Differential gene expression in trigeminal ganglia of male and female rats following chronic constriction of the infraorbital nerve

Korczeniewska, Olga A.; Husain, Shahid; Khan, Junad; Eliav, Eli; Soteropoulos, Patricia; Benoliel, Rafael

doi:10.1002/ejp.1174

Cited by 28 publications

(26 citation statements)

References 59 publications

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“…Very recent gene expression profiling studies have suggested strikingly different chronic pain-related gene expression between the sexes. On examination of 84 genes preselected as relevant to pain, it was 90 observed that chronic constriction injury of the infraorbital nerve in rats regulated the Chrna4 gene in male but not female mice and the Cck, Il1a, Pla2g1b and Tnf genes in female but not male mice. rNA sequencing after chronic constriction injury of the rat sciatic nerve 91 showed that only 6% of genes examined (862 of 14,403) were differentially expressed by the sexes at the baseline; however, of the 3,127 genes regulated by the injury in either sex, only 514 (16%) were common to both males and females, and in nine cases were regulated in opposite directions in male and female rats 91 .…”

Section: Pleiotropymentioning

confidence: 99%

Qualitative sex differences in pain processing: emerging evidence of a biased literature

2020

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Although most patients with chronic pain are women, the preclinical literature regarding pain processing and the pathophysiology of chronic pain has historically been derived overwhelmingly from the study of male rodents. This Review describes how the recent adoption by a number of funding agencies of policies mandating the incorporation of sex as a biological variable into preclinical research has correlated with an increase in the number of studies investigating sex differences in pain and analgesia. Trends in the field are analysed, with a focus on newly published findings of qualitative sex differences: that is, those findings that are suggestive of differential processing mechanisms in each sex. It is becoming increasingly clear that robust differences exist in the genetic, molecular, cellular and systems-level mechanisms of acute and chronic pain processing in male and female rodents and humans.

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Section: Pleiotropymentioning

confidence: 99%

Qualitative sex differences in pain processing: emerging evidence of a biased literature

2020

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“…Altered gene expression patterns in the DRG (Hammer et al, 2010; Raju, Englander, Capobianco, Tsinoremas, & Lerch, 2014) and TG (Korczeniewska et al, 2018) following peripheral nerve injury have been implicated in the aetiology of NP, which nevertheless remains elusive. Kogelman et al investigated gene expression levels in the DRG and TG of the naïve rats and identified genes that were differentially expressed between the two ganglia (Kogelman et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Differential gene expression changes in the dorsal root versus trigeminal ganglia following peripheral nerve injury in rats

Korczeniewska

Rider

Gajra

et al. 2020

European Journal of Pain

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Background The dorsal root (DRG) and trigeminal (TG) ganglia contain cell bodies of sensory neurons of spinal and trigeminal systems, respectively. They are homologs of each other; however, differences in how the two systems respond to injury exist. Trigeminal nerve injuries rarely result in chronic neuropathic pain (NP). To date, no genes involved in the differential response to nerve injury between the two systems have been identified. We examined transcriptional changes involved in the development of trigeminal and spinal NP. Methods Trigeminal and spinal mononueropathies were induced by chronic constriction injury to the infraorbital or sciatic nerve. Expression levels of 84 genes in the TG and DRG at 4, 8 and 21 days post‐injury were measured using real‐time PCR. Results We found time‐dependent and ganglion‐specific transcriptional regulation that may contribute to the development of corresponding neuropathies. Among genes significantly regulated in both ganglia Cnr2, Grm5, Htr1a, Il10, Oprd1, Pdyn, Prok2 and Tacr1 were up‐regulated in the TG but down‐regulated in the DRG at 4 days post‐injury; at 21 days post‐injury, Adora1, Cd200, Comt, Maob, Mapk3, P2rx4, Ptger1, Tnf and Slc6a2 were significantly up‐regulated in the TG but down‐regulated in the DRG. Conclusions Our findings suggest that spinal and trigeminal neuropathies due to trauma are differentially regulated. Subtle but important differences between the two ganglia may affect NP development. Significance We present distinct transcriptional alterations in the TG and DRG that may contribute to differences observed in the corresponding mononeuropathies. Since the trigeminal system seems more resistant to developing NP following trauma our findings lay ground for future research to detect genes and pathways that may act in a protective or facilitatory manner. These may be novel and important therapeutic targets.

