Prolactin receptor expression in mouse dorsal root ganglia neuronal subtypes is sex-dependent

Sensory neurones exhibit sex-dependent responsiveness to prolactin (PRL). This could contribute to sexual dimorphism in pathological pain conditions. The present study aimed to determine the mechanisms underlying sex-dependent PRL sensitivity in sensory neurones. A quantitative reverse transcriptase-polymerase chain reaction shows 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(cre/+);Rosa26(LSL-tDTomato/+) reporter mice, percentages of Prlr(+) sensory neurones in female and male DRG are also similar. Characterisation of Prlr(+) DRG neurones using immunohistochemistry and electrophysiology revealed that Prlr(+) DRG neurones are mainly peptidergic nociceptors in females and males. However, sensory neurone 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 neurones are predominantly medium-large sized in males and are proportionally more comprised of small-sized sensory neurones in females. Specifically, Prlr(+)/IB4(+)/CGRP(+) neurones are four- to five-fold higher in numbers in female DRG. By contrast, Prlr(+)/IB4(-)/CGRP(+)/5HT3a(+)/NPYR2(-) are predominant in male DRG. Prlr(+)/IB4(-)/CGRP(-), Prlr(+)/IB4(-)/CGRP(+) and Prlr(+)/IB4(-)/CGRP(+)/NPYR2(+) neurones 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 by which sensory neurone type-dependent expression of Prlr could explain the unique sex dimorphism in responsiveness of nociceptors to PRL.