title: Pharmacodynamic effects of a D-amino acid oxidase inhibitor indicate a spinal site of action in rat models of neuropathic 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.
authors.affiliation: Sunovion Pharmaceuticals Inc, 84 Waterford Dr., Marlborough, MA 01752, USA. seth.hopkins@sunovion.com
authors.forename: Seth C
authors.initials: SC
authors.lastname: Hopkins
authors.forename: Fei-Yue
authors.initials: FY
authors.lastname: Zhao
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Bowen
authors.forename: Xin
authors.initials: X
authors.lastname: Fang
authors.forename: Haifeng
authors.initials: H
authors.lastname: Wei
authors.forename: Michele L R
authors.initials: ML
authors.lastname: Heffernan
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Spear
authors.forename: David C
authors.initials: DC
authors.lastname: Spanswick
authors.forename: Mark A
authors.initials: MA
authors.lastname: Varney
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Large
mesh_terms: D000588:Amines / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003251:Constriction, Pathologic / Q000473:pathology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005620:Freund's Adjuvant; D005663:Furans / Q000494:pharmacology; D000077206:Gabapentin; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000523:psychology; D008026:Ligation; D008297:Male; D009437:Neuralgia / Q000188:drug therapy*; D010812:Physical Stimulation; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000493:pharmacokinetics; D013116:Spinal Cord / Q000187:drug effects*; D013127:Spinal Nerves / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: C582204:4H-furo(3,2-b)pyrrole-5-carboxylic acid; D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005663:Furans; D011758:Pyrroles; D012694:Serine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D005620:Freund's Adjuvant; D003605:D-Amino-Acid Oxidase