Sex differences in nociceptor translatomes contribute to divergent prostaglandin signaling in male and female mice

Abstract

Background: There are clinically relevant sex differences in acute and chronic pain mechanisms, but we are only beginning to understand their mechanistic basis. Transcriptome analyses of rodent whole dorsal root ganglion (DRG) have revealed sex differences, mostly in immune cells. We examined the transcriptome and translatome of the mouse DRG with the goal of identifying sex differences. Methods: We used Translating Ribosome Affinity Purification (TRAP) sequencing and behavioral pharmacology to test the hypothesis that nociceptor (Nav1.8 expressing neurons) translatomes would differ by sex. Results: We found 66 genes whose mRNA were sex-differentially bound to nociceptor ribosomes. Many of these genes have known neuronal functions but have not been explored in sex differences in pain. We focused on Ptgds, which was increased in female mice. The mRNA encodes the prostaglandin D2 (PGD2) synthesizing enzyme. We observed increased Ptgds protein and PGD2 in female mouse DRG. The Ptgds inhibitor AT-56 caused intense pain behaviors in male mice but was only effective at high doses in females. Conversely, female mice responded more robustly to another major prostaglandin, PGE2, than did male mice. Ptgds protein expression was also higher in female cortical neurons, suggesting DRG findings may be generalizable to other nervous system structures. Conclusions: Nociceptor TRAP sequencing (TRAP-seq) reveals unexpected sex differences in one of the oldest known nociceptive signaling molecule families, the prostaglandins. Our results demonstrate that translatome analysis reveals physiologically relevant sex differences important for fundamental protective behaviors driven by nociceptors.

Age-associated changes in knee osteoarthritis, pain-related behaviors, and dorsal root ganglia immunophenotyping of male and female mice

“…Interestingly, sexual dimorphism in the age-related decline of several mouse behaviors has been reported (59), and there are known transcriptional and translational sex differences in mouse sensory neurons (73, 74). Thus, here we studied both males and females, and we found a greater increase in DRG macrophages in aged males than aged females and this coincided with a significant decrease in CCR2+ cells in female DRGs (Figs.…”

Sexual Dimorphism of Early Transcriptional Reprogramming in Dorsal Root Ganglia After Peripheral Nerve Injury

“…Recent transcriptomics data in animals identified sex-specific PNI responses in DRG ( North et al, 2019 ; Ray et al, 2019 ; Stephens et al, 2019 ; Chernov et al, 2020 ; Mecklenburg et al, 2020 ; Paige et al, 2020 ; Tavares-Ferreira et al, 2020 ; Yu et al, 2020 ). However, sex differences in the immediate post-injury early-response transcriptional events remain not well understood.…”

“…Likewise, emerging research has revealed sexual dimorphism in rodent DRG transcriptomes in response to peripheral nerve injury ( Stephens et al, 2019 ; Ahlström et al, 2021 ), hyperalgesic priming by interleukin 6 (Il-6; Paige et al, 2020 ), sciatic nerve injection of myelin basic protein (MBP) derived peptides ( Chernov et al, 2020 ), and other stimuli. Transcriptome differences in DRG have been implicated in female-prevalent hypersensitivity partly due to the activity of prostaglandin signaling and neuroendocrine mechanisms involving prolactin receptors ( North et al, 2019 ; Ray et al, 2019 ; Chernov et al, 2020 ; Mecklenburg et al, 2020 ; Paige et al, 2020 ; Tavares-Ferreira et al, 2020 ).…”

The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of central nervous system activity with repeated dosing

“…In addition to TRPV1 sensitization, PGE 2 induces hyperexcitability of DRG neurons, which is another key peripheral process that contributes to nociceptive sensitization in the context of inflammation. 4,18,62,91,99,100 We used patch clamp electrophysiology to examine whether CB-13 can reduce PGE 2 -induced changes in DRG action potential firing (Figs. 5A-F).…”