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      Selective Inflammatory Pain Insensitivity in the African Naked Mole-Rat (Heterocephalus glaber)

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          Abstract

          In all mammals, tissue inflammation leads to pain and behavioral sensitization to thermal and mechanical stimuli called hyperalgesia. We studied pain mechanisms in the African naked mole-rat, an unusual rodent species that lacks pain-related neuropeptides (e.g., substance P) in cutaneous sensory fibers. Naked mole-rats show a unique and remarkable lack of pain-related behaviors to two potent algogens, acid and capsaicin. Furthermore, when exposed to inflammatory insults or known mediators, naked mole-rats do not display thermal hyperalgesia. In contrast, naked mole-rats do display nocifensive behaviors in the formalin test and show mechanical hyperalgesia after inflammation. Using electrophysiology, we showed that primary afferent nociceptors in naked mole-rats are insensitive to acid stimuli, consistent with the animal's lack of acid-induced behavior. Acid transduction by sensory neurons is observed in birds, amphibians, and fish, which suggests that this tranduction mechanism has been selectively disabled in the naked mole-rat in the course of its evolution. In contrast, nociceptors do respond vigorously to capsaicin, and we also show that sensory neurons express a transient receptor potential vanilloid channel-1 ion channel that is capsaicin sensitive. Nevertheless, the activation of capsaicin-sensitive sensory neurons in naked mole-rats does not produce pain-related behavior. We show that capsaicin-sensitive nociceptors in the naked mole-rat are functionally connected to superficial dorsal horn neurons as in mice. However, the same nociceptors are also functionally connected to deep dorsal horn neurons, a connectivity that is rare in mice. The pain biology of the naked mole-rat is unique among mammals, thus the study of pain mechanisms in this unusual species can provide major insights into what constitutes “normal” mammalian nociception.

          Author Summary

          Chemicals such as capsaicin and acid are considered noxious because they cause irritation and pain when applied to the skin. Acid is, for example, a very noxious stimulus and can cause intense pain. Indeed, acid is both noxious and painful to all animals including amphibians and fish. Here we describe a member of the rodent family, the African naked mole-rat ( Heterocephalus glaber), that is behaviorally completely oblivious to capsaicin and acid. Tissue injury and inflammation increase sensitivity to normally non painful stimuli, a phenomenon called hyperalgesia. Here we show that the naked mole-rat does not experience hyperalgesia to painful thermal stimuli after inflammation. To our knowledge, no other mammal has so far been described that is selectively insensitive to chemical pain or that lacks thermal hyperalgesia. Naked mole-rats live in very large subterranean social groups and are remarkably tolerant to low-oxygen and high–carbon dioxide conditions. We hypothesize that naked mole-rats are selectively pain insensitive partly because of selection pressure arising from the extremity of their normal habitat.

          Abstract

          Naked but far from vulnerable, the African naked mole-rat is an unusual mammal that is unique because it is impervious to painful chemicals that cause severe pain in all other species studied.

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          Most cited references64

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          Impaired nociception and pain sensation in mice lacking the capsaicin receptor.

          The capsaicin (vanilloid) receptor VR1 is a cation channel expressed by primary sensory neurons of the "pain" pathway. Heterologously expressed VR1 can be activated by vanilloid compounds, protons, or heat (>43 degrees C), but whether this channel contributes to chemical or thermal sensitivity in vivo is not known. Here, we demonstrate that sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli. VR1-/- mice showed normal responses to noxious mechanical stimuli but exhibited no vanilloid-evoked pain behavior, were impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation. Thus, VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia.
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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 vanilloid receptor: a molecular gateway to the pain pathway.

              The detection of painful stimuli occurs primarily at the peripheral terminals of specialized sensory neurons called nociceptors. These small-diameter neurons transduce signals of a chemical, mechanical, or thermal nature into action potentials and transmit this information to the central nervous system, ultimately eliciting a perception of pain or discomfort. Little is known about the proteins that detect noxious stimuli, especially those of a physical nature. Here we review recent advances in the molecular characterization of the capsaicin (vanilloid) receptor, an excitatory ion channel expressed by nociceptors, which contributes to the detection and integration of pain-producing chemical and thermal stimuli. The analysis of vanilloid receptor gene knockout mice confirms the involvement of this channel in pain sensation, as well as in hypersensitivity to noxious stimuli following tissue injury. At the same time, these studies demonstrate the existence of redundant mechanisms for the sensation of heat-evoked pain.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Biol
                pbio
                plbi
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                1544-9173
                1545-7885
                January 2008
                29 January 2008
                : 6
                : 1
                : e13
                Affiliations
                [1 ] Laboratory of Integrative Neuroscience, Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, United States of America
                [2 ] Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois, United States of America
                [3 ] Max-Delbrück Center for Molecular Medicine, Berlin, Germany
                [4 ] Department of Electron Microscopy, Max-Delbrück Center for Molecular Medicine, Berlin, Germany
                [5 ] Klinik für Anaesthesiologie und Operative Intensivmedizin, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
                [6 ] Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America
                University of California San Francisco, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: tpark@ 123456uic.edu (TJP); glewin@ 123456mdc-berlin.de (GRL)
                Article
                06-PLBI-RA-1254R4 plbi-06-01-11
                10.1371/journal.pbio.0060013
                2214810
                18232734
                05141856-a7bf-48e6-a75b-30f854816d95
                Copyright: © 2008 Park et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 14 July 2006
                : 10 December 2007
                Page count
                Pages: 15
                Categories
                Research Article
                Evolutionary Biology
                Neuroscience
                Physiology
                Custom metadata
                Park TJ, Lu Y, Jüttner R, Smith ESJ, Hu J, et al. (2008) Selective inflammatory pain insensitivity in the African naked mole-rat ( Heterocephalus glaber). PLoS Biol 6(1): e13. doi: 10.1371/journal.pbio.0060013

                Life sciences
                Life sciences

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