Local Anesthetics Have Different Mechanisms and Sites of Action at Recombinant 5-HT3 Receptors

Ueta, Kazuyoshi; Suzuki, Takahiro; Sugimoto, Masahiro; Uchida, Ichirō; Mashimo, Takashi

doi:10.1097/00115550-200711000-00002

Cited by 28 publications

(19 citation statements)

References 20 publications

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“…shown to interact at a similar site in GABA and glycine receptors. [49,50] These compounds illicit similar effects on the 5-HT3 receptor. [11] Since the structure of one such anesthetic, lidocaine, had a degree of structural similarity to serotonin and the ginger compounds, our study focused on the latter allosteric site.…”

Section: Serotonin Binding Site Resultsmentioning

confidence: 99%

In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

Lohning

Marx

Isenring

2016

Journal of Molecular Graphics and Modelling

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. In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale).. Retrieved from http://dx.doi. org/10.1016/j.jmgm.2016.10.008 1 Abstract Gingerols and shogaols are the primary non-volatile actives within ginger (Zingiber officinale).These compounds have demonstrated in vitro to exert 5-HT3 receptor antagonism which could benefit chemotherapy-induced nausea and vomiting (CINV). The site and mechanism of action by which these compounds interact with the 5-HT3 receptor is not fully understood although research indicates they may bind to a currently unidentified allosteric binding site. Using in silico techniques, such as molecular docking and GRID analysis, we have characterized the recently available murine 5-HT3 receptor by identifying sites of strong interaction with particular functional groups at both the orthogonal (serotonin) site and a proposed allosteric binding site situated at the interface between the transmembrane region and the extracellular domain. These were assessed concurrently with the top-scoring poses of the docked ligands and included key active gingerols, shogaols and dehydroshogaols as well as competitive antagonists (e.g. setron class of pharmacologically active drugs), serotonin and its structural analogues, curcumin and capsaicin, non-competitive antagonists and decoys. Unexpectedly, we found that the ginger compounds and their structural analogs generally outscored other ligands at both sites. Our results correlated well with previous site-directed mutagenesis studies in identifying key binding site residues. We have identified new residues important for binding the ginger compounds. Overall, the results suggest that the ginger compounds and their structural analogues possess a high binding affinity to both sites. Notwithstanding the limitations of such theoretical analyses, these results suggest that the ginger compounds could act both competitively or non-competitively as has been shown for palonosetron and other modulators of CYS loop receptors. KeywordsGinger antiemetic Zingiber officinale gingerol shogaols chemotherapy induced nausea vomiting 2

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Section: Serotonin Binding Site Resultsmentioning

confidence: 99%

In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

Lohning

Marx

Isenring

2016

Journal of Molecular Graphics and Modelling

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“…These routine procedures can generate various stressors that have the potential to affect the performance and welfare of the fish (Takahashi, Abreu, Biller, & Urbinati, 2006;Vidal et al, 2008;Weber, Peleteiro, Martín, & Aldegunde, 2009;Delbon & Paiva, 2012 physiological functions is, therefore, crucial in maintaining the welfare of the fish throughout the production process (Ueta, Suzuki, Sugimoto, Uchida, & Mashimo, 2007;Brandão, Gomes, Crescêncio, & Carvalho, 2008;Adamante, Nuñer, Barcellos, Soso, & Finco, 2008). The physiological responses of fish to stressors are generally classified as primary and secondary (Gonçalves, Santos, Fernandes, & Takahashi, 2008;Zahl, Kiessling, Samuelsen, & Hansen, 2009), and each of these is associated with alterations in specific hematological or biochemical parameters that may be employed as stress indicators (Barbosa, Moraes, & Inoue, 2007;Morgan & Iwama, 1997).…”

Section: Introductionmentioning

confidence: 99%

<b>Physiological and hematological responses of Nile tilapia (<i>Oreochromis Niloticus</i>) to different anesthetics during simulated transport conditions

Navarro¹,

Franca

Paludo

et al. 2016

Acta Sci. Technol.

