Background & Aims
Pediatric chronic pain is a growing epidemic, with ~20% of youth that undergo surgery developing persistent post-surgical pain 1. The heightened neuroplasticity associated with early life stress may increase ones’ risk for persistent pain, with the perinatal period being particularly sensitive to epigenetic change 2. A common stressor in the prenatal period is intimate partner violence (IPV), with at least 25% of pregnant women experiencing IPV 3. Additional stressors, such as early life neglect, often co-occur with adversities such as IPV 4. The prefrontal cortex (PFC) plays a role in higher order cognitive and executive functions and of interest, is highly sensitive to stress exposure 5. Acute stress alters signaling pathways and weakens synaptic connectivity, with chronic stress leading to loss of spines and dendrites in the PFC 6. Therefore, this study aimed to examine the effect of perinatal trauma on post-surgical pain sensitivity along with changes in gene expression in the PFC.
Methods
Sprague Dawley rat dams were randomly assigned to a control or IPV condition (TBI + 60s hypoxia) during gestation (G17). Following birth, their male and female pups were randomized to no stress (No MS) or early life stress (maternal separation (MS)) (p2-12) groups, then further into a sham or surgery (plantar incision surgery) condition (p30) (n’s =5/group). All pups were tested for mechanical and thermal nociception via the von Frey and cold plate tasks (p39-44) respectively. Three-way ANOVAs with IPV, MS, and Surgery as factors were run. At euthanasia (p47) brain regions were collected and purified mRNA from the PFC was utilized for RNA sequencing. DESeq2R package was used to perform differential expression analysis. The clusterProfiler R package was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of differentially expressed genes (DEGs). A false discovery corrected p value of <0.05 was considered statistically significant.
Results
IPV animals had shorter latencies to react on the cold plate (p’s <.001), indicating increased thermal nociceptive sensitivity. On the von Frey, IPV and MS groups reacted to smaller filament weights (p’s <.001), indicating increased mechanical nociceptive sensitivity. Compared with the control group (No IPV/ No MS/ Sham), the IPV/ MS/ Surgery group had a total number of 2799 DEGs (1372 upregulated, 1427 downregulated, adjusted p = 0.05). Results from GO enrichment analysis showed the DEGs to be most enriched in: peptide biosynthetic process, peptide metabolic process, amide biosynthetic process, translation, cellular amide metabolic process, ribonucleoprotein complex, ribosome, structural constituent of ribosome, and structural molecule activity. KEGG analysis showed the most enriched pathways to be: Parkinson disease, Prion disease, Huntington disease, Alzheimer disease, ribosome, and amyotrophic lateral sclerosis.
Conclusions
In summary, our study found that when combined, IPV and MS resulted in heightened nociceptive sensitivity and altered gene expression in pathways involved in peptide and amide processes, ribosomes, and degenerative diseases. Beyond identifying behavioural changes in nociception, indicating that perinatal trauma increases susceptibility to developing chronic pain, our study characterized gene expression changes within the PFC across the genome in rats subjected to perinatal trauma. Through systematic identification of critical genes and pathways involved in perinatal trauma pathology, we contribute to the ongoing exploration of these complex mechanisms. Our RNA sequencing analysis provides invaluable insight into the mechanisms involved in trauma and pain and provides a foundation for future research.
References
1)Rabbitts, J. A., Fisher, E., Rosenbloom, B. N., & Palermo, T. M. (2017). Prevalence and predictors of chronic postsurgical pain in children: a systematic review and meta-analysis. The journal of pain, 18(6), 605-614.
2)Kodila, Z. N., Shultz, S. R., Yamakawa, G. R., & Mychasiuk, R. (2023). Critical Windows: Exploring the Association Between Perinatal Trauma, Epigenetics, and Chronic Pain. The Neuroscientist, 10738584231176233.
3)Thompson, R. S., Bonomi, A. E., Anderson, M., Reid, R. J., Dimer, J. A., Carrell, D., & Rivara, F. P. (2006). Intimate partner violence: Prevalence, types, and chronicity in adult women. American journal of preventive medicine, 30(6), 447-457.
4)Felitti, V. J., Anda, R. F., Nordenberg, D., Williamson, D. F., Spitz, A. M., Edwards, V., & Marks, J. S. (1998). Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults: The Adverse Childhood Experiences (ACE) Study. American journal of preventive medicine, 14(4), 245-258.
5)Arnsten, A. F. (2009). Stress signalling pathways that impair prefrontal cortex structure and function. Nature reviews neuroscience, 10(6), 410-422.
6)Woo, E., Sansing, L. H., Arnsten, A. F., & Datta, D. (2021). Chronic stress weakens connectivity in the prefrontal cortex: Architectural and molecular changes. Chronic Stress, 5, 24705470211029254.
Presenting Author
Sabrina Salberg
Poster Authors
Sabrina Salberg
PhD
Department of Neuroscience, Monash University, Melbourne, VIC, Australia
Lead Author
Marissa Sgro (PhD)
Department of Neuroscience, Monash University, Melbourne, VIC, Australia
Lead Author
Zoe Kodila (Hons)
Department of Neuroscience, Monash University, Melbourne, VIC, Australia
Lead Author
Crystal Li
MSc
Department of Neuroscience, Monash University, Melbourne, VIC, Australia
Lead Author
Madeleine J. Smith
Department of Neuroscience, Monash University, Melbourne, VIC, Australia
Lead Author
James Freeman
Department of Neuroscience, Monash University, Melbourne, VIC, Australia
Lead Author
Elaina Vlassopoulos (Hons)
Department of Neuroscience, Monash University, Melbourne, VIC, Australia
Lead Author
Sydney Harris
Department of Neuroscience, Monash University, Melbourne, VIC, Australia
Lead Author
Sandy Shultz
PhD
Department of Neuroscience, Monash University, Melbourne, VIC, Australia
Lead Author
Glenn Yamakawa
PhD
Department of Neuroscience, Monash University, Melbourne, VIC, Australia
Lead Author
Melanie Noel
Department of Psychology, University of Calgary, Calgary, Canada
Lead Author
Richelle Mychasiuk
Department of Neuroscience, Monash University, Melbourne, VIC, Australia
Lead Author
Topics
- Pain in Special Populations: Infants/Children