title: Presynaptic inhibitory actions of pregabalin on excitatory transmission in superficial dorsal horn of mouse spinal cord: further characterization of presynaptic mechanisms.
abstract: Pregabalin is widely used as an analgesic for the treatment of neuropathic pain. In the present experiments using mouse spinal slices, we recorded electrically evoked glutamatergic excitatory postsynaptic currents (eEPSCs) from superficial dorsal horn neurons. Pregabalin reduced the amplitude of eEPSCs, and increased the paired pulse ratio. Pregabalin also inhibited the frequency of spontaneously occurring miniature EPSCs without affecting their amplitude. Partial ligation of the sciatic nerve increased the expression of the calcium channel α2δ-1 subunit, and increased the presynaptic inhibitory action of pregabalin. Intrathecal injection of antisense oligodeoxynucleotide against the α2δ-1 subunit, decreased the expression of α2δ-1 mRNA in the spinal dorsal horn, and decreased pregabalin's action. These results provide further evidence that pregabalin exerts its presynaptic inhibitory action via binding with the α2δ subunit in a state-dependent manner. Furthermore, presynaptic actions of pregabalin were attenuated in knockout mice lacking the protein syntaxin 1A, a component of the synaptic vesicle release machinery, indicating that syntaxin 1A is required for pregabalin to exert its full presynaptic inhibitory action. These observations might suggest that direct and/or indirect interactions with the presynaptic proteins composing the release machinery underlie at least some part of pregabalin's presynaptic actions.
authors.affiliation: Department of Physiology and Biological Information, Dokkyo Medical University, Kitakobayashi 880, Mibu, Tochigi 321-0293, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Matsuzawa
authors.affiliation: Department of Cell Physiology, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Department of Physiology and Biological Information, Dokkyo Medical University, Kitakobayashi 880, Mibu, Tochigi 321-0293, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Nemoto
authors.affiliation: Department of Physiology and Biological Information, Dokkyo Medical University, Kitakobayashi 880, Mibu, Tochigi 321-0293, Japan.
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Department of Physiology and Biological Information, Dokkyo Medical University, Kitakobayashi 880, Mibu, Tochigi 321-0293, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Department of Cell Physiology, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan.
authors.forename: Kimio
authors.initials: K
authors.lastname: Akagawa
authors.affiliation: Department of Physiology and Biological Information, Dokkyo Medical University, Kitakobayashi 880, Mibu, Tochigi 321-0293, Japan. Electronic address: horiy@dokkyomed.ac.jp.
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Hori
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D018345:Mice, Knockout; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000502:physiology; D000069583:Pregabalin; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries; D009435:Synaptic Transmission / Q000187:drug effects; D050827:Syntaxin 1 / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000700:Analgesics; D015220:Calcium Channels; D016376:Oligonucleotides, Antisense; D021122:Protein Subunits; D012333:RNA, Messenger; D050827:Syntaxin 1; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid
keywords: Excitatory synaptic transmission; Pregabalin; Release machinery; Spinal dorsal horn; Syntaxin 1A knockout; Tight-seal whole-cell recording