Journal of pharmacological sciences
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Comparative Study
Blockade of glycine transporter (GlyT) 2, but not GlyT1, ameliorates dynamic and static mechanical allodynia in mice with herpetic or postherpetic pain.
Glycine is an inhibitory neurotransmitter in the spinal dorsal horn and its extracellular concentration is regulated by glial glycine transporter (GlyT) 1 and neuronal GlyT2. This study was conducted to elucidate the effects of intrathecal injections of GlyT1 and GlyT2 inhibitors on two distinct types of mechanical allodynia, dynamic and static allodynia, in mice with herpetic or postherpetic pain. The GlyT2 inhibitor ALX1393, but not the GlyT1 inhibitor sarcosine, suppressed dynamic and static allodynia at the herpetic and postherpetic stages. ⋯ Glycine receptor alpha1-subunit mRNA was decreased in the lumbar dorsal horn at the herpetic, but not postherpetic stage, without alteration in alpha3-subunit mRNA. The results suggest that GlyT2 is a potential target for treatment of dynamic and static allodynia in patients with herpes zoster and postherpetic neuralgia. The lack of efficacy of GlyT1 inhibitor may be explained by activation of NMDA receptors and the down-regulation of GlyT1 in the lumbar dorsal horn.
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Although the central role of ameloblasts in synthesis and resorption of enamel matrix proteins during amelogenesis is well documented, the Ca(2+)-transport/extrusion mechanism remains to be fully elucidated. To clarify Ca(2+)-transport in rat ameloblasts, we investigated expression and localization of Na(+)-Ca(2+) exchanger (NCX) isoforms and the functional characteristics of their ion transporting/pharmacological properties. ⋯ Ca(2+) influx by Na(+)-Ca(2+) exchange, measured by fura-2 fluorescence, showed dependence on extracellular Ca(2+) concentration, and it was blocked by NCX inhibitors KB-R7943, SEA0400, and SN-6. These results showed significant expression of NCX1 and NCX3 in ameloblasts, indicating their involvement in the directional Ca(2+) extrusion pathway from cells to the enamel mineralizing front.
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Oxaliplatin is a platinum-based chemotherapy drug characterized by the development of acute and chronic peripheral neuropathies. Mexiletine, an orally available Na(+)-channel blocker, has widely been used in patients with chronic painful diabetic neuropathy. ⋯ Lidocaine (30, but not 3 and 10, mg/kg, i.p.) also significantly relieved both pain behaviors. These results suggest that mexiletine may be effective in relieving the oxaliplatin-induced neuropathic pain clinically.
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The activity of pyruvate dehydrogenase (PDH) is reduced in diabetic patients. Phosphorylation of the PDH E1alpha subunit by PDH kinase contributes to the suppression of PDH activity. PDH requires thiamine as a coenzyme. ⋯ The O-glycosylated protein was markedly increased in RCFs exposed to high glucose, which was inhibited by thiamine. These results suggest that thiamine ameliorates diabetes-induced PDH inhibition by suppressing the increased expression of the O-glycosylated protein. The O-glycosylation of PDH E1alpha may be involved in the regulation of the PDH activity.
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Linopirdine is a well known blocker of voltage-gated potassium channels from the Kv7 (or KCNQ) family that generate the so called M current in mammalian neurons. Kv7 subunits are also expressed in pain-sensing neurons in dorsal root ganglia, in which they modulate neuronal excitability. In this study we demonstrate that linopirdine acts as an agonist of TRPV1 (transient receptor potential vanilloid type 1), another ion channel expressed in nociceptors and involved in pain signaling. ⋯ Linopirdine also activates an inward current in TRPV1-expressing HEK293 cells that is almost completely blocked by the selective TRPV1 antagonist capsazepine. At low concentrations linopirdine sensitizes both recombinant and native TRPV1 channels to heat, in a manner that is not prevented by the Kv7-channel opener flupirtine. Taken together, these results indicate that linopirdine exerts an excitatory action on mammalian nociceptors not only through inhibition of the M current but also through activation of the capsaicin receptor TRPV1.