title: Interactions of the potent D-amino acid oxidase inhibitor CBIO with morphine in pain and tolerance to analgesia.
abstract: A series of experiments using technologies of gene mutation and silencing as well as chemical biology have demonstrated that spinal D-amino acid oxidase (DAAO) contributes to the development of central sensitization-mediated chronic pain and might be a potential molecular target for the treatment of chronic pain. DAAO inhibitors are now under clinical investigations for the management of chronic neuropathic pain. This study examined the interactions between morphine and the DAAO inhibitor CBIO (5-chloro-benzo[d]isoxazol-3-ol) in pain and analgesia tolerance mainly in the formalin test. Given subcutaneously CBIO acutely interacted with morphine in analgesia in an additive manner both in the acute nociception settings (the formalin acute phase nociception, hot-plate test and tail immersion test) and in formalin-induced tonic pain. Bi-daily exposure of CBIO given subcutaneously for 7 days did not produce self-tolerance to analgesia or cross-tolerance to morphine whereas 7-day subcutaneous morphine induced self-tolerance to analgesia but not cross-tolerance to CBIO. More importantly, subcutaneous co-administrations or even single dose of CBIO completely prevented or reversed morphine tolerance to analgesia (exhibited by a single dose or a dose-response curve of morphine) in both formalin-induced acute phase nociception and tonic phase pain. These results, for the first time, identified DAAO as an efficacious molecule mediating morphine tolerance, in addition to clarifying the complex interactions between morphine and DAAO inhibitors probed by CBIO, and provided a pharmacological basis for DAAO inhibitors in combination with morphine to clinically manage pain.
authors.affiliation: King's Lab, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Gong
authors.forename: Yan-Chao
authors.initials: YC
authors.lastname: Wang
authors.forename: Hui-Li
authors.initials: HL
authors.lastname: Wang
authors.forename: Ai-Niu
authors.initials: AN
authors.lastname: Ma
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
chemical_list: C531067:5-chlorobenzo(d)isoxazol-3-ol; D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D007555:Isoxazoles; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D009020:Morphine; D003605:D-Amino-Acid Oxidase