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

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 (PRL_pit) and extra-pituitary PRL (PRL_ext) 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 PRL_ext. Immunohistochemistry (IHC) revealed incision-triggered induction of PRL_ext 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. PRL_pit plays critical role in activation of PRLR during stress-induced pain conditions. However, blockade of PRL_pit 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 GLAST^cre-ER/-/DTA^fl/- 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 PRL_ext 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.