Local anaesthetics inhibit signalling of human NMDA receptors recombinantly expressed in Xenopus laevis oocytes: role of protein kinase C

Hahnenkamp, Klaus; Durieux, Marcel E.; Hahnenkamp, Anke; Schauerte, S.; Hoenemann, Christian W.; Vegh, Vladimir; Theilmeier, Gregor; Hollmann, Markus W.

doi:10.1093/bja/aei271

Cited by 94 publications

(62 citation statements)

References 31 publications

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“…investigations suggest lidocaine-mediated effects among others on G␣i protein function, 38 NMDA receptors, 39 thromboxane A2 signaling, 40 and glycinergic neurotransmission. 19 Clinically, intravenous lidocaine exerts a variety of effects, some of which are of benefit in perioperative settings.…”

Section: Pain Medicinementioning

confidence: 99%

Lidocaine Metabolites Inhibit Glycine Transporter 1

Werdehausen¹,

Kremer²,

Brandenburger³

et al. 2012

Anesthesiology

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Background: Lidocaine exerts antinociceptive effects when applied systemically. The mechanisms are not fully understood but glycinergic mechanisms might be involved. The synaptic glycine concentration is controlled by glycine transporters. Whereas neurons express two types of glycine transporters, astrocytes specifically express glycine transporter 1 (GlyT1). This study focuses on effects of lidocaine and its major metabolites on GlyT1 function. Methods: The effects of lidocaine and its metabolites monoethylglycinexylidide (MEGX), glycinexylidide, and N-ethylglycine on GlyT1 function were investigated in uptake experiments with [14 C]-labeled glycine in primary rat astrocytes. Furthermore, the effect of lidocaine and its metabolites on glycine-induced currents were investigated in GlyT1-expressing Xenopus laevis oocytes. Results: Lidocaine reduced glycine uptake only at toxic concentrations. The metabolites MEGX, glycinexylidide, and N-ethylglycine, however, significantly reduced glycine uptake (P Ͻ 0.05). Inhibition of glycine uptake by a combination of lidocaine with its metabolites at a clinically relevant

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Section: Pain Medicinementioning

confidence: 99%

Lidocaine Metabolites Inhibit Glycine Transporter 1

Werdehausen¹,

Kremer²,

Brandenburger³

et al. 2012

Anesthesiology

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“…Many data in basic research have been accumulated on possible effects of LA beyond sodium ion channel blockage, such as anti-inflammatory [17,18] and immune-stimulating effects [19]. Clinical data of 227 publications about positive effects of LA in chronic inflammation have been summarized in 2006 [19].…”

Section: Case Reportmentioning

confidence: 99%

Successful Therapy of Vulvodynia with Local Anesthetics: A Case Report

Weinschenk

Brocker²,

Hotz³

et al. 2013

Complement Med Res

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SummaryBackground: Vulvodynia often occurs with unexplained vulvar pain and hyperesthesia, sexual dysfunction, and psychological disability, lacking an organic or microbiological substrate. Case Report: A 25-year-old woman with generalized, unprovoked vulvodynia for 12 years was treated repeatedly with procaine 1% for 14 sessions after she had previously had numerous unsatisfying multidisciplinary treatments. We observed a decrease in pain scores on the visual analogue scale (VAS) from initially 8-9 to presently 0-2. Injection sites were: Head's zones and trigger points of the lower abdomen, regional hypogastric ganglia, bilateral maxillary sinus, and scars of the lower jaw. No major adverse events were observed. Injections to remote sites improved symptoms more strongly than local or regional therapy. After a 3-year follow-up the patient is free of symptoms. Conclusion: Therapy with local anesthetics (TLA, neural therapy) can be a useful additional therapy in complicated cases of vulvodynia. Further studies on the underlying mechanism of injections into remote foci (interference field, stoerfeld) and the effectiveness of TLA in chronic pain syndromes should be performed.

