Papers of the Week

Sensory neurons exhibit sex-dependent responsiveness to prolactin (PRL). This could contribute to sexual dimorphism in pathological pain conditions. The aim of this study is to elucidate mechanisms underlying sex-dependent PRL sensitivity in sensory neurons. Quantitative RT-PCR show that prolactin receptor (Prlr) long and short isoform mRNAs are expressed at comparable levels in female and male mouse dorsal root ganglia (DRG). In Prlr ;Rosa26 reporter mice, percentages of Prlr sensory neurons in female and male DRG are also similar. Characterization of Prlr DRG neurons using immunohistochemistry and electrophysiology revealed that Prlr DRG neurons are mainly peptidergic nociceptors in females and males. However, sensory neuron type-dependent expression of Prlr is sex dimorphic. Thus, Prlr populations fell into three small- and two medium-large-sized sensory neuronal groups. Prlr DRG neurons are predominantly medium-large sized in males and are proportionally more comprised of small-sized sensory neurons in females. Specifically, Prlr /IB4 /CGRP neurons are 4-5-fold higher in numbers in female DRG. In contrast, Prlr /IB4 /CGRP /5HT3a /NPYR2 are predominant in male DRG. Prlr /IB4 /CGRP , Prlr /IB4 /CGRP and Prlr /IB4 /CGRP /NPYR2 neurons are evenly encountered in female and male DRG. These differences were confirmed using an independently generated single-cell sequencing dataset. Overall, we propose a novel mechanism whereby sensory neuron type-dependent expression of Prlr could explain the unique sex dimorphism in responsiveness of nociceptors to PRL. This article is protected by copyright. All rights reserved.