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Glycine inhibitory dysfunction turns touch into pain through astrocyte-derived D-serine

Miraucourt, Loïs S.a,b,c,d; Peirs, Cédrica,b; Dallel, Radhouanea,b,*; Voisin, Daniel L.a,b,c,d,*

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doi: 10.1016/j.pain.2011.02.021
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Glycine inhibitory dysfunction provides a useful experimental model for studying the mechanism of dynamic mechanical allodynia, a widespread and intractable symptom of neuropathic pain. In this model, allodynia expression relies on N-methyl-D-aspartate receptors (NMDARs), and it has been shown that astrocytes can regulate their activation through the release of the NMDAR coagonist D-serine. Recent studies also suggest that astrocytes potentially contribute to neuropathic pain. However, the involvement of astrocytes in dynamic mechanical allodynia remains unknown. Here, we show that after blockade of glycine inhibition, orofacial tactile stimuli activated medullary dorsal horn (MDH) astrocytes, but not microglia. Accordingly, the glia inhibitor fluorocitrate, but not the microglia inhibitor minocycline, prevented allodynia. Fluorocitrate also impeded activation of astrocytes and blocked activation of the superficial MDH neural circuit underlying allodynia, as revealed by study of Fos expression. MDH astrocytes are thus required for allodynia. They may also produce D-serine because astrocytic processes were selectively immunolabeled for serine racemase, the D-serine synthesizing enzyme. Accordingly, selective degradation of D-serine with D-amino acid oxidase applied in vivo prevented allodynia and activation of the underlying neural circuit. Conversely, allodynia blockade by fluorocitrate was reversed by exogenous D-serine. These results suggest the following scenario: removal of glycine inhibition makes tactile stimuli able to activate astrocytes; activated astrocytes may provide D-serine to enable NMDAR activation and thus allodynia. Such a contribution of astrocytes to pathological pain fuels the emerging concept that astrocytes are critical players in pain signaling.

Glycine disinhibition makes tactile stimuli able to activate astrocytes, which may provide D-serine to enable NMDA receptor activation and thus allodynia.

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aClermont Université, Université d’Auvergne, Neurobiologie de la douleur trigéminale, BP 10448, F-63000 Clermont-Ferrand, France

bInserm, U929, F-63000 Clermont-Ferrand, CHU Clermont-Ferrand, Service d’Odontologie, F-63003 Clermont-Ferrand, France

cInserm, U862, Neurocentre Magendie, F-33077 Bordeaux, France

dUniversité de Bordeaux, F-33077 Bordeaux, France

*Corresponding authors. Address: Inserm, U929, Neurobiologie de la douleur trigéminale, Faculté de Chirurgie Dentaire, 11 boulevard Charles de Gaulle, 63000 Clermont-Ferrand, France. Tel.: +33 5 57 57 37 35; fax: +33 5 57 57 37 50.

E-mail address:radhouane.dallel@u-clermont1.fr

E-mail address:daniel.voisin@inserm.fr

Article history: Received 22 August 2010; Received in revised form 13 January 2011; Accepted 7 February 2011.

© 2011 Lippincott Williams & Wilkins, Inc.
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