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Research ArticleNeuropharmacology

Pharmacodynamic Effects of a d-Amino Acid Oxidase Inhibitor Indicate a Spinal Site of Action in Rat Models of Neuropathic Pain

Seth C. Hopkins, Fei-Yue Zhao, Carrie A. Bowen, Xin Fang, Haifeng Wei, Michele L. R. Heffernan, Kerry L. Spear, David C. Spanswick, Mark A. Varney and Thomas H. Large
Journal of Pharmacology and Experimental Therapeutics June 2013, 345 (3) 502-511; DOI: https://doi.org/10.1124/jpet.113.204016
Seth C. Hopkins
Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts (S.C.H., C.A.B., M.L.R.H., K.L.S., M.A.V., T.H.L.); Neurosolutions Ltd., Coventry, United Kingdom (F.-Y.Z., X.F., H.W., D.C.S.); Department of Physiology, Monash University, Clayton, Victoria, Australia (D.C.S.); and Warwick Medical School, University of Warwick, Coventry, United Kingdom (D.C.S.)
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Fei-Yue Zhao
Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts (S.C.H., C.A.B., M.L.R.H., K.L.S., M.A.V., T.H.L.); Neurosolutions Ltd., Coventry, United Kingdom (F.-Y.Z., X.F., H.W., D.C.S.); Department of Physiology, Monash University, Clayton, Victoria, Australia (D.C.S.); and Warwick Medical School, University of Warwick, Coventry, United Kingdom (D.C.S.)
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Carrie A. Bowen
Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts (S.C.H., C.A.B., M.L.R.H., K.L.S., M.A.V., T.H.L.); Neurosolutions Ltd., Coventry, United Kingdom (F.-Y.Z., X.F., H.W., D.C.S.); Department of Physiology, Monash University, Clayton, Victoria, Australia (D.C.S.); and Warwick Medical School, University of Warwick, Coventry, United Kingdom (D.C.S.)
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Xin Fang
Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts (S.C.H., C.A.B., M.L.R.H., K.L.S., M.A.V., T.H.L.); Neurosolutions Ltd., Coventry, United Kingdom (F.-Y.Z., X.F., H.W., D.C.S.); Department of Physiology, Monash University, Clayton, Victoria, Australia (D.C.S.); and Warwick Medical School, University of Warwick, Coventry, United Kingdom (D.C.S.)
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Haifeng Wei
Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts (S.C.H., C.A.B., M.L.R.H., K.L.S., M.A.V., T.H.L.); Neurosolutions Ltd., Coventry, United Kingdom (F.-Y.Z., X.F., H.W., D.C.S.); Department of Physiology, Monash University, Clayton, Victoria, Australia (D.C.S.); and Warwick Medical School, University of Warwick, Coventry, United Kingdom (D.C.S.)
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Michele L. R. Heffernan
Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts (S.C.H., C.A.B., M.L.R.H., K.L.S., M.A.V., T.H.L.); Neurosolutions Ltd., Coventry, United Kingdom (F.-Y.Z., X.F., H.W., D.C.S.); Department of Physiology, Monash University, Clayton, Victoria, Australia (D.C.S.); and Warwick Medical School, University of Warwick, Coventry, United Kingdom (D.C.S.)
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Kerry L. Spear
Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts (S.C.H., C.A.B., M.L.R.H., K.L.S., M.A.V., T.H.L.); Neurosolutions Ltd., Coventry, United Kingdom (F.-Y.Z., X.F., H.W., D.C.S.); Department of Physiology, Monash University, Clayton, Victoria, Australia (D.C.S.); and Warwick Medical School, University of Warwick, Coventry, United Kingdom (D.C.S.)
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David C. Spanswick
Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts (S.C.H., C.A.B., M.L.R.H., K.L.S., M.A.V., T.H.L.); Neurosolutions Ltd., Coventry, United Kingdom (F.-Y.Z., X.F., H.W., D.C.S.); Department of Physiology, Monash University, Clayton, Victoria, Australia (D.C.S.); and Warwick Medical School, University of Warwick, Coventry, United Kingdom (D.C.S.)
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Mark A. Varney
Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts (S.C.H., C.A.B., M.L.R.H., K.L.S., M.A.V., T.H.L.); Neurosolutions Ltd., Coventry, United Kingdom (F.-Y.Z., X.F., H.W., D.C.S.); Department of Physiology, Monash University, Clayton, Victoria, Australia (D.C.S.); and Warwick Medical School, University of Warwick, Coventry, United Kingdom (D.C.S.)
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Thomas H. Large
Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts (S.C.H., C.A.B., M.L.R.H., K.L.S., M.A.V., T.H.L.); Neurosolutions Ltd., Coventry, United Kingdom (F.-Y.Z., X.F., H.W., D.C.S.); Department of Physiology, Monash University, Clayton, Victoria, Australia (D.C.S.); and Warwick Medical School, University of Warwick, Coventry, United Kingdom (D.C.S.)
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Abstract

Inhibition of d-amino acid oxidase (DAAO) activity is a potential target for the treatment of chronic pain. Here we characterized the effects of systemic administration of the DAAO inhibitor 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN) in rat models of neuropathic and inflammatory pain. Oral administration of SUN dose dependently attenuated tactile allodynia induced by ligation of the L5 spinal nerve (SNL) and similarly reversed thermal hyperalgesia produced by chronic constriction injury. In addition, SUN was efficacious against complete Freund’s adjuvant-induced thermal hyperalgesia. In these models, maximal reversal of pain-related behaviors corresponded with maximum rates of increase in brain and plasma d-serine concentrations, indicative of full inhibition of DAAO activity. To investigate the possible site(s) of action, we recorded spontaneous nerve activity and mechanically evoked responses of central spinal cord dorsal horn neurons and compared these with spontaneous activity of peripheral dorsal root filaments in anesthetized SNL model animals. Oral SUN reduced spontaneous activity in both central and peripheral recordings at doses and pretreatment times that corresponded to reduced mechanical allodynia in behavioral experiments. After intravenous administration of SUN, the onset of action for this central effect was rapid (maximal effects within 30 minutes), but was abolished by severing afferent inputs to the dorsal horn. Overall, these results indicate that inhibition of DAAO in peripheral afferent spinal circuits reduced spontaneous neuronal activity to attenuate pain-related behaviors in rat models of neuropathic and inflammatory pain.

Footnotes

    • Received February 20, 2013.
    • Accepted March 20, 2013.
  • This work was supported by Sunovion Pharmaceuticals Inc.

  • dx.doi.org/10.1124/jpet.113.204016.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 345 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 345, Issue 3
1 Jun 2013
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Research ArticleNeuropharmacology

DAAO Inhibitor Neuropathic Pain

Seth C. Hopkins, Fei-Yue Zhao, Carrie A. Bowen, Xin Fang, Haifeng Wei, Michele L. R. Heffernan, Kerry L. Spear, David C. Spanswick, Mark A. Varney and Thomas H. Large
Journal of Pharmacology and Experimental Therapeutics June 1, 2013, 345 (3) 502-511; DOI: https://doi.org/10.1124/jpet.113.204016

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Research ArticleNeuropharmacology

DAAO Inhibitor Neuropathic Pain

Seth C. Hopkins, Fei-Yue Zhao, Carrie A. Bowen, Xin Fang, Haifeng Wei, Michele L. R. Heffernan, Kerry L. Spear, David C. Spanswick, Mark A. Varney and Thomas H. Large
Journal of Pharmacology and Experimental Therapeutics June 1, 2013, 345 (3) 502-511; DOI: https://doi.org/10.1124/jpet.113.204016
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