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Research ArticleNeuropharmacology

Novel TRPM8 Antagonist Attenuates Cold Hypersensitivity after Peripheral Nerve Injury in Rats

Ryan Patel, Leonor Gonçalves, Robert Newman, Feng Li Jiang, Anne Goldby, Jennifer Reeve, Alan Hendrick, Martin Teall, Duncan Hannah, Sarah Almond, Nicola Brice and Anthony H. Dickenson
Journal of Pharmacology and Experimental Therapeutics April 2014, 349 (1) 47-55; DOI: https://doi.org/10.1124/jpet.113.211243
Ryan Patel
University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom (R.P., L.G., A.H.D.); Takeda Cambridge Ltd, Cambridge, United Kingdom (R.N., A.G., J.R., A.H., M.T., D.H., S.A., N.B.); and Takeda Singapore Pte Ltd, Chromos, Singapore (F.L.J.)
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Leonor Gonçalves
University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom (R.P., L.G., A.H.D.); Takeda Cambridge Ltd, Cambridge, United Kingdom (R.N., A.G., J.R., A.H., M.T., D.H., S.A., N.B.); and Takeda Singapore Pte Ltd, Chromos, Singapore (F.L.J.)
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Robert Newman
University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom (R.P., L.G., A.H.D.); Takeda Cambridge Ltd, Cambridge, United Kingdom (R.N., A.G., J.R., A.H., M.T., D.H., S.A., N.B.); and Takeda Singapore Pte Ltd, Chromos, Singapore (F.L.J.)
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Feng Li Jiang
University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom (R.P., L.G., A.H.D.); Takeda Cambridge Ltd, Cambridge, United Kingdom (R.N., A.G., J.R., A.H., M.T., D.H., S.A., N.B.); and Takeda Singapore Pte Ltd, Chromos, Singapore (F.L.J.)
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Anne Goldby
University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom (R.P., L.G., A.H.D.); Takeda Cambridge Ltd, Cambridge, United Kingdom (R.N., A.G., J.R., A.H., M.T., D.H., S.A., N.B.); and Takeda Singapore Pte Ltd, Chromos, Singapore (F.L.J.)
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Jennifer Reeve
University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom (R.P., L.G., A.H.D.); Takeda Cambridge Ltd, Cambridge, United Kingdom (R.N., A.G., J.R., A.H., M.T., D.H., S.A., N.B.); and Takeda Singapore Pte Ltd, Chromos, Singapore (F.L.J.)
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Alan Hendrick
University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom (R.P., L.G., A.H.D.); Takeda Cambridge Ltd, Cambridge, United Kingdom (R.N., A.G., J.R., A.H., M.T., D.H., S.A., N.B.); and Takeda Singapore Pte Ltd, Chromos, Singapore (F.L.J.)
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Martin Teall
University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom (R.P., L.G., A.H.D.); Takeda Cambridge Ltd, Cambridge, United Kingdom (R.N., A.G., J.R., A.H., M.T., D.H., S.A., N.B.); and Takeda Singapore Pte Ltd, Chromos, Singapore (F.L.J.)
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Duncan Hannah
University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom (R.P., L.G., A.H.D.); Takeda Cambridge Ltd, Cambridge, United Kingdom (R.N., A.G., J.R., A.H., M.T., D.H., S.A., N.B.); and Takeda Singapore Pte Ltd, Chromos, Singapore (F.L.J.)
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Sarah Almond
University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom (R.P., L.G., A.H.D.); Takeda Cambridge Ltd, Cambridge, United Kingdom (R.N., A.G., J.R., A.H., M.T., D.H., S.A., N.B.); and Takeda Singapore Pte Ltd, Chromos, Singapore (F.L.J.)
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Nicola Brice
University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom (R.P., L.G., A.H.D.); Takeda Cambridge Ltd, Cambridge, United Kingdom (R.N., A.G., J.R., A.H., M.T., D.H., S.A., N.B.); and Takeda Singapore Pte Ltd, Chromos, Singapore (F.L.J.)
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Anthony H. Dickenson
University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom (R.P., L.G., A.H.D.); Takeda Cambridge Ltd, Cambridge, United Kingdom (R.N., A.G., J.R., A.H., M.T., D.H., S.A., N.B.); and Takeda Singapore Pte Ltd, Chromos, Singapore (F.L.J.)
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Abstract

Abnormal cold sensitivity is a common feature of a range of neuropathies. In the murine somatosensory system, multiple aspects of cold sensitivity are dependent on TRPM8, both short term and in response to peripheral nerve injury. The specialized nature of cold-sensitive afferents and the restricted expression of TRPM8 render it an attractive target for the treatment of cold hypersensitivity. This current study examines the effect of a novel TRPM8 antagonist (M8-An) in naive and spinal nerve-ligated rats through behavioral and in vivo electrophysiological approaches. In vitro, M8-An inhibited icilin-evoked Ca2+ currents in HEK293 cells stably expressing human TRPM8 with an IC50 of 10.9 nM. In vivo, systemic M8-An transiently decreased core body temperature. Deep dorsal horn recordings were made in vivo from neurons innervating the hind paw. M8-An inhibited neuronal responses to innocuous and noxious cooling of the receptive field in spinal nerve-ligated rats but not in naive rats. No effect on neuronal responses to mechanical and heat stimulation was observed. In addition, M8-An also attenuated behavioral responses to cold but not mechanical stimulation after nerve ligation without affecting the uninjured contralateral response. The data presented here support a contribution of TRPM8 to the pathophysiology of cold hypersensitivity in this model and highlight the potential of the pharmacological block of TRPM8 in alleviating the associated symptoms.

Footnotes

    • Received November 13, 2011.
    • Accepted January 24, 2014.
  • This study was supported by Biotechnology and Biological Sciences Research Council [Grant BB/H016597/1] (CASE studentship award in association with Takeda Cambridge Ltd.).

  • dx.doi.org/10.1124/jpet.113.211243

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 349 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 349, Issue 1
1 Apr 2014
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Research ArticleNeuropharmacology

TRPM8 and Cold Sensitivity in Neuropathy

Ryan Patel, Leonor Gonçalves, Robert Newman, Feng Li Jiang, Anne Goldby, Jennifer Reeve, Alan Hendrick, Martin Teall, Duncan Hannah, Sarah Almond, Nicola Brice and Anthony H. Dickenson
Journal of Pharmacology and Experimental Therapeutics April 1, 2014, 349 (1) 47-55; DOI: https://doi.org/10.1124/jpet.113.211243

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Research ArticleNeuropharmacology

TRPM8 and Cold Sensitivity in Neuropathy

Ryan Patel, Leonor Gonçalves, Robert Newman, Feng Li Jiang, Anne Goldby, Jennifer Reeve, Alan Hendrick, Martin Teall, Duncan Hannah, Sarah Almond, Nicola Brice and Anthony H. Dickenson
Journal of Pharmacology and Experimental Therapeutics April 1, 2014, 349 (1) 47-55; DOI: https://doi.org/10.1124/jpet.113.211243
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