Spinal antinociceptive effect of the PnTx4(5-5) peptide is possibly mediated by the NMDA autoreceptors.

IF 1.8 3区医学 Q4 TOXICOLOGY Journal of Venomous Animals and Toxins Including Tropical Diseases Pub Date : 2024-11-25 eCollection Date: 2024-01-01 DOI:10.1590/1678-9199-JVATITD-2023-0103

Mariana Murta de Abreu, Nancy Scardua Binda, Marcos Paulo Ferreira Corrêa Alves Reis, Danuza Montijo Diniz, Marta do Nascimento Cordeiro, Márcia Helena Borges, Maria Elena de Lima, Fabíola Mara Ribeiro, Marcus Vinícius Gomez, Juliana Figueira da Silva

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Abstract

Background: Medications currently used to treat pain are frequently associated with serious adverse effects and rapid development of tolerance. Thus, there is a need to develop more effective, and safer medicines for the population. Blocking NMDA receptors (NMDAR) has shown to be a promising target for the development of new drugs. That statement is due to NMDAR activation and glutamate release in the spinal cord which affects chronic pain modulation. Therefore, the aim of this study was to evaluate the possible spinal antinociceptive activity of PnTx4(5-5) toxin. The peptide is purified from the venom of the spider P. nigriventer and its affinity for NMDAR and sodium channels Nav1.2-1.6 has already been established.

Methods: We compared its effect and safety with MK-801 (NMDAR antagonist) and evaluated its influence on glutamate and reactive oxygen species (ROS) levels in CSF. PnTx4(5-5) was administered intrathecally in the Formalin test and co-administered with NMDA in the Spontaneous pain test. After three minutes of observation, mice cerebrospinal fluid was collected to measure glutamate and ROS levels.

Results: The spider peptide inhibited nociception as post-treatment in the inflammatory phase of the Formalin test. Furthermore, it inhibited spontaneous nociception induced by NMDA, being more potent and effective than MK-801 in both models tested. A glutamate rise level in the CSF of mice was significantly reduced by the toxin, but ROS increase was not affected. The animals' motor skills were not affected by the tested doses of NMDAR inhibitors.

Conclusion: In conclusion, the results suggest PnTx4(5-5) may mediate its antinociceptive effect in the spinal cord not only by inhibiting postsynaptic receptors but probably also by acting on autoreceptors. This effect does not affect the motricity of mice at the highest dose tested, which suggests that it has therapeutic potential and safety for use as a painkiller.

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背景：目前用于治疗疼痛的药物经常会产生严重的不良反应，并很快产生耐受性。因此，有必要为人们开发更有效、更安全的药物。阻断 NMDA 受体 (NMDAR) 已被证明是开发新药的一个有前途的靶点。这是因为 NMDAR 在脊髓中的激活和谷氨酸释放会影响慢性疼痛的调节。因此，本研究旨在评估 PnTx4(5-5) 毒素可能具有的脊髓抗痛活性。该肽是从黑蜘蛛（P. nigriventer）的毒液中纯化出来的，其对 NMDAR 和钠通道 Nav1.2-1.6 的亲和力已经得到证实：我们比较了它与 MK-801（NMDAR 拮抗剂）的效果和安全性，并评估了它对脑脊液中谷氨酸和活性氧（ROS）水平的影响。在福尔马林试验中，经皮下注射 PnTx4(5-5)；在自发疼痛试验中，与 NMDA 同时注射 PnTx4(5-5)。观察三分钟后，收集小鼠脑脊液以测量谷氨酸和 ROS 水平：结果：在福尔马林试验的炎症阶段，蜘蛛肽作为后处理抑制了痛觉。此外，它还能抑制 NMDA 诱导的自发痛觉，在两种测试模型中，它比 MK-801 更强更有效。该毒素能显著降低小鼠脑脊液中谷氨酸的升高水平，但不影响 ROS 的升高。动物的运动技能未受到测试剂量的 NMDAR 抑制剂的影响：总之，研究结果表明，PnTx4(5-5)可能不仅通过抑制突触后受体，还可能通过作用于自身受体来介导其在脊髓中的抗痛觉效应。在测试的最高剂量下，这种作用不会影响小鼠的运动能力，这表明它具有治疗潜力，可以安全地用作止痛药。

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来源期刊

Journal of Venomous Animals and Toxins Including Tropical Diseases 医学-毒理学

CiteScore

4.80

自引率

8.30%

发文量

审稿时长

6-12 weeks

期刊介绍： Journal of Venomous Animals and Toxins including Tropical Diseases (JVATiTD) is a non-commercial academic open access publication dedicated to research on all aspects of toxinology, venomous animals and tropical diseases. Its interdisciplinary content includes original scientific articles covering research on toxins derived from animals, plants and microorganisms. Topics of interest include, but are not limited to:systematics and morphology of venomous animals;physiology, biochemistry, pharmacology and immunology of toxins;epidemiology, clinical aspects and treatment of envenoming by different animals, plants and microorganisms;development and evaluation of antivenoms and toxin-derivative products;epidemiology, clinical aspects and treatment of tropical diseases (caused by virus, bacteria, algae, fungi and parasites) including the neglected tropical diseases (NTDs) defined by the World Health Organization.