Effects of pregabalin on spinal d-serine content and NMDA receptor-mediated synaptic transmission in mice with neuropathic pain

• Published in: Neuroscience letters 2017-01, Vol.636, p.270-275
• Main Authors: Kato, Eiko, Matsuzawa, Rie, Kobayashi, Shunsaku, Fukushima, Teruyuki, Maekawa, Masao, Hori, Yuuichi
• Format: Article
• Language: English
• Subjects: Animals; d-Serine; Disease Models, Animal; Excitatory Postsynaptic Potentials - drug effects; gamma-Aminobutyric Acid - metabolism; Male; Mice; Neuralgia - drug therapy; Neuralgia - metabolism; Neurons - drug effects; Neurons - metabolism; Neuropathic pain; NMDAR mediated synaptic current; Pregabalin; Pregabalin - pharmacology; Receptors, N-Methyl-D-Aspartate - drug effects; Serine - metabolism; Spinal superficial dorsal horn; Synaptic Transmission - drug effects; Tight-seal whole-cell recording
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2016.10.053

•Pregabalin attenuated nerve injury-induced increases in spinal d-serine content.•Pregabalin attenuated injury-induced increases in the NMDA/non-NMDA ratio of EPSCs.•Pregabalin shortened prolonged NMDA-EPSC decay time induced by nerve injury.•Bath-applied d-serine reversed pregabalin-induced effects on NMDA-EPSCs.•Pregabalin decreases d-serine and alters synaptic plasticity in the dorsal horn. 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.