# Spinal glial cell derived extra-pituitary prolactin contributes to postoperative pain in females

## TL;DR

Spinal glial cells produce a hormone called prolactin that increases pain in females after surgery.

## Contribution

The study identifies spinal glial-derived extra-pituitary prolactin as a key contributor to female-specific postoperative pain.

## Key findings

- Extra-pituitary prolactin (PRLext) is primarily responsible for activating pain-related signaling in dorsal root ganglion neurons.
- Spinal GLAST+ astrocytes are a major source of PRLext that promotes pain hypersensitivity in females.
- Blocking PRLext with a receptor antagonist reduces postoperative pain in female rodents.

## Abstract

Peripheral and spinal prolactin (PRL) receptor (PRLR) signaling contributes to the female-selective regulation of pain. This study investigated the relative roles of pituitary-derived PRL (PRLpit) and extra-pituitary PRL (PRLext) in these effects. Using STAT5 phosphorylation (pSTAT5) as a surrogate marker of PRL-responsive cells, we found that hindpaw incision-induced pSTAT5 in dorsal root ganglion (DRG) neurons depends primarily on PRLext. Immunohistochemistry (IHC) revealed incision-triggered induction of PRLext in rodent female myelinated peripheral nerves, the epidermis, medium-to-large DRG neurons, and a subset of spinal astrocytes, some of which co-expressed the glial glutamate transporter GLAST. PRLpit plays critical role in activation of PRLR during stress-induced pain conditions. However, blockade of PRLpit by hypophysectomy or bromocriptine did not substantially alter incision- or IL-6–induced heat or mechanical hypersensitivity. In contrast, the PRLR antagonist Δ1–9-G129R-hPRL (ΔPRL) reduced pSTAT5 in DRG neurons and reversed postoperative hypersensitivity in females. Postnatal ablation of GLAST+ cells in GLASTcre−ER/−/DTAfl/− mice attenuated incision-induced hypersensitivity in females but not in males, and ΔPRL had no additional effect in these mice, indicating that spinal GLAST+ astrocytes are a major source of pain-promoting PRLext in female rodents. These results demonstrate that extra-pituitary PRL, particularly from spinal GLAST+ astrocytes, is a key contributor to female-selective regulation of postoperative and inflammatory pain.