Background & Aims
Chronic pain development can be predicted prior or circa its onset based
on susceptibility factors like genetics, blood-deprived and psychological aspects. 1–3 However, the
biological underpins of protection or susceptibility remains elusive. Neuroimmune interactions,
crucial for chronic pain pathogenesis, have been strongly linked. 4,5 This study hypothesized that
preemptive treatment with an immunomodulatory drug can provide sustained protection against
chronic pain progression and its comorbidities.
Methods
2–3-month-old male Wistar Han rats were used in all experiments. The spared nerve
injury (SNI) was used to model chronic neuropathic pain. Dimethyl fumarate (DMF) was
administered 7 days before SNI; control rats received vehicle (VEH). After SNI, half of the animals
shift groups for additional 7 days resulting in 4 groups: continuous treatment (DMF-DMF),
pretreatment (DMF-VEH), early treatment (VEH-DMF) and control (VEH-VEH). Mechanical and
cold allodynia were measured weekly while depression-, anxiety- and cognitive-related were used
as readouts at the end of the experiment.
Results
DMF-DMF, DMF-VEH, and VEH-DMF reduced allodynia and attenuated anhedonia
when compared to VEH-VEH. The pretreatment alleviated anxiety-like behaviors manifested in
SNI rats. Trigonelline, a nrf-2 inhibitor, when paired with DMF largely abolished its protective
effects. Pretreatment with DMF significantly diminished SNI-induced ATF-3 even at day 49 after
treatment. Nrf-2 and its downstream enzyme, HO-1, were also assessed, but no significant
discrepancy was recorded between treatments.
Conclusions
We demonstrated that preexposure to an anti-inflammatory drug provided rats with higher
resilience to long-term allodynia and pain-related manifestations. This proved that pain trajectories
and chronic pain progression can be altered by modulating the immune system prior to pain onset.
Regarding mechanisms, besides possible direct changes in immune cell composition towards an
anti-inflammatory state, both nrf-2 and ATF-3 play significant roles, although the potential
involvement of other factors cannot be dismissed.
References
1. Sluka, K. A. et al. Predicting chronic postsurgical pain: current evidence and a novel
program to develop predictive biomarker signatures. Pain 164, 1912 (2023).
2. Liu, Q. R. et al. Predictors and predictive effects of acute pain trajectories after
gastrointestinal surgery. Sci Rep 12, (2022).
3. Pinto, P. R., McIntyre, T., Soares, V. A., Almeida, A. & Costa, P. Psychological factors
predict an unfavorable pain trajectory after hysterectomy: a prospective cohort study on
chronic postsurgical pain. Pain 159, 956–967 (2018).
4. Ren, K. & Dubner, R. Interactions between the immune and nervous systems in pain.
Nature Medicine 2010 16:11 16, 1267–1276 (2010).
5. Marchand, F., Perretti, M. & McMahon, S. B. Role of the Immune system in chronic pain.
Nature Reviews Neuroscience 2005 6:7 6, 521–532 (2005).
Presenting Author
Le Cong Tuan Anh
Poster Authors
Cong Tuan Anh Le
MSc
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal.
Lead Author
Mariana Teixeira Sampaio
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal.
Lead Author
Sara Silva
PhD
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal.
Lead Author
Joana Silva
PhD
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal.
Lead Author
Hugo Leite-Almeida
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal.
Lead Author
Topics
- Mechanisms: Biological-Molecular and Cell Biology