Cobra neurotoxin produces central analgesic and hyperalgesic actions via adenosine A1 and A2A receptors.

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.