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“…The gene Chrna4, coding for the neuronal acetylcholine receptor subunit alpha-4 (nAChRα4), displayed signi cant downregulation in DRG in males only. Previously, CCI of the infraorbital nerve in rats showed greater mechanical allodynia and increased expression of Chrna4 in females [39]. With an overall sex-dependent change in the same direction, and the fact that nicotinic receptors (of which nAChRα4 is one) mediate fast depolarisations at synapses [81], upregulation of Chrna4 might sensitize neurotransmission in a sex-speci c manner.…”

Section: Neuronal Transmissionmentioning

confidence: 93%

“…Previous studies have reported varying results in sex differences in behaviour following PNI. For example, greater mechanical allodynia in female rats has been reported in at least one PNI study and, in another study, following CCI of the infraorbital nerve [8,39]. In two other studies, no behavioural differences were reported, even though differences in the mechanisms of putative sex differences were hypothesized [9,10].…”

Section: Behavioural Testsmentioning

confidence: 94%

Spared nerve injury causes sexually dimorphic mechanical allodynia and differential gene expression in spinal cords and dorsal root ganglia in rats

Ahlström

Mätlik

Viisanen

et al. 2020

Preprint

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BACKGROUND Neuropathic pain (NP) is more prevalent in women. However, females are under-represented in animal experiments, and the mechanisms of sex differences remain inadequately understood. Using the spared nerve injury (SNI) model in rats, we characterized sex differences in behaviour, analysed dorsal root ganglion (DRG) and spinal cord (SC) tissues with transcriptomics and immunohistochemistry assays, and examined the proteome of cerebrospinal fluid (CSF). METHODS The study comprised two experiments, with male and female Sprague-Dawley rats subjected to SNI- and sham-surgeries. Mechanical and cold allodynias were assessed using von Frey filaments and the acetone test, respectively. Samples were extracted on Day 21 for CSF proteome and DRG and SC analysis for neuronal markers (IB4 and CGRP) and glial cell markers (IBA1 and GFAP), respectively, in Experiment I. Lumbar 4-5 DRGs and SC segments were collected for RNA-seq analysis on Day 7 in Experiment II. Differential gene expression in DRG and SC was calculated using DESeq2, and pathway analyses were conducted using iPathwayguide. RESULTS Females developed stronger mechanical allodynia in both experiments. Equivalent decreases in CGRP and IB-4 positive cell counts in DRG and increases in glial cells markers in the SC were seen in both sexes. No CSF protein showed change following SNI in any group. RNASeq of 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). Analyses of biological processes revealed differences in T and B cell functions in DRG and neuronal processes in both DRG and SC. CONCLUSIONS We observed significantly stronger mechanical allodynia in females and many 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 and underline the importance of investigating NP in both sexes.

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Differential gene expression in trigeminal ganglia of male and female rats following chronic constriction of the infraorbital nerve

Abstract: We present novel sex-specific transcriptional regulation in trigeminal ganglia that may contribute to male-/female-based differences in trigeminal neuropathic pain. These findings are expected to open new research horizons, particularly in male versus female targeted therapeutic regimens.

Cited by 28 publications

References 59 publications

Qualitative sex differences in pain processing: emerging evidence of a biased literature

Qualitative sex differences in pain processing: emerging evidence of a biased literature

Differential gene expression changes in the dorsal root versus trigeminal ganglia following peripheral nerve injury in rats

Spared nerve injury causes sexually dimorphic mechanical allodynia and differential gene expression in spinal cords and dorsal root ganglia in rats

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