Background & Aims
Chronic pain remains difficult to manage despite advancements in modern therapeutics, due to its complex, multifaceted nature.1,2 Although extensively studied, a deeper understanding of pain signaling mechanisms is necessary to develop more effective analgesics. Top-down neuroimaging studies have identified patterns of cerebral structures activated by different painful stimuli; however, they tend to oversimplify the complexity of pain processing.3 Our study takes a novel, bottom-up approach, by alternatively focusing on characterizing the primary nociceptive relay point from the periphery to the brain, the dorsal horn of the spinal cord.4 The main objectives of this study are to 1) determine the unique genetic fingerprint of the dorsal horn, 2) identify brain region(s) of similar enriched genetic composition, and 3) further characterize our region of interests’ structural and functional characteristics in relation to both acute and chronic pain.
Methods
RNA-isoform data obtained from the Human Protein Atlas underwent transcriptomic analyses using R packages (DESeq2, edgeR) to determine the unique, upregulated genetic fingerprint of the dorsal horn. Gene set enrichment analysis using the package Enrichr referencing the Allen Brain Atlas was then used to map the upregulated genetic fingerprint to a brain region of most similar enriched composition. To characterize structural differences, the identified brain region of interest was segmented from T1W MRI images, and various radiomic features were analyzed in relation to pain sensitivity in 50 individuals (Age: 27.6 ± 6.4 years; 26 females). Pain sensitivity ratings were obtained in response to noxious laser stimuli. Functional characteristics were analyzed using arterial spin labeling data, looking at local variances in blood flow to determine differences in baseline activity. The same structural and functional analyses will also be completed in individuals with chronic pain.
Results
Transcriptomic analyses resulted in an enriched genetic fingerprint involved in sensory transmission. This genetic fingerprint was mapped to the Bed Nuclei of the Stria Terminalis (BNST), a sexually dimorphic, small cluster of grey matter nuclei involved in the limbic circuit of the brain.5 Analyses indicate a significant volume difference between the male (139mm^3 ± 20.1mm^3) and female (123mm^3 ± 19.8mm^3) BNSTs (p-value = 0.006457). Preliminary analyses revealed that a larger BNST volume (130.9mm^3 ± 21.3mm^3) is correlated with lower pain (3.38 ± 1.49) ratings (Pearson’s r = -0.301, p-value = 0.03506).
Conclusions
This study presents a novel, bottom-up method to studying pain signaling pathways in humans. The dorsal horn’s enriched transcriptome was mapped to the BNST which is not well studied in the context of pain in humans, with only a few studies analyzing its properties in animal models. Our preliminary findings indicate potential involvement for the BNST in acute pain processing in humans.
References
1.Burgess G, Williams D. The discovery and development of analgesics: new mechanisms, new modalities. Journal of Clinical Investigation. 2010;120(11):3753-3759. doi:10.1172/JCI43195
2.Raffaeli W, Tenti M, Corraro A, et al. Chronic Pain: What Does It Mean? A Review on the Use of the Term Chronic Pain in Clinical Practice. J Pain Res. 2021;Volume 14:827-835. doi:10.2147/JPR.S303186
3.Berger SE, Baria AT. Assessing Pain Research: A Narrative Review of Emerging Pain Methods, Their Technosocial Implications, and Opportunities for Multidisciplinary Approaches. Frontiers in Pain Research. 2022;3. doi:10.3389/fpain.2022.896276
4.Doubell T, Mannion RJ, Woold CJ. The dorsal horn: State-dependent sensory processing, plasticity and the generation of pain. In: Wall P, Melzack R, eds. The Textbook of Pain . 4th ed. Churchill Livingstone; 1999:165-182.
5.Lebow MA, Chen A. Overshadowed by the amygdala: the bed nucleus of the stria terminalis emerges as key to psychiatric disorders. Mol Psychiatry. 2016;21(4):450-463. doi:10.1038/mp.2016.1
6.Shaheen N, Shaheen A, Elgendy A, et al. Deep brain stimulation for chronic pain: a systematic review and meta-analysis. Front Hum Neurosci. 2023;17. doi:10.3389/fnhum.2023.1297894
Presenting Author
Ryan Loke
Poster Authors
Ryan Loke
BSc(Hons)
University of British Columbia
Lead Author
Topics
- Mechanisms: Biological-Systems (Physiology/Anatomy)