Antinociceptive effect of PnTx4(5-5), a peptide from Phoneutria nigriventer spider venom, in rat models and the involvement of glutamatergic system

Abstract

Background: The venom of Phoneutria nigriventer spider is a source of numerous bioactive substances, including some toxins active in insects. An example is PnTx4(5-5) that shows a high insecticidal activity and no apparent toxicity to mice, although it inhibited NMDA-evoked currents in rat hippocampal neurons. In this work the analgesic activity of PnTx4(5-5) (renamed Γ-ctenitoxin-Pn1a) was investigated. Methods: The antinociceptive activity was evaluated using the paw pressure test in rats, after hyperalgesia induction with intraplantar injection of carrageenan or prostaglandin E 2 (PGE 2). Results: PnTx4(5-5), subcutaneously injected, was able to reduce the hyperalgesia induced by PGE 2 in rat paw, demonstrating a systemic effect. PnTx4(5-5) administered in the plantar surface of the paw caused a peripheral and dose-dependent antinociceptive effect on hyperalgesia induced by carrageenan or PGE 2. The hyperalgesic effect observed in these two pain models was completely reversed with 5 µg of PnTx4(5-5). Intraplantar administration of L-glutamate induced hyperalgesic effect that was significantly reverted by 5 μg of PnTx4(5-5) injection in rat paw. Conclusion: The antinociceptive effect for PnTx4(5-5) was demonstrated against different rat pain models, i.e. induced by PGE 2 , carrageenan or glutamate. We suggest that the antinociceptive effect of PnTx4(5-5) may be related to an inhibitory activity on the glutamatergic system.

Intravitreal injection of peptides PnPa11 and PnPa13, derivatives of Phoneutria nigriventer spider venom, prevents retinal damage

“…Research for candidate molecules extracted from venomous animals has been intense during the last decades and contributes to the development of new drugs. Spider venoms, including that of Phoneutria nigriventer, are rich in protein and peptide toxins that have an affinity for a wide range of tissue receptors [13,14,15]. A valuable tool to investigate the neurodegeneration process is the alteration of N-methyl-D-aspartate (NMDA) receptors, once glutamate is the main excitatory neurotransmitter in the retina.…”

PnAn13, an antinociceptive synthetic peptide inspired in the Phoneutria nigriventer toxin PnTx4(6–1) (δ-Ctenitoxin-Pn1a)

“…We obtained that amino acid residues 24 to 30 were considered the most exposed. We also compared the amino acid sequence of PnTx4(6–1) and PnTx4(5-5) (Γ-ctenitoxin-Pn1a), another Phoneutria nigriventer antinociceptive toxin from the same venom ( Oliveira et al, 2019 ) and one of the most conserved region in these sequences are the residues 21 to 33 ( Fig. 1 ).…”

“…PnTx4(5-5) (Γ-ctenitoxin-Pn1a) reversibly inhibited the current of N-methyl-D-aspartate (NMDA), a subtype of ionotropic glutamate receptors, in rat hippocampal neurons ( de Figueiredo et al, 2001 ). This toxin was able to reduce the hyperalgesia, induced by prostaglandin E 2 (PGE 2 ) in the rat paw when systemically administered ( Oliveira et al, 2019 ). Concerning the local effect, PnTx4(5-5) promoted a peripheral and dose-dependent antinociceptive effect on hyperalgesia induced by carrageenan and PGE 2 ( Oliveira et al, 2019 ).…”

“…This toxin was able to reduce the hyperalgesia, induced by prostaglandin E 2 (PGE 2 ) in the rat paw when systemically administered ( Oliveira et al, 2019 ). Concerning the local effect, PnTx4(5-5) promoted a peripheral and dose-dependent antinociceptive effect on hyperalgesia induced by carrageenan and PGE 2 ( Oliveira et al, 2019 ). In previous work, it was shown that PnTx4(6–1), also named δ-Ctenitoxin-Pn1a ( King et al, 2008 ), initially characterized as an insect-toxin ( Figueiredo et al, 1995 ), induced a clear analgesic effect in inflammatory, neuropathic and nociceptive in vivo pain models.…”

Gene sequence analysis of toxins from the spider Phoneutria nigriventer revealed an intronless feature

“…Unlike these two first toxins, PnTx4(5-5) is toxic only to insects [25], showing a remarkable effect on insect sodium channels inactivation [26]. This toxin also seems to hold a biotechnological potential use as a neuroprotective [27] and analgesic drug lead [28].…”