Background & Aims

More than 23 million patients annually undergo surgery at the risk of developing persistent postsurgical pain (PPP). Several prior studies have shown that various inflammatory chemicals accumulate near the skin incision site after surgery, including GM-CSF and CCL17. Clinical trials targeting GM-CSF using a monoclonal antibody have demonstrated therapeutic efficacy for rheumatoid arthritis in terms of clinical outcomes and pain scores. Treatment with anti-GM-CSF is also linked to a decrease in the presence of circulating CCL17. This project aims to use mouse models to determine whether GM-CSF exhibits pro-nociceptive effects on acute sensory thresholds and whether anti-GM-CSF can attenuate persistent post surgical pain.

Methods

We employed a mouse model of PPP using a hyperalgesic priming paradigm. Initially, we induced acute pain by implementing the Brennan model of hindpaw incision as the ‘priming’ stimulus. Subsequently, we induced the expression of latent hypersensitivity and a prolonged phase of pain in the mouse by administering intraplantar PGE2. Animals received systemic dosages of monoclonal antibodies that specifically targeted either GM-CSF or CCL17. Pain behaviour was then assessed in response to administering various sensory stimuli.

Results

In vivo behavioural tests indicated acute GM-CSF decreases mechanical and thermal pain standards. Fos expression and dorsal horn broad dynamic range neuron action potential firing were increased. In vehicle-primed animals, GM-CSF generates latent and wide hypersensitivity to intraplantar PGE2, which only causes acute inflammatory pain. To test if downstream CCL17 expression is required for GM-CSF-induced latent hypersensitivity, anti-CCL17 was given 24 hours before or after PGE2 therapy. CCL17 was not needed for GM-CSF-mediated hyperalgesic priming. Using a hindpaw incision and intraplantar PGE2 to produce latent hypersensitivity, mice developed nociplastic discomfort. Monoclonal anti-GM-CSF and anti-CCL17 systemic (i.p.) therapy was given to hyperalgesic primed mice with extended post-surgical discomfort. We found that anti-GM-CSF and anti-CLL17 significantly reduced mechanical hypersensitivity. We assessed GM-CSF and signature gene transcription in the hindpaw incision, blood, DRG.

Conclusions

CCL17 and GM-CSF are essential for the development of PPP. Injecting GM-CSF directly into the paw decreases acute mechanical and thermal pain thresholds, and serves as a priming stimulus to trigger latent hypersensitivity and widespread pain. In an animal model of PPP, singficant attenuation of pain behaviour is achieved by targeting GM-CSF and CCL17 with a monoclonal antibody.

References

1. Weiser et al. (2008). doi: 10.1172/JCI87828.
2. Silva et al. (2022). doi: 10.1073/pnas.2118238119
3. Achuthan et al. (2016). doi: 10.1172/JCI87828
4. Cook et al. (2018). doi: 10.1172/jci.insight.99249.
5. Cook et al. (2001). doi: 10.1186/ar318
6. Moy et al. (2019). doi: 10.1016/j.ynpai.2018.10.001.

Presenting Author

Niloofar Ketabi

Poster Authors

Niloofar Ketabi

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Nociplastic and chronic widespread pain