Background & Aims

Synaptic plasticity that allows for memory in the brain has mechanistic and functional parallels to synaptic plasticity that occurs between neurons in the spinal dorsal horn.1 The small peptide, amyloid-beta (A?), is associated with memory loss in Alzheimer’s disease and modulates synaptic plasticity towards synaptic depression. The exact mechanism by which A? acts on synapses is poorly understood as A? is present at endogenously low concentrations in brains of healthy individuals. We hypothesize that A? contributes to synaptic plasticity and sensory processing in the spinal dorsal horn. We use murine pain models to induce central sensitization for investigating synaptic plasticity in the spinal cord. Our overall aim is to modulate A? in the spinal dorsal horn to improve hypersensitivity in pain models.

Methods

A? was found in the spinal cord during central sensitization, induced acutely with intraplantar capsaicin, at different levels in male and female mice using Enzyme Linked Immunosorbent Assay (ELISA). To determine if A? plays a role in the plastic process that allow for central sensitization we modulated endogenous levels of A? in a nerve injury model of neuropathic pain. We increased A? levels transiently via intrathecal injection of synthetic A? and decreased A? levels via a gamma-secretase inhibitor DAPT. Prolonged delivery of synthetic A? was spatiotemporally controlled via intrathecal hydrogel. We also used a knockout mouse model of the A? precursor protein (APP KO) which does not produce A? and an APP mouse model that over produces A? (TgCRND8). Mechanical sensitivity was tested by paw withdrawal threshold using Von Frey filaments. Thermal sensitivity was tested by paw withdrawal time using Hargreaves assay.

Results

An inflammatory model of central sensitization, CFA, mechanically sensitized wildtype animals but was not impacted by varying levels of A? via synthetic and DAPT injection. Interestingly APP KO mice did not respond with a change in mechanical sensitivity after CFA and in contrast TgCRND8 male mice did show improved mechanical sensitivity. A neuropathic model of central sensitization, spared nerve injury, did show improvement in mechanical sensitivity after DAPT injection in both sexes and after A? injection in females only. Hydrogel delivery of A? prolonged improvement in mechanical sensitivity.

Conclusions

Taken together, our results thus far indicate modulation of A? may play a role in the mechanical sensitivity attributed to a model of neuropathic pain. Future experiments will investigate potential mechanisms of how A? contributes to synaptic plasticity and sensory processing in the spinal cord by contrasting the mechanisms by which A? modulates pain behaviour in inflammatory and neuropathic pain models.

References

Ji, R. R., Kohno, T., Moore, K. A., & Woolf, C. J. (2003). Central sensitization and LTP: Do pain and memory share similar mechanisms? Trends in Neurosciences, 26(12), 696–705. https://doi.org/10.1016/j.tins.2003.09.017

Presenting Author

Laura A. Bennett

Poster Authors

Laura Bennett

BSc

University of Toronto

Lead Author

E-mail

Hantao Zhang

BSc

University of Toronto

Lead Author

E-mail

Timothy H. Cheung

BSc

University of Toronto

Lead Author

E-mail

Maham Zain

University of Toronto

Lead Author

E-mail

Quinn Pauli

BSc

University of Toronto

Lead Author

E-mail

Molly S. Shoichet

BSc

University of Toronto

Lead Author

E-mail

Robert Bonin

PhD

University of Toronto

Lead Author

E-mail

Topics

  • Models: Chronic Pain - Neuropathic