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

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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.

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