Leukotriene enhances NMDA-induced inward currents in dorsal horn neurons of the rat spinal cord after peripheral nerve injury.
BACKGROUND
LTB4 is classified as a leukotriene (LT), a group of lipid mediators that are derived from arachidonic acid. It is recognized that leukotrienes are involved in the pathogenesis of many diseases, including peripheral inflammatory pain. However, little is known about the effects of leukotrienes on the spinal dorsal horn during neuropathic pain. Previously, we reported that there was increased expression of 5-lipoxygenase (5-LO) at spinal microglia, and the leukotriene B4 receptor 1 (BLT1), a high affinity receptor of LTB4, in spinal neurons in spared nerve injury (SNI) model rats. In the present study, we examined the effects of LTB4 on spinal dorsal horn neurons in both naïve and SNI model rats using patch-clamp methods.


RESULTS
Bath application of LTB4 did not change AMPA receptor-mediated spontaneous excitatory postsynaptic currents (sEPSCs) or membrane potentials. However, we found that LTB4 enhanced the amplitude of NMDA receptor-mediated sEPSCs and significantly increased exogenous NMDA-induced inward currents in SNI model rats. This increase of inward currents could be inhibited by a selective LTB4 antagonist, U75302, as well as a GDP-β-S, a G-protein inhibitor. These results indicate that both increased LTB4 from spinal microglia or increased BLT1 in spinal neurons after peripheral nerve injury can enhance the activity of NMDA receptors through intracellular G-proteins in spinal dorsal horn neurons.


CONCLUSIONS
Our findings showed that LTB4, which may originate from microglia, can activate BLT1 receptors which are expressed on the membrane of spinal dorsal horn neurons during neuropathic pain. This glia-neuron interaction induces the enhancement of NMDA currents through intracellular G-proteins. The enhancement of NMDA receptor sensitivity of dorsal horn neurons may lead to central sensitization, leading to mechanical pain hypersensitivity.
Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. kiyo8492@hotmail.co.jp.|Pain Research Center, Kansai University of Health Sciences, 2-11-1 Wakaba Kumatori-cho, Osaka, 590-0482, Japan. kiyo8492@hotmail.co.jp.
Yasukuni
Y
Kiyoyuki
Department of Orthopedic Surgery, Wakayama Medical University, 811-1 Mimiidera, Wakayama, 641-8510, Japan. twatarun@gmail.com.
Wataru
W
Taniguchi
Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. okubo@hyo-med.ac.jp.
Masamichi
M
Okubo
Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. yamanaka@hyo-med.ac.jp.
Hiroki
H
Yamanaka
Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. ki-kobay@hyo-med.ac.jp.
Kimiko
K
Kobayashi
Department of Orthopedic Surgery, Wakayama Medical University, 811-1 Mimiidera, Wakayama, 641-8510, Japan. ckpsn852@yahoo.co.jp.
Naoko
N
Nishio
Pain Research Center, Kansai University of Health Sciences, 2-11-1 Wakaba Kumatori-cho, Osaka, 590-0482, Japan. nakatsuka@kansai.ac.jp.
Terumasa
T
Nakatsuka
Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. noguchi@hyo-med.ac.jp.
Koichi
K
Noguchi
D000818:Animals; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects*; D007975:Leukotriene B4 / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D059348:Peripheral Nerve Injuries / Q000378:metabolism* / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D012333:RNA, Messenger; D018091:Receptors, AMPA; D018077:Receptors, Leukotriene; D007975:Leukotriene B4; D016202:N-Methylaspartate; D019204:GTP-Binding Proteins