Journal ArticleDOI
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,Bowen Carrie A,Xin Fang,Haifeng Wei,Michelle L. R. Heffernan,Kerry L. Spear,David Spanswick,Mark A. Varney,Thomas H. Large +9 more
TLDR
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.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.read more
Citations
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Journal ArticleDOI
Discovery and analgesic evaluation of 8-chloro-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione as a novel potent d-amino acid oxidase inhibitor
Dongsheng Xie,Jun Lu,Jin Xie,Junjun Cui,Teng-Fei Li,Yan-Chao Wang,Yuan Chen,Nian Gong,Xin-Yan Li,Lei Fu,Yong-Xiang Wang +10 more
TL;DR: This research provided a new class of chemical entities with oral application potential for the treatment of chronic pain and morphine analgesic tolerance and confirmed the analgesic effect of the DAAO inhibitors.
Journal ArticleDOI
In vivo electrophysiological recording techniques for the study of neuropathic pain in rodent models.
Fei Yue Zhao,Ross Jeggo,Haifeng Wei,Andrew D. Whyment,Xin Fang,David Spanswick,David Spanswick,David Spanswick +7 more
TL;DR: Techniques designed to record pathophysiological electrical activity associated with neuropathic pain at the level of the periphery, in single fibers of primary sensory neurons, and from wide dynamic range (WDR) neurons of the dorsal horn of the spinal cord are described.
Patent
Benzo[d]isoxazol-3-ol daao inhibitors
TL;DR: In this article, the authors present methods for increasing D-Serine concentration and reducing concentration of the toxic products of D- Serine oxidation, for enhancing learning, memory and/or cognition, or for treating schizophrenia, Alzheimer's disease, ataxia, or neuropathic pain, or preventing loss in neuronal function characteristic of neurodegenerative diseases.
Journal ArticleDOI
Dual role of D-amino acid oxidase in experimental pain models.
TL;DR: The knockdown of DAAO gene or pharmacological inhibition of D AAO reduces pain, reverses tolerance to morphine and hyperalgesia, and attenuates the pain in experimental studies.
Patent
Pyrrole and pyrazole DAAO inhibitors
TL;DR: In this article, the authors proposed a general formula for increasing the concentration of D-serine and decreasing the concentrations of Dserine oxidative toxic products, a method for enhancing learning, memory and / or cognition, or schizophrenia, Alzheimer's disease, ataxia or neuropathic pain.
References
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Journal ArticleDOI
A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.
Gary J. Bennett,Y.-K. Xie +1 more
TL;DR: A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve and the postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain were produced.
Journal ArticleDOI
An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.
Sun Ho Kim,Jin Mo Chung +1 more
TL;DR: Results suggested that the surgical procedure in all 3 groups produced a long-lasting hyperalgesia to noxious heat and mechanical allodynia of the affected foot and there were behavioral signs of the presence of spontaneous pain in the affectedFoot.
Journal ArticleDOI
d-Serine is an endogenous ligand for the glycine site of the N-methyl-d-aspartate receptor
Jean-Pierre Mothet,Angèle T. Parent,Angèle T. Parent,Herman Wolosker,Roscoe O. Brady,David J. Linden,Christopher D. Ferris,Michael A. Rogawski,Solomon H. Snyder +8 more
TL;DR: D-serine is an endogenous modulator of the glycine site of NMDA receptors and fully occupies this site at some functional synapses and greatly attenuates NMDA receptor-mediated neurotransmission as assessed by using whole-cell patch-clamp recordings or indirectly by using biochemical assays of the sequelae of NMda receptor- mediated calcium flux.
Journal ArticleDOI
Glia-Derived d-Serine Controls NMDA Receptor Activity and Synaptic Memory
Aude Panatier,Dionysia T. Theodosis,Jean-Pierre Mothet,Bastien Touquet,Loredano Pollegioni,Dominique A. Poulain,Stéphane H. R. Oliet +6 more
TL;DR: The degree of astrocytic coverage of neurons governs the level of glycine site occupancy on the NMDA receptor, thereby affecting their availability for activation and thus the activity dependence of long-term synaptic changes.
Journal ArticleDOI
Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists
Thomas Papouin,Laurent Ladépêche,Laurent Ladépêche,Jérôme Ruel,Jérôme Ruel,Silvia Sacchi,Marilyne Labasque,Marwa Hanini,Laurent Groc,Laurent Groc,Loredano Pollegioni,Jean-Pierre Mothet,Stéphane H. R. Oliet,Stéphane H. R. Oliet +13 more
TL;DR: It is demonstrated that long-term potentiation and NMDA-induced neurotoxicity rely on synaptic NMDARs only, and long- term depression requires both synaptic and extrasynaptic receptors.
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