JVATiTD - Articles
Official publication of CEVAP/UNESP
Spinal antinociceptive effect of the PnTx4(5-5) peptide is possibly mediated by the NMDA autoreceptors
Mariana Murta de Abreu1, Nancy Scardua Binda1, Marcos Paulo Ferreira Corrêa Alves Reis2, Danuza Montijo Diniz3, Marta do Nascimento Cordeiro4, Márcia Helena Borges4, Maria Elena de Lima3, Fabíola Mara Ribeiro5, Marcus Vinícius Gomez3, Juliana Figueira da Silva1 [ + show more ]
Received: 17 December 2024 | Accepted: 11 September 2024 | Published online: 25 November 2024
Collection: Spotlighting toxinology: from animal toxins to next-generation technologies and products
https://doi.org/10.1590/1678-9199-JVATITD-2023-0103
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.
Keywords: Analgesics; Spinal cord; Spider toxin; PnTx4(5-5); Dizocilpine; NMDA receptors; Glutamate; ROS.