                dmm
                DMM
                Disease Models & Mechanisms
                The Company of Biologists Limited
                1754-8403
                1754-8411
                July 2013
                : 6
                : 4
                : 889-895
                Affiliations
                [1 ]Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
                [2 ]Molecular Medicine Partnership Unit of the European Molecular Biology Laboratory and the University of Heidelberg Medical Faculty, Heidelberg, Germany
                Author notes
                Article
                0060889
                10.1242/dmm.011502
                3701208
                23828645
                c51015c1-4290-4dee-b64c-e987040130e0
                © 2013. Published by The Company of Biologists Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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                Molecular medicine
                Molecular medicine

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