Prolactin Receptor Long Isoform ΔS1 Expression is Reduced in the Dorsal Root Ganglia of Humans with Chronic Pain

Prolactin receptor (PRLR) isoforms, specifically the short (PRLR-S) and long (PRLR-L), are differentially expressed in pathological conditions and may be involved in the induction and maintenance of pain in females. PRLR sex-dependent actions are well studied in rodent models of chronic pain, but the translatability of these findings have only been assessed in electrophysiology studies that found consistent results with previous sex differences described in mice. To increase our understanding of the sexual dimorphic nature of prolactin actions on sensory neurons and our knowledge of how this body of work applies to the human nervous system, we characterized the expression of the short and long isoforms of PRLR with RNAscope in situ hybridization in human dorsal root ganglion (DRG) neurons. Based on data in mice, we hypothesized PRLR-S and PRLR-L would be equally expressed in human DRG neurons, with higher expression in females. To test this, we used DRG tissues recovered from male and female organ donors and cervix as a positive control. Our results demonstrated human DRG neurons express more PRLR-L, specifically transcript variant 6 (ΔS1), than PRLR-S in both sexes and that female donors had a higher expression of PRLR overall. In DRGs from female organ donors with a history of chronic pain we observed less PRLR-L expression, a finding consistent with previous studies in pain models in female mice. Expression for both PRLR isoforms in cervix was consistent with previous reports. An analysis of previously published RNA sequencing studies on human DRGs revealed that PRLR expression is confined mostly to TRPV1-positive nociceptors in humans, consistent with our RNAscope-based findings. We conclude that the PRLR-L (ΔS1) form is the major isoform expressed in human DRG neurons, that this expression is higher in females than in males, and that PRLR-L (ΔS1) expression is suppressed in chronic pain conditions in females.