Oral + Poster 9th Venoms to Drugs 2026

Resurgent-like currents induced by MoTxA as the cause of de novo sensory neuron cold hypersensitivity (#006)

Tabea Klasfauseweh 1 , Jennifer R. Deuis 1 , Mathilde R. Israel 2 , Anna Partridge 1 3 , Hue N. T. Tran 1 , Thomas Durek 1 4 , David A. Andersson 2 , Andreas Leffler 5 , Irina Vetter 1 6
  1. Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
  2. Wolfson SPaRC, Institute of Psychiatry, Psychology & Neuroscience, King's College, London, United Kingdom
  3. Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands
  4. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, St Lucia, QLD, Australia
  5. Department of Anaesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
  6. School of Pharmacy, The University of Queensland, Woolloongabba, QLD, Australia

Introduction. Cold allodynia is the painful perception of a cold stimulus that normally does not provoke pain. It is a common side effect of some chemotherapy treatments that has a huge impact on patients’ quality of life and can only be managed by reducing the chemotherapy dose. Although the role of transient receptor potential (TRP) channels and voltage-gated sodium (NaV) channels in temperature sensing and signalling has been established, the exact mechanism of cold allodynia remains unknown. We discovered a novel class of toxins called gympietides from Australian stinging nettles Dendrocnide spp. One of these toxins is Moroidotoxin A (MoTxA) from the Australian stinging nettle Dendrocnide moroides. MoTxA causes severe, long-lasting pain as well as long-lasting cold allodynia characterised by burning pain, shooting and pricking sensations.

Methods. We established a novel MoTxA-induced cold allodynia mouse model to study the effect of MoTxA at different temperatures as well as the contribution of ion channels in MoTxA-induced cold allodynia in vivo. To further delineate the mechanism by which MoTxA causes cold allodynia, we performed calcium imaging in peripheral sensory neurons and automated patch-clamp electrophysiology in heterologous expression systems.

Results. After administration of MoTxA, mice exhibited nocifensive behaviours already at 25°C, which increased with decreasing temperatures. Surprisingly, MoTxA-induced cold allodynia did not involve cold-sensing TRPA1 and TRPM8 channels; instead, it was dependent on the TTX-sensitive NaV channels NaV1.1/NaV1.6 and partially NaV1.7. Calcium imaging in peripheral sensory neurons revealed that MoTxA conferred de novo cold sensitivity to normally/previously cold insensitive large and small sized neurons. MoTxA caused resurgent-like current in NaV1.6 and NaV1.7 channels that was shifted towards hyperpolarised potentials with decreasing temperature.

Conclusion. In summary, we established a novel model to study cold allodynia using gympietide toxins from Australian stinging nettles. MoTxA causes long-lasting cold allodynia at innocuous temperatures by targeting TTX-sensitive NaV channels independently of TRP channels, likely by inducing resurgent-like current that is shifted by temperature. These findings reveal a novel explanation for the underlying mechanism of cold allodynia.