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Pharmacodynamic effects of a D-amino acid oxidase inhibitor indicate a spinal site of action in rat models of neuropathic pain.
J Pharmacol Exp Ther. 2013 Jun; 345(3):502-11.JP

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.

Authors+Show Affiliations

Sunovion Pharmaceuticals Inc, 84 Waterford Dr., Marlborough, MA 01752, USA. seth.hopkins@sunovion.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23520265

Citation

Hopkins, Seth C., et al. "Pharmacodynamic Effects of a D-amino Acid Oxidase Inhibitor Indicate a Spinal Site of Action in Rat Models of Neuropathic Pain." The Journal of Pharmacology and Experimental Therapeutics, vol. 345, no. 3, 2013, pp. 502-11.
Hopkins SC, Zhao FY, Bowen CA, et al. Pharmacodynamic effects of a D-amino acid oxidase inhibitor indicate a spinal site of action in rat models of neuropathic pain. J Pharmacol Exp Ther. 2013;345(3):502-11.
Hopkins, S. C., Zhao, F. Y., Bowen, C. A., Fang, X., Wei, H., Heffernan, M. L., Spear, K. L., Spanswick, D. C., Varney, M. A., & Large, T. H. (2013). Pharmacodynamic effects of a D-amino acid oxidase inhibitor indicate a spinal site of action in rat models of neuropathic pain. The Journal of Pharmacology and Experimental Therapeutics, 345(3), 502-11. https://doi.org/10.1124/jpet.113.204016
Hopkins SC, et al. Pharmacodynamic Effects of a D-amino Acid Oxidase Inhibitor Indicate a Spinal Site of Action in Rat Models of Neuropathic Pain. J Pharmacol Exp Ther. 2013;345(3):502-11. PubMed PMID: 23520265.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacodynamic effects of a D-amino acid oxidase inhibitor indicate a spinal site of action in rat models of neuropathic pain. AU - Hopkins,Seth C, AU - Zhao,Fei-Yue, AU - Bowen,Carrie A, AU - Fang,Xin, AU - Wei,Haifeng, AU - Heffernan,Michele L R, AU - Spear,Kerry L, AU - Spanswick,David C, AU - Varney,Mark A, AU - Large,Thomas H, Y1 - 2013/03/21/ PY - 2013/3/23/entrez PY - 2013/3/23/pubmed PY - 2013/7/17/medline SP - 502 EP - 11 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 345 IS - 3 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/23520265/Pharmacodynamic_effects_of_a_D_amino_acid_oxidase_inhibitor_indicate_a_spinal_site_of_action_in_rat_models_of_neuropathic_pain_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=23520265 DB - PRIME DP - Unbound Medicine ER -