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ABSTRACT. Minimization of stress during the transportation of live fish is essential in maintaining the welfare and performance of the animals. In order to test the hypothesis that stress during transport of fingerlings of Nile tilapia (Oreochromis niloticus) can be reduced with the aid of the anesthetics menthol, eugenol or benzocaine, we have assessed the effects of these agents at various concentrations on the physiological parameters and survival rates of fish subjected to conditions simulating those normally used in transportation. , maintained levels of plasma cortisol and glucose that were lower than those of the stressed but untreated controls and within the physiological limits of the baseline values for this species. Under these conditions, the survival rate was 100%, suggesting that stress was substantially reduced despite dense consignment. Treatments involving higher doses of the studied agents induced significant anesthetic toxicity. , mantiveram níveis de cortisol no plasma e de glucose que foram menores do que os dos controles não tratados e estressados, mas dentro dos limites fisiológicos dos valores da linha de base para esta espécie. Sob estas condições, a taxa de sobrevivência foi de 100%, o que sugere que o estresse foi substancialmente reduzido, apesar da remessa densa. Os tratamentos que envolvem doses mais elevadas dos agentes estudados induzindo uma toxicidade anestésica mais significativa.Palavras-chave: mentol, bezocaína, eugenol, peixe.

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“…Thus, from the dose-response curves of each individual agent, the dose resulting in 50% of the effect (ED 50 ) can be determined. However, considering a maximal effect of 100% as the total suppression of formalin-induced flinches, it appeared that lumiracoxib and lidocaine were unable to achieve a 50% response, and thus the calculation of ED 50 was not feasible. Therefore, we estimated the ED 40 instead of ED 50 [28].…”

Section: Discussionmentioning

confidence: 99%

“…Lumiracoxib may decrease the excitability of presynaptic neurons by the inhibition of TP receptor [24] and the activation of the nitric oxide-cyclic GMP pathway and K + channels [19]. Lidocaine may synergize with these effects through its ability to inhibit Na + and Ca ++ channels, and 5-HT 3 and NMDA receptors [45][46][47][48][49][50], which would reduce the excitability of presynaptic neurons and postsynaptic dorsal horn neurons.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Synergistic Interaction Between Lidocaine and Lumiracoxib on the 1% Formalin Test in Rats

Ortiz¹

2011

TOPAINJ

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Abstract:It has been shown that the association of non-steroidal anti-inflammatory drugs (NSAIDs) with analgesic agents can increase their antinociceptive activity, allowing the use of lower doses and thus limiting side effects. Therefore, the aim of the present study was to examine the possible pharmacological interaction between lumiracoxib and lidocaine at the local peripheral level in the rat using the 1% formalin test and isobolographic analysis. Lumiracoxib, lidocaine or fixed-dose ratio (1:1) lumiracoxib-lidocaine combinations were administered locally in the formalin-injured paw and the antinociceptive effect was evaluated. All treatments produced a dose-dependent antinociceptive effect. ED 40 values were estimated for the individual drugs and an isobologram was constructed. The derived theoretical ED 40 for the lumiracoxiblidocaine combination was 599.3 ± 58.8 g/paw, being significantly higher than the actually observed experimental ED 40 value, 393.6 ± 39.7 g/paw. This result correspond to a synergistic interaction between lumiracoxib and lidocaine at the local peripheral level, potency being about one and half times higher with regard to that expected from the addition of the effects of the individual drugs. Data suggest that low doses of the lumiracoxib-lidocaine combination can interact synergistically at the peripheral level and therefore this drug association may represent a therapeutic advantage for the clinical treatment of procedural or inflammatory pain.

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Local Anesthetics Have Different Mechanisms and Sites of Action at Recombinant 5-HT3 Receptors

Cited by 28 publications

References 20 publications

In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

<b>Physiological and hematological responses of Nile tilapia (<i>Oreochromis Niloticus</i>) to different anesthetics during simulated transport conditions

Peripheral Synergistic Interaction Between Lidocaine and Lumiracoxib on the 1% Formalin Test in Rats

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