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.