Background & Aims

Uncontrolled and persistent pain strongly associates with anxiety and depressive disorders, and is among the most common cause of disability impairing the quality of life. (1). Over the last 10 years, our group has established and validated paradigms designed to model this comorbidity in male mouse (Yalcin et al., 2011). We then exploited this model to uncover individual brain structures and molecular mechanisms affected by chronic pain. Among candidates, the anterior cingulate cortex (ACC) appears critical in pain and emotional processing. Our rodent studies further supported the implication of the ACC in mood control by showing that lesion or optogenetic inhibition of the ACC blocks anxiodepressive-like consequences of neuropathic pain. Since chronic pain and mood disorders being twice more prevalent in women than men, our project focuses on sex-specific differences in chronic pain-induced depression (CPID). Besides the behavioural characterization, we also aimed at determining the t

Methods

Neuropathic pain was induced using peripheral nerve injury which consists of implanting a polyethylene cuff around the main branch of sciatic nerve in C57BL/6J mice. A battery of behavioural test including quantitative sensory testing (von Frey filaments, Hargreaves, Hot plate test), ongoing pain unpleasantness (conditioned place preference), and anxiety/depression-like tests (novelty suppressed feeding test, splash test, forced swim test, elevated plus maze, open-field test, light-dark box and nesting) were used to characterize the behavioral consequences of neuropathic pain in female.
Quantification of Plasma corticosterone with ELISA to understand the baseline and the effect of acute stress at pre-determined time points after the induction of chronic pain to assess if HPA axis is implicated in chronic pain-induced depression.
RNA and EM sequencing to understand the molecular basis of chronic neuropathic pain induced depression on both DNA and RNA level.

Results

The behavioral characterization of the peripheral nerve injury revealed that female mice develop mechanical allodynia and thermal hyperalgesia similar to one observed in male mice. However, these somatosensory responses last longer in female than male. Interestingly, female mice do not show any anxiety-like behavior while they elicits depressive-like behavior evidenced by decreased grooming in splash and increased immobility time in forced swimming test.
Subsequent examination of the hypothalamic-pituitary-adrenal axis (HPA axis) in female mice with chronic pain revealed no significant changes in plasma corticosterone levels at 2 and 8 weeks post-injury, suggesting unaffected HPA axis function in CPID.
In parallel, transcriptomic and epigenetic analyses in the anterior cingulate cortex (ACC) of male and female mice with CPID were initiated using RNA and Enzymatic Methylation Sequencing. Utilizing bioinformatic approaches, particularly the weighted gene co-expression network analysis

Conclusions

In summary, the behavioral characterization of peripheral nerve injury in mice highlighted distinct responses between genders, with females exhibiting prolonged somatosensory and depressive-like behaviors. Interestingly, the hypothalamic-pituitary-adrenal axis in females with chronic pain remained unaffected. While the molecular investigations, including transcriptomic and epigenetic analyses in the anterior cingulate cortex are currently in the analysis part, these preliminary findings emphasize the need for further exploration to unravel the intricate molecular mechanisms contributing to the observed gender-specific differences in chronic pain responses.

References

1. Yalcin et al. 2011 Biol Psychiatry 70, 946–53.
2. Sellmeijer et al. 2018 J Neurosci 38, 3102–15.
3. Alba-Delgado et al. 2013 Biol Psychiatry 73, 54–62.
4. Gonçalves et al. 2008 Exp Neurol 213, 48–56.
5. Deng et al. 2019 World Neurosurg 121, 196–200.
6. Steele et al. 2008 Biol Psychiatry 63, 670–77.
7. Strohman et al. 2024 J Neurosci e1011232023.
8. Drevets & Price, in Biology of Depression pp. 427–65.
9. Drevets et al. 2008 Brain Struct Funct 213, 93–118.
10. Barthas et al. 2015 Biol Psychiatry 77, 236–45.
11. Becker et al. 2023 Nat Commun 14, 2198.
12. Barthas et al. 2017 Biol Psychiatry 82, 370–79.

Presenting Author

Vandana Shree Vedartham Srinivasan

Poster Authors

Vandana Shree Vedartham Srinivasan

MSc

University of Strasbourg

Lead Author

E-mail

Topics

  • Models: Chronic Pain - Neuropathic