Targeting Prolactin May Ease Post-Surgery Pain In Women

A team of scientists at the University of Arizona Health Sciences has uncovered a promising approach to reducing post-operative pain in women by inhibiting pituitary prolactin—a hormone elevated by pre-surgical stress. Their findings, recently published in the Proceedings of the National Academy of Sciences, may pave the way for therapies that lessen the reliance on opioids following surgery.

Prolactin, a neurohormone traditionally recognized for its role in mammary gland development and lactation, is naturally found at higher levels in females compared to males. Led by Frank Porreca, Ph.D., research director of the U of A Health Sciences Comprehensive Center for Pain & Addiction, the team demonstrated that prolactin sensitizes female nociceptors—specialized nerve cells responsible for transmitting pain signals to the brain. Importantly, stress boosts circulating prolactin levels in women, creating a “perfect storm” for heightened post-operative pain.

“Clinicians often observe that patients exhibiting higher anxiety and stress before surgery tend to experience more severe post-operative pain. Women, in particular, display stronger stress responses,” said Porreca, the Cosden Professor of Pain and Addiction Studies at the U of A College of Medicine–Tucson.

Prolactin release is regulated by the pituitary gland and normally suppressed by dopamine from the hypothalamus. However, stress can disrupt this inhibitory control, causing prolactin levels to rise.

Using mouse models, the research team tested three key hypotheses: that elevated prolactin exacerbates and prolongs post-surgical pain; that stress primes this prolactin-driven mechanism; and that reducing prolactin prior to surgery improves pain outcomes. The results affirmed each prediction.

“Our study highlights that psychological stress related to anticipated surgery drives prolactin-mediated increases in nociceptor sensitivity, amplifying pain signals to the central nervous system,” Porreca explained.

The team successfully lowered prolactin levels and mitigated post-operative pain in female mice through three strategies: gene therapy; treatment with cabergoline—a dopamine receptor agonist that inhibits prolactin release; and administration of PL 200,019, a novel monoclonal antibody developed by the researchers to block prolactin’s effects.

“By targeting prolactin preemptively in patients facing surgery-related stress, we can potentially improve post-operative pain management specifically for women,” Porreca said.

Cabergoline, already FDA-approved for other indications, is slated for clinical trials to evaluate its efficacy as a pre-surgical pain intervention. Meanwhile, PL 200,019 remains in development but shows strong promise for future clinical use.

Both therapies hold potential to reduce the transition from acute to chronic pain and decrease opioid requirements after surgery, a crucial benefit given the risks associated with opioid use.

“While opioids remain essential for managing trauma and surgical pain, lowering their use shortens hospital stays, accelerates recovery, and minimizes adverse effects such as addiction and respiratory depression,” Porreca noted.

This research builds on Porreca’s earlier work, including studies published in BRAIN that linked stress-induced hypothalamic activation to prolactin elevation and identified sex-specific nociceptor sensitization pathways—prolactin in women and orexin in men.

The University of Arizona’s findings offer a compelling new direction for improving pain outcomes in women through targeted hormone modulation, with the potential to transform post-operative care and reduce reliance on opioids.