Cobra neurotoxin produces central analgesic and hyperalgesic actions via adenosine A₁ and A_2A receptors

Abstract

Cobra neurotoxin, a short-chain peptide isolated from snake venom of Naja naja atra, showed both a central analgesic effect and a hyperalgesic effect in mice tests. In order to explore mechanisms, a hypothesis is put forward that cobra neurotoxin takes effect through adenosine receptor pathway. The central effects of cobra neurotoxin were evaluated using the hot plate test (a model of acute pain) and the spinal cord injury (a model of central pain) in mice and using A1 receptor antagonist (DPCPX) and A2A receptor antagonist (ZM241385); behaviors were scored and signal molecules such as reactive oxygen species and adenosine triphosphate levels and mitogen-activated protein kinases/extracellular signal-regulated protein kinase expression were measured. Low dose of cobra neurotoxin (25 µg/kg) had analgesic effects which were inhibited by DPCPX, while high dose of cobra neurotoxin (100 µg/kg) had hyperalgesic effects which were blocked by ZM241385. Cobra neurotoxin reduced reactive oxygen species and increased adenosine triphosphate in brain tissues, and extracellular signal-regulated protein kinase expression was markedly inhibited by cobra neurotoxin. Cobra neurotoxin may take effect through mitogen-activated protein kinases/extracellular signal-regulated protein kinase pathway inhibition by activating adenosine A1Rs and cause changes of reactive oxygen species and adenosine triphosphate through feedback mechanisms. Overdose cobra neurotoxin further activates the adenosine A2ARs to generate pain sensitization. This research proposes a new central analgesic mechanism of cobra neurotoxin and discloses dual regulation of pain.

pH-sensitive dual drug loaded janus nanoparticles by oral delivery for multimodal analgesia

“…It has been reported that a high dose of αCT (100 μg·kg −1 ) via intraperitoneal injection can significantly enhance pain sensitivity, while a low dose of αCT can improve the pain threshold and action ability in animal models [ 20 ]. The purpose of this study was to investigate the analgesic effect of the drugs, so low-dose αCT was selected (50 µg kg −1 ), and the dose of Res was set on this basis.…”

Unveiling the Pain Relief Potential: Harnessing Analgesic Peptides from Animal Venoms

“…This result in the induction of analgesia in pain protocols, specifically within the contexts of cold hypersensitivity through ciguatoxin-induced expression and and also mechanical hypersensitivity provoked by bradykinin- and zymosan-induced expression [ 73 ]. Najanalgesin and cobra neurotoxin induce analgesia through adenosine receptor (A1 and A2A) pathway activation in acute pain models induced by hot plate and spinal cord injury [ 74 ] and the c-Jun N-terminal kinase (JNK) inhibitor in neuropathic pain induced by spinal nerve ligation [ 75 ]. However, the induction of analgesia promoted by µ-EPTX-Na1 involves the Nav1.8 channel inhibitor [ 69 ], while mabalgin 1 and 3 present a common analgesia mechanism via acid-sensing ion channel (ASIC) inhibitors, as evidenced by the motor behavior tests such as the accelerated rotarod test and the grip strength test.…”

Neurotoxins Acting at Synaptic Sites: A Brief Review on Mechanisms and Clinical Applications

“…It might have dual pain regulation, and there is a hypothesis to explain this phenomenon, namely, that cobrotoxin might activate the adenosine A 1 Rs and then inhibit the mitogen-activated protein kinases/extracellular signal-regulated protein kinase pathway to exert analgesic effects. However, with the increasing dose of cobrotoxin, the adenosine A 2A Rs are activated to produce sensitization to pain [ 306 ]. Besides the analgesic effects, cobrotoxin can also exert the effect of anti-inflammation by interacting with the NF-κB signaling pathway [ 307 ].…”