Background & Aims

Chronic stressors like social isolation can cause long-lasting changes in behavioral and neurological phenotypes especially in adolescence. Data indicate that there is a relationship between pain and social isolation, but there has been little research into whether and how social factors influence determinants in the affected peripheral nervous system. Our aim was to study the influence of social factors on the affected peripheral nervous system in bortezomib (BTZ) induced neuropathy in an animal model.

Methods

Sixty male Wistar rats were divided randomly into four groups. Animals were housed for four weeks in either a group of three rats per cage or isolated with one rat per cage. Then they were given i.p. injections of either vehicle (5% DMSO) or BTZ 0.2 mg/kg on days 1, 4, 8 and 11. Rats were monitored until day 25 after the first injection. To measure mechanical allodynia, cold and heat sensitivity, we performed von-Frey, acetone and Hargreaves’ tests. Also, we screened gait and functional performance via CatWalk and wheel running tests. Sciatic nerves were assessed for the presence of ED1-positive macrophages, and for structural damage on toluidine blue stained semithin sections. Skin innervation was assessed via intraepidermal nerve fiber density (IENFD) measurements on PGP 9.5-immunoreacted sections.

Results

We could see mechanical hypersensitivity both in BTZ and in vehicle treated rats, which would resolve by day 25, but variability was high. In footpad skin, we found no reduction in IENFD in either group. Semithin sections of sciatic nerves did not show signs of nerve degeneration except of mild axonal swelling in both groups. Moderate numbers of macrophages were present in nerves in both groups without differences. Interestingly, social isolation as such, independent of drug treatment, was associated with high motor activity in the wheel running test.

Conclusions

Higher doses and longer treatment with BTZ may be necessary to induce neuropathy in rats. Secondly, the data raise the awareness that DMSO as a vehicle may have an effect on pain behavior. The presence of axonal swelling in some axons in both groups may indicate DMSO neurotoxicity if used in certain doses. Neurofilament light measurements from rat blood are underway to test this notion. DMSO may be a confounder when used as vehicle in models of chemotherapy induced neuropathy. Social isolation did not change baseline pain thresholds but motor activity, which should be considered when studying social isolation.

References

1.Sailer,et al. Front Behav Neurosci 16 (2022): 931549. https://doi.org/10.3389/fnbeh.2022.931549.
2.Ross, et al. Horm Behav 116 (Nov 2019): 104578. https://doi.org/10.1016/j.yhbeh.2019.104578.
3.McWain, et al. Exp Brain Res 240, no. 10 (Oct 2022): 2803-15. https://doi.org/10.1007/s00221-022-06449-w.
4.https://doi.org/10.1007/BF00433816
5.Burgess et al. Oncol Ther. 2021;9(2):385-450. https://doi.org/10.1007/s40487-021-00168-y.
6.Pitzer et al. Molecular Pain. 2016;12:1744806916656635. https://doi.org/10.1177/1744806916656635.
7.Yamamoto et al. J Pharmacol Sci. 2015;129(1):43-50. https://doi.org/10.1016/j.jphs.2015.08.006.
8.Duggett NA, Flatters SJL. Characterization of a rat model of bortezomib-induced painful neuropathy. Br J Pharmacol. 2017;174(24):4812-25.
9.Ayilara et al. IBRO Neurosci Rep. 2023;15:31-41. https://doi.org/10.1016/j.ibneur.2023.05.010.
10.Cavaletti et al. 2000;118(1-2):103-7.

Presenting Author

Mona Hashemian

Poster Authors

Mona Hashemianahmadi

MSc

Universität klinikum Würzburg

Lead Author

E-mail

Elisabete Bóf Ramos

PhD

Department of Neurology, University Hospital Würzburg, Würzburg, Germany

Lead Author

E-mail

Heike Rittner

University Hospital Wuerzburg

Lead Author

E-mail

Claudia Sommer

Prof. Dr. MD

Institute for neurology, university hospital Würzburg, Germany

Lead Author

E-mail

Topics

  • Models: Chronic Pain - Neuropathic