Intracellular mGluR5 plays a critical role in neuropathic pain

Kathleen Vincent, Virginia M. Cornea, Yuh-Jiin I. Jong, André Laferrière, Naresh Kumar, Aiste Mickeviciute, Jollee S. T. Fung, Pouya Bandegi, Alfredo Ribeiro-da-Silva, Karen L. O’Malley () and Terence J. Coderre ()
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Kathleen Vincent: Alan Edwards Centre for Research on Pain, McGill University
Virginia M. Cornea: Alan Edwards Centre for Research on Pain, McGill University
Yuh-Jiin I. Jong: Washington University School of Medicine
André Laferrière: Alan Edwards Centre for Research on Pain, McGill University
Naresh Kumar: Alan Edwards Centre for Research on Pain, McGill University
Aiste Mickeviciute: Alan Edwards Centre for Research on Pain, McGill University
Jollee S. T. Fung: Alan Edwards Centre for Research on Pain, McGill University
Pouya Bandegi: Alan Edwards Centre for Research on Pain, McGill University
Alfredo Ribeiro-da-Silva: Alan Edwards Centre for Research on Pain, McGill University
Karen L. O’Malley: Washington University School of Medicine
Terence J. Coderre: Alan Edwards Centre for Research on Pain, McGill University

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Spinal mGluR5 is a key mediator of neuroplasticity underlying persistent pain. Although brain mGluR5 is localized on cell surface and intracellular membranes, neither the presence nor physiological role of spinal intracellular mGluR5 is established. Here we show that in spinal dorsal horn neurons >80% of mGluR5 is intracellular, of which ∼60% is located on nuclear membranes, where activation leads to sustained Ca2+ responses. Nerve injury inducing nociceptive hypersensitivity also increases the expression of nuclear mGluR5 and receptor-mediated phosphorylated-ERK1/2, Arc/Arg3.1 and c-fos. Spinal blockade of intracellular mGluR5 reduces neuropathic pain behaviours and signalling molecules, whereas blockade of cell-surface mGluR5 has little effect. Decreasing intracellular glutamate via blocking EAAT-3, mimics the effects of intracellular mGluR5 antagonism. These findings show a direct link between an intracellular GPCR and behavioural expression in vivo. Blockade of intracellular mGluR5 represents a new strategy for the development of effective therapies for persistent pain.

Date: 2016
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DOI: 10.1038/ncomms10604

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