Distinct transcriptional responses of mouse sensory neurons in models of human chronic pain conditions.

M.A Bangash,Sonia Santana-Varela,Edward C Emery,Janka Erdos,Larissa De Clauser,Sascha R.A Alles,Freija Ter Heegde,Queensta Millet,James J Cox,Shengnan Li,Samuel J Gossage,Ana P Luiz,Vanessa Pereira,Jing Zhao,John N Wood,Jane E Sexton,Shafaq Sikandar,Abdella M Habib

doi:10.12688/wellcomeopenres.14641.1

M.A Bangash, Sonia Santana-Varela + Show 16 more

Open Access

https://doi.org/10.12688/wellcomeopenres.14641.1

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Abstract

Background: Sensory neurons play an essential role in almost all pain conditions, and have recently been classified into distinct subsets on the basis of their transcriptomes. Here we have analysed alterations in dorsal root ganglia (DRG) gene expression using microarrays in mouse models related to human chronic pain. Methods: Six different pain models were studied in male C57BL/6J mice: (1) bone cancer pain using cancer cell injection in the intramedullary space of the femur; (2) neuropathic pain using partial sciatic nerve ligation; (3) osteoarthritis pain using mechanical joint loading; (4) chemotherapy-induced pain with oxaliplatin; (5) chronic muscle pain using hyperalgesic priming; and (6) inflammatory pain using intraplantar complete Freund's adjuvant. Microarray analyses were performed using RNA isolated from dorsal root ganglia and compared to sham/vehicle treated controls. Results: Differentially expressed genes (DEGs) were identified. Known and previously unreported genes were found to be dysregulated in each pain model. The transcriptomic profiles for each model were compared and expression profiles of DEGs within subsets of DRG neuronal populations were analysed to determine whether specific neuronal subsets could be linked to each of the pain models. Conclusions: Each pain model exhibits a unique set of altered transcripts implying distinct cellular responses to different painful stimuli. No simple direct link between genetically distinct sets of neurons and particular pain models could be discerned.

Highlights

Chronic pain is a major clinical problem affecting roughly 20% of the population with more than 6% suffering debilitating levels of pain1,2
Non-neuronal cells such as glia6 and immune system cells are found within sensory ganglia, with leukocytes alone making up 5–10% of cells in DRG7,8
Bone mineral density (BMD) was evaluated as an additional indicator of the cancer phenotype and was shown to be significantly decreased in cancer mice compared to sham controls (Figure 1C, D)

Summary

Introduction

Chronic pain is a major clinical problem affecting roughly 20% of the population with more than 6% suffering debilitating levels of pain. With the wider availability of high-throughput RNA-seq, there has been a major effort to define DRG transcriptomes, both at the level of whole ganglia and single neurons. With the wider availability of high-throughput RNA-seq, there has been a major effort to define DRG transcriptomes, both at the level of whole ganglia and single neurons4,5 This has allowed a new classification of sets of sensory neurons based on genetic identity, rather than on the rate of action potential propagation (A fibres and C fibres). We have analysed alterations in dorsal root ganglia (DRG) gene expression using microarrays in mouse models related to human chronic pain. The transcriptomic profiles for each model were compared and expression profiles of DEGs within subsets of DRG neuronal populations were analysed to determine whether specific neuronal subsets could be linked to each of the pain models. No simple direct link between genetically distinct sets of neurons and particular pain models could be discerned

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