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“…For PKC activator experiments, five sweeps of acid-activated currents (activated with ND96 pH 4.0 solution) were recorded, the flow of solutions was stopped, and the oocyte was unclamped before and during the addition of PMA or PdBu to the bath solution to a final 1 M concentration for 5 min (21). After the PMA incubation period, the oocyte was clamped at Ϫ60 mV, and another five acid-activated peaks were recorded.…”

Section: Generation Of Hasic1b Phosphorylation Mutantsmentioning

confidence: 99%

Two PKC consensus sites on human acid-sensing ion channel 1b differentially regulate its function

Bashari

Qadri²,

Zhou³

et al. 2009

American Journal of Physiology-Cell Physiology

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Fuller CM, Benos DJ. Two PKC consensus sites on human acid-sensing ion channel 1b differentially regulate its function. Am J Physiol Cell Physiol 296: C372-C384, 2009; doi:10.1152/ajpcell.00200.2008.-Human acid-sensing ion channel 1b (hASIC1b) is a H ϩ -gated amiloride-sensitive cation channel. We have previously shown that glioma cells exhibit an amiloride-sensitive cation conductance. Amiloride and the ASIC1 blocker psalmotoxin-1 decrease the migration and proliferation of glioma cells. PKC also abolishes the amiloride-sensitive conductance of glioma cells and inhibits hASIC1b open probability in planar lipid bilayers. In addition, hASIC1b's COOH terminus has been shown to interact with protein interacting with C kinase (PICK)1, which targets PKC to the plasma membrane. Therefore, we tested the hypothesis that PKC regulation of hASIC1b at specific PKC consensus sites inhibits hASIC1b function. We mutated three consensus PKC phosphorylation sites (T26, S40, and S499) in hASIC1b to alanine, to prevent phosphorylation, and to glutamic acid or aspartic acid, to mimic phosphorylation. Our data suggest that S40 and S499 are critical sites mediating the modulation of hASIC1b by PKC. We expressed mutant hASIC1b constructs in Xenopus oocytes and measured acid-activated currents by two-electrode voltage clamp. T26A and T26E did not exhibit acid-activated currents. S40A was indistinguishable from wild type (WT), whereas S40E, S499A, and S499D currents were decreased. The PKC activators PMA and phorbol 12,13-dibutyrate inhibited WT hASIC1b and S499A, and PMA had no effect on S40A or on WT hASIC1b in oocytes pretreated with the PKC inhibitor chelerythrine. Chelerythrine inhibited WT hASIC1b and S40A but had no effect on S499A or S40A/S499A. PKC activators or the inhibitor did not affect the surface expression of WT hASIC1b. These data show that the two PKC consensus sites S40 and S499 differentially regulate hASIC1b and mediate the effects of PKC activation or PKC inhibition on hASIC1b. This will result in a deeper understanding of PKC regulation of this channel in glioma cells, information that may help in designing potentially beneficial therapies in their treatment.two-electrode voltage clamp; Xenopus laevis oocytes; phorbol 12-myristate 13-acetate; chelerythrine; mutagenesis; phorbol 12,13-dibutyrate; protein kinase C ACID-SENSING ION CHANNELS (ASICs) are activated by extracellular protons and belong to the epithelial Na ϩ channel (ENaC)/ degenerin (Deg) family of ion channels. Four ASIC genes (ASIC1-ASIC4) have been cloned, and ASIC1-ASIC3 have splice variants (19,28,29,31,42). ASICs are permeable to Na ϩ but also to other monovalent and divalent cations like Ca 2ϩ (in the case of ASIC1), Li ϩ , K ϩ , and H ϩ (41, 42). ASIC subunits are expressed in peripheral nervous system neurons, where they have been implicated in nociception during tissue acidosis and in mechanosensation (42). In the central nervous system (CNS), ASIC1 has been mostly studied in mouse and rat brains, where it is abundantly expressed, and ASIC1a, ...

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Local anaesthetics inhibit signalling of human NMDA receptors recombinantly expressed in Xenopus laevis oocytes: role of protein kinase C

Cited by 94 publications

References 31 publications

Lidocaine Metabolites Inhibit Glycine Transporter 1

Lidocaine Metabolites Inhibit Glycine Transporter 1

Successful Therapy of Vulvodynia with Local Anesthetics: A Case Report

Two PKC consensus sites on human acid-sensing ion channel 1b differentially regulate its function

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