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Peripheral Pain Modulation of Chrysaora pacifica Jellyfish Venom Requires Both Ca2+ Influx and TRPA1 Channel Activation in Rats

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Abstract

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 Ca2+ channel blockers, or HC030031, a transient receptor potential cation ankyrin 1 (TRPA1) channel blocker, while another Ca2+ channel blocker, nimodipine, was ineffective. Also, treatment with Ca2+ chelators (EGTA and BaptaAM) significantly alleviated the CpV-induced pain response. These results indicate that CpV-induced pain modulation may require both Ca2+ influx through the T-type Ca2+ 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.

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Acknowledgments

The work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No.NRF-2016R1D1A1B0101086).

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Author notes

  1. Hye-Ji Kim, Jin-Woo Noh, Khulan Amarsanaa and Sang-Chan Jeon contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, School of Medicine, Jeju National University, Jeju, 63243, Republic of Korea

    Hye-Ji Kim, Jin-Woo Noh, Khulan Amarsanaa, Sang-Chan Jeon, Na-Hye Hwang, Eun-A Ko & Sung-Cherl Jung

  2. Department of Structure and Function of Neural Network, Korea Brain Research Institute, Daegu, 41068, Republic of Korea

    Yoon-Sil Yang

  3. Department of Emergency Medicine, School of Medicine, Jeju National University, Jeju, 63243, Republic of Korea

    Young-Joon Kang

  4. Institute of Medical Science, Jeju National University, Jeju, 63243, Republic of Korea

    Young-Joon Kang & Sung-Cherl Jung

  5. Interdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, Jeju, 63243, Republic of Korea

    Sung-Cherl Jung

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  1. Hye-Ji Kim
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Highlights

1. The venom of jellyfish, Chrysaora pacifica, exhibits persistent mechanical pain response in behavioral tests of rats.

2. Mechanical pain modulation by the venom of Chrysaora pacifica depends on both T-type Ca2+ channels and TRPA1 channels.

3. The cellular mechanism of the persistent pain induced by jellyfish venom may be attributed to the Ca2+-mediated oxidative neurotoxicity in nerve endings of primary afferent neurons.

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Kim, HJ., Noh, JW., Amarsanaa, K. et al. Peripheral Pain Modulation of Chrysaora pacifica Jellyfish Venom Requires Both Ca2+ Influx and TRPA1 Channel Activation in Rats. Neurotox Res 38, 900–913 (2020). https://doi.org/10.1007/s12640-020-00282-1

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  • DOI: https://doi.org/10.1007/s12640-020-00282-1

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