Isobolographic analysis reveals antinociceptive synergism between Phα1β recombinant toxin and morphine in a model of cancer pain in C57BL/6J mice.

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Accounts of Chemical Research Pub Date : 2021-08-25 eCollection Date: 2021-01-01 DOI:10.1590/1678-9199-JVATITD-2021-0027

Caio Tavares Aoki, Rodrigo Andrade Moura, Luana Assis Ferreira, Mariana Garcia Mendes, Duana Carvalho Santos, Marcio Junior Rezende, Marcus Vinícius Gomez, Célio José Castro-Junior

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引用次数: 5

Abstract

Background: Phoneutria nigriventer venom contains Phα1β. This toxin and its recombinant form have a remarkable analgesic potential that is associated with blockage of voltage-gated calcium channels and TRPA1 receptors. Although morphine is a mainstay drug to treat moderate and severe pain related to cancer, it has serious and dose-limiting side effects. Combining recombinant Phα1β and morphine to treat pain is an interesting approach that has been gaining attention. Therefore, a quantitative and reliable method to establish the strength of the antinociceptive interaction between these two substances is necessary. The present study was designed to investigate the nature of the functional antinociceptive (analgesic) interaction between Phα1β recombinant toxin and morphine in a model of cancer pain.

Methods: Melanoma was produced by intraplantar inoculation of B16-F10 cells into the right paw of C57BL/6J mice. Von Frey filaments measured the paw-withdrawal threshold after intrathecal administration of morphine, recombinant Phα1β, and their combination. Thermal hyperalgesia was assessed using Hargreaves apparatus. The degree of interaction was evaluated using isobolographic analysis. Spontaneous and forced motor performance was assessed with the open-field and rotarod tests, respectively.

Results: Co-administration of recombinant Phα1β and morphine synergistically reverses the melanoma-induced mechanical hyperalgesia. The potency of the mixture, measured as the effective dose to reach 50% of maximum possible effect (MPE) in ameliorating mechanical hyperalgesia, was about twice fold higher than expected if the interaction between morphine and recombinant Phα1β was merely additive. Treatment with the combination at doses necessary to reach 50% of MPE caused no spontaneous nor forced motor alterations.

Conclusion: The combinatorial use of recombinant Phα1β and morphine allows significant and effective dose reduction of both agents, which has translational potential for opioid-sparing approaches in pain management related to cancer.

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等尺度分析揭示了Phα1β重组毒素和吗啡在C57BL/6J小鼠癌痛模型中的协同作用。

背景:黑耳鼠毒液含有Phα1β。这种毒素及其重组形式具有显著的镇痛潜力，与电压门控钙通道和TRPA1受体的阻断有关。虽然吗啡是治疗与癌症相关的中度和重度疼痛的主要药物，但它有严重的副作用和剂量限制。结合重组phα - 1β和吗啡治疗疼痛是一种有趣的方法，已引起人们的关注。因此，需要一种定量和可靠的方法来确定这两种物质之间的抗感受性相互作用的强度。本研究旨在探讨Phα1β重组毒素与吗啡在癌痛模型中的功能性抗痛觉(镇痛)相互作用的性质。方法:用B16-F10细胞在C57BL/6J小鼠右足跖内接种产生黑色素瘤。Von Frey丝测定鞘内给药吗啡、重组Phα1β及其联合给药后的爪子戒断阈值。采用哈格里夫斯仪评估热痛觉过敏。相互作用的程度是用等温分析来评估的。自发和强制运动性能分别通过开场和旋转杆测试进行评估。结果:重组Phα1β与吗啡联合给药可协同逆转黑色素瘤所致的机械性痛觉过敏。以达到最大可能效应(MPE)的50%的有效剂量来衡量，该混合物的效力比吗啡与重组Phα1β之间的相互作用仅为添加剂时的预期效力高约2倍。以达到MPE 50%所需剂量的联合治疗不会引起自发或强制的运动改变。结论:重组Phα1β与吗啡联合使用可显著有效减少两种药物的剂量，这在癌症相关疼痛管理中具有阿片类药物节约方法的转化潜力。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.