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
{"title":"Spinal antinociceptive effect of the PnTx4(5-5) peptide is possibly mediated by the NMDA autoreceptors.","authors":"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","doi":"10.1590/1678-9199-JVATITD-2023-0103","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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 <i>P. nigriventer</i> and its affinity for NMDAR and sodium channels Nav1.2-1.6 has already been established.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":17565,"journal":{"name":"Journal of Venomous Animals and Toxins Including Tropical Diseases","volume":"30 ","pages":"e20230103"},"PeriodicalIF":1.8000,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649190/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Venomous Animals and Toxins Including Tropical Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1590/1678-9199-JVATITD-2023-0103","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q4","JCRName":"TOXICOLOGY","Score":null,"Total":0}
Spinal antinociceptive effect of the PnTx4(5-5) peptide is possibly mediated by the NMDA autoreceptors.
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.
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.
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