How prolactin influences pain and what can be done about it

When most of us think about preparing for surgery, we picture the operating room, the steady hands of a surgeon, and maybe the long list of instructions about when to stop eating or which medications to avoid. What we don't often consider is the quieter but influential role stress plays in recovery. For women, in particular, the combination of pre-surgery stress and biology may help explain why pain after surgery can be more intense and longer lasting.

A study published in May 2025 in the Proceedings of the National Academy of Sciences helps clarify why this happens and points to an unexpected factor: the hormone prolactin, best known for its role in breastfeeding. The researchers also report early success with an antibody therapy that targets prolactin, which could eventually help reduce postsurgical pain in women, limit opioid use, and lower the risk of chronic pain.

Clinicians have long observed that women, on average, report higher levels of pain after surgery and are more likely to develop long-term complications such as chronic pain. Stress and anxiety before a procedure, already common, tend to intensify this effect. Until recently, however, the biological mechanisms behind these differences were poorly understood.

Prolactin offers an important clue. Although both men and women produce the hormone, women generally have higher circulating levels, in part because estrogen regulates its release. Stress further increases prolactin levels. The study shows that prolactin directly affects nociceptors, the nerve cells responsible for detecting painful stimuli.

Crucially, this effect appears to be sex-specific. In the experiments, prolactin sensitized pain-sensing neurons in females, while male neurons were largely unaffected. As a result, stress-related hormone surges can leave women's nervous systems more reactive, increasing the likelihood that ordinary sensations are experienced as painful.

The research was led by researchers from the University of Arizona. The team brought together expertise in neuroscience, pharmacology, pain medicine, and molecular biology. Their goal was to identify the role of prolactin in stress-related pain and explore practical ways to interrupt that process.

To do this, the researchers combined experiments in mice, nonhuman primates, and human sensory neurons donated by patients. The results were consistent across species. Stress before surgery increased pain afterward, particularly in females. Prolactin levels rose under stress, altering how nociceptors responded in female subjects. Blocking prolactin signaling reduced postsurgical pain, again only in females.

These findings point to a conserved biological pathway that has persisted across species and is therefore likely to be relevant in human medicine.

The team also tested a monoclonal antibody, PL200,019, designed to bind to human prolactin and block its activity. In female mice engineered to produce human prolactin, the antibody produced notable effects. It prevented stress-related sensitization of nociceptors, it reduced pain after surgery, and it did so without suppressing normal protective pain responses.

Similar results were seen in lab-grown human sensory neurons, where the antibody prevented prolactin from driving excessive neural excitability.

If these findings translate to clinical settings, they could have meaningful implications. One of them is reduced reliance on opioids. Postsurgical opioids are effective but carry risks of dependence and side effects. Addressing pain at its biological source could lower the need for these drugs. Another possible outcome is lower risk of chronic pain. By interrupting the stress-hormone-pain cycle early, the therapy could help prevent acute pain from becoming chronic. Also, the research could potentially lead to more precise treatment for women. The study identifies a clear sex-specific mechanism, supporting a more tailored approach to pain management.

One relevant aspect of the research is how directly it connects psychological stress with measurable biological changes. Stress is often treated as an abstract factor, yet here it clearly alters hormone signaling and neural sensitivity. In practical terms, stress does not just affect how patients feel, it can completely change how their nervous system processes pain.

Targeting this link may offer a way to better reflect and address the experiences of female patients, who have long reported more severe pain after surgery.

Significant challenges remain. Antibody therapies are costly and must undergo extensive clinical testing before approval. Researchers will also need to confirm that suppressing prolactin does not interfere with its other important functions, particularly those related to reproduction.

The idea of addressing postsurgical pain by managing stress-related hormone signaling represents a shift in how pain is understood and treated. Rather than relying solely on stronger painkillers, this approach focuses on intervening earlier and more precisely.

While prolactin-targeting therapies may still be years away from routine use, the research highlights a broader point: effective pain care may depend as much on understanding biology and stress as on developing new analgesics.

If you want to learn more, read the original article titled "A prolactin-targeting antibody to prevent stress-induced peripheral nociceptor sensitization and female postoperative pain" on Proceedings of the National Academy of Sciences at http://dx.doi.org/10.1073/pnas.2501229122.