title: Effects of pregabalin on spinal d-serine content and NMDA receptor-mediated synaptic transmission in mice with neuropathic pain.
abstract: Pregabalin (PGB) is a chemical derivative of the inhibitory neurotransmitter γ-aminobutyric acid, and is successfully used for the treatment of neuropathic pain. Substantial evidence suggests that d-serine, an endogenous co-agonist at the strychnine-insensitive glycine site of the NMDA receptor, counteracts the antinociceptive actions of PGB at the level of the spinal cord. In the present study, we examined the impact of PGB treatment on spinal d-serine content and NMDA receptor-mediated synaptic transmission in the superficial dorsal horn of peripheral nerve-ligated neuropathic mice. Mechanical allodynia was assessed using von Frey filaments. On post-surgical day 9 (after 5days of treatment with PGB [50mg/kg] or saline vehicle), the lumbar spinal cord was removed, homogenized, and ultrafiltrated. Supernatant samples were treated with Marfey's reagent and analyzed with liquid chromatography-mass spectrometry to measure d-serine content. In the electrophysiological experiments, tight-seal whole-cell recording was performed on neurons in the superficial dorsal horn of spinal cord slices. Partial sciatic nerve ligation increased spinal d-serine content, increased the NMDA/non-NMDA ratio of EPSC amplitudes, and slowed the decay phase of the NMDA component of EPSCs (NMDA-EPSCs). PGB treatment attenuated mechanical allodynia and reduced spinal d-serine content, decreased the NMDA/non-NMDA ratio, and shortened the decay time of NMDA-EPSCs. Furthermore, bath-applied d-serine attenuated the effects of PGB treatment. Although the precise mechanism for the effect of PGB on d-serine metabolism and abundance is unknown, the antinociceptive action of PGB likely involves the reduction of spinal d-serine content and subsequent attenuation of NMDA receptor-mediated synaptic transmission in the superficial dorsal horn.
authors.affiliation: Department Physiology and Biological Information, Dokkyo Medical University, Kitakobayashi 880, Mibu, Tochigi 321-0293, Japan.
authors.forename: Eiko
authors.initials: E
authors.lastname: Kato
authors.affiliation: Department 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 Physiology and Biological Information, Dokkyo Medical University, Kitakobayashi 880, Mibu, Tochigi 321-0293, Japan.
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Department 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 Physiology and Biological Information, Dokkyo Medical University, Kitakobayashi 880, Mibu, Tochigi 321-0293, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Maekawa
authors.affiliation: Department 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: D000818:Animals; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D000069583:Pregabalin / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D012694:Serine / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid
keywords: NMDAR mediated synaptic current; Neuropathic pain; Pregabalin; Spinal superficial dorsal horn; Tight-seal whole-cell recording; d-Serine