Background & Aims

Paclitaxel represents a promising chemotherapeutic agent to treat cancers including breast, ovarian and lung, by stabilising microtubules and preventing cancerous cells dividing. However, approximately 60% of patients receiving this treatment experience paclitaxel-induced peripheral neuropathy (PIPN), a highly distressing adverse effect associated with symptoms such as mechanical hypersensitivity. Emergence of PIPN often leads to dosage reduction or treatment termination, yet in extreme cases PIPN persists. Thus, understanding the mechanisms underlying PIPN is vital to generate approaches to alleviate this adverse effect and improve treatment adherence, thereby reducing patient mortality rates. Whilst changes in the peripheral nervous system have been reported in PIPN, central changes in the spinal cord are also observed; however these changes have not been fully understood. Hence, we aimed to examine changes in the spinal cord that may contribute to PIPN.

Methods

To address this research question, we used a Phox2a::Cre mouse line, which labels approximately 50-60% of lamina I projection neurons, and administered intraperitoneal injections of paclitaxel, or saline as a control, to investigate whether paclitaxel induces physiological or morphological changes within this neuronal population. A semi-intact ex vivo spinal cord preparation was then obtained from animals, and patch-clamp recordings were obtained from projection neurons to characterise firing properties from lamina I projection neurons exposed to paclitaxel or saline. Morphological analyses were also performed to identify anatomical changes induced by paclitaxel treatment.

Results

We have observed differences in the physiological properties between projection neurons exposed to paclitaxel and saline, which may underly symptoms attributable to PIPN. Furthermore, anatomical differences between these neuronal populations were also examined, revealing further insight regarding the central nervous system changes elicited by paclitaxel exposure.

Conclusions

Overall, our findings aid in further understanding the spinal mechanisms which contribute to PIPN, which is crucial to identify novel therapeutic targets to alleviate this adverse effect.

References

Junichi Hachisuka., Kyle M Baumbauer., Yu Omori., Lindsey M Snyder H., Richard Koerber., Sarah E Ross (2016). Semi-intact ex vivo approach to investigate spinal somatosensory circuits eLife 5:e22866

Alsulaiman, W.A.A., Quillet, R., Bell, A.M. et al. Characterisation of lamina I anterolateral system neurons that express Cre in a Phox2a-Cre mouse line. Sci Rep 11, 17912 (2021). https://doi.org/10.1038/s41598-021-97105-w

Presenting Author

Anna McFarlane

Poster Authors

Anna McFarlane

MSc

University of Glasgow

Lead Author

Madoka Koyanagi

School of Pharmaceutical Sciences, Wakayama Medical University

Lead Author

Kieran Boyle

PhD

University of Glasgow

Lead Author

Raphaëlle Quillet

PhD

University of Glasgow

Lead Author

Allen Dickie

PhD

University of Glasgow

Lead Author

Junichi Hachisuka

MD

University of Glasgow

Lead Author

Topics

  • Mechanisms: Biological-Molecular and Cell Biology