Journal of pharmacological sciences
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G protein-coupled receptors, in particular, Ca(2+)-mobilizing G(q)-coupled receptors have been reported to be targets for anesthetics. Opioids are commonly used analgesics in clinical practice, but the effects of anesthetics on the opioid mu-receptors (muOR) have not been systematically examined. We report here an electrophysiological assay to analyze the effects of anesthetics and ethanol on the functions of muOR in Xenopus oocytes expressing a muOR fused to chimeric Galpha protein G(qi5) (muOR-G(qi5)). ⋯ Propofol and halothane inhibited the DAMGO-induced currents only at higher concentrations. These findings suggest that ketamine and ethanol may inhibit muOR functions in clinical practice. We propose that the electrophysiological assay in Xenopus oocytes expressing muOR-G(qi5) would be useful for analyzing the effects of anesthetics and analgesics on opioid receptor function.
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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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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.
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Development of next-generation analgesics requires a better understanding of the molecular and cellular mechanisms underlying pathological pain. Accumulating evidence suggests that the activation of glia contributes to the central sensitization of pain signaling in the spinal cord. The role of microglia in pathological pain has been well documented, while that of astrocytes still remains unclear. ⋯ Although astrocyte-to-neuron signals implicated in pathological pain is poorly understood, activated astrocytes, as well as microglia, produce proinflammatory cytokines and chemokines, which lead to adaptation of the dorsal horn neurons. Furthermore, it has been suggested that glial glutamate transporters in the spinal astrocytes are down-regulated in pathological pain and that up-regulation or functional enhancement of these transporters prevents pathological pain. This review will briefly discuss novel findings on the role of spinal astrocytes in pathological pain and their potential as a therapeutic target for novel analgesics.
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Recent randomized controlled trials showed that blockade of the renin-angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II-receptor blockers (ARBs) reduced cardiovascular and renal events. These drugs are widely used in the management of cardiovascular and renal diseases. Results from Randomized Controlled Trials (RCTs) so far, however, also raise several questions to be addressed. ⋯ Such insufficient efficacy of RAS inhibition may result from the fact that neither ACE inhibitors nor ARBs completely suppress activity of RAS. Since then effort has been made to determine whether the dual blockade of RAS could provide further improvement in cardiovascular and renal outcome. This review extracts unsolved questions in the treatment with RAS inhibitors from outcome studies and discusses them from the clinical pharmacological point of view.