Peripheral Pain Modulation ofChrysaora pacificaJellyfish Venom Requires Both Ca2+Influx and TRPA1 Channel Activation in Rats

The venom of jellyfish triggers severe dermal pain along with inflammation and tissue necrosis, and occasionally, induces internal organ dysfunction. However, the basic mechanisms underlying its cytotoxic effects are still unknown. Here, we report one of the mechanisms involved in peripheral pain modulation associated with inflammatory and neurotoxic oxidative signaling in rats using the venom of jellyfish,Chrysaora pacifica(CpV). This jellyfish is identified by brown tentacles carrying nematocysts filled with cytotoxic venom that induces severe pain, pruritus, tentacle marks, and blisters. The subcutaneous injection of CpV into rat forepaws in behavioral tests triggered nociceptive response with a decreased threshold for mechanical pain perception. These responses lasted up to 48 h and were completely blocked by verapamil and TTA-P2, T-type Ca(2+)channel blockers, or HC030031, a transient receptor potential cation ankyrin 1 (TRPA1) channel blocker, while another Ca(2+)channel blocker, nimodipine, was ineffective. Also, treatment with Ca(2+)chelators (EGTA and BaptaAM) significantly alleviated the CpV-induced pain response. These results indicate that CpV-induced pain modulation may require both Ca(2+)influx through the T-type Ca(2+)channels and activation of TRPA1 channels. Furthermore, CpV induced Ca2+-mediated oxidative neurotoxicity in the dorsal root ganglion (DRG) and cortical neurons dissociated from rats, resulting in decreased neuronal viability and increased intracellular levels of ROS. Taken together, CpV may activate Ca2+-mediated oxidative signaling to produce excessive ROS acting as an endogenous agonist of TRPA1 channels in the peripheral terminals of the primary afferent neurons, resulting in persistent inflammatory pain. These findings provide strong evidence supporting the therapeutic effectiveness of blocking oxidative signaling against pain and cytotoxicity induced by jellyfish venom.