Spared Nerve Injury Causes Sexually Dimorphic Mechanical Allodynia and Differential Gene Expression in Spinal Cords and Dorsal Root Ganglia in Rats

F.H.G Ahlström,P.V Rauhala,H Viisanen,K Mätlik,E.A Kalso,T.O Lilius,K.J Blomqvist,Y Sidorova,X Liu

doi:10.1007/s12035-021-02447-1

F.H.G Ahlström, P.V Rauhala + Show 7 more

Open Access

https://doi.org/10.1007/s12035-021-02447-1

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Journal: Molecular Neurobiology	Publication Date: Jul 30, 2021
Citations: 28	License type: open-access

Affiliation: University of Helsinki

Abstract

Neuropathic pain is more prevalent in women. However, females are under-represented in animal experiments, and the mechanisms of sex differences remain inadequately understood. We used the spared nerve injury (SNI) model in rats to characterize sex differences in pain behaviour, unbiased RNA-Seq and proteomics to study the mechanisms. Male and female rats were subjected to SNI- and sham-surgery. Mechanical and cold allodynia were assessed. Ipsilateral lumbar dorsal root ganglia (DRG) and spinal cord (SC) segments were collected for RNA-seq analysis with DESeq2 on Day 7. Cerebrospinal fluid (CSF) samples for proteomic analysis and DRGs and SCs for analysis of IB-4 and CGRP, and IBA1 and GFAP, respectively, were collected on Day 21. Females developed stronger mechanical allodynia. There were no differences between the sexes in CGRP and IB-4 in the DRG or glial cell markers in the SC. No CSF protein showed change following SNI. DRG and SC showed abundant changes in gene expression. Sexually dimorphic responses were found in genes related to T-cells (cd28, ctla4, cd274, cd4, prf1), other immunological responses (dpp4, c5a, cxcr2 and il1b), neuronal transmission (hrh3, thbs4, chrna4 and pdyn), plasticity (atf3, c1qc and reg3b), and others (bhlhe22, mcpt1l, trpv6). We observed significantly stronger mechanical allodynia in females and numerous sexually dimorphic changes in gene expression following SNI in rats. Several genes have previously been linked to NP, while some are novel. Our results suggest gene targets for further studies in the development of new, possibly sex-specific, therapies for NP.

Highlights

Neuropathic pain (NP) affects 7–8% of the adult population [1]
We demonstrate a female-only upregulation of Dntt, a lymphocytespecific-DNA polymerase involved in adding nucleotides to T-cell receptors, which are essential for the function of T cells [52, 53]
The microglial or astrocytic proliferation and activation do not reveal a dichotomous role for these cells in either sex under these circumstances in the spinal cord (SC), nor did the proteome of Cerebrospinal fluid (CSF) reveal new insights

Summary

Introduction

Neuropathic pain (NP) affects 7–8% of the adult population [1]. It is refractory to the majority of clinically used drugs [2]. Gender differences in NP or responses to drugs used in NP have not been systematically assessed. Female subjects have often been excluded from clinical trials [3], even though NP, as well as chronic pain in general, is more prevalent among women [4, 5]. A systematic review concerning studies of human experimental pain found no consistent pattern in gender differences [6]. Several psychological and sociocultural phenomena may influence pain perception differently in the two genders. Non-human studies are needed to uncover the underlying pathophysiologic mechanisms explaining possible sex differences in pain perception [7]

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Discussion

Conclusion