TUCSON, Arizona — University of Arizona Health Sciences researchers identified a potential way to reduce female post-operative pain by inhibiting pituitary prolactin generated by pre-operative stress. The paper, published in the journal Proceedings of the National Academy of Science , could lead to ways to reduce post-operative pain and decrease the need for opioids for pain relief after surgical procedures in women.
Prolactin, naturally found at higher levels in females than in males, is a neurohormone best known for assisting mammary gland development and stimulating milk production. Recent research led by Frank Porreca, PhD, research director for the U of A Health Sciences Comprehensive Center for Pain & Addiction , found that it also excites female nociceptors, the nerve cells responsible for transmitting pain signals to the brain. Stress can increase the circulating level of prolactin in women, leading to a pre- and post-operative perfect storm of pain.
"Many clinicians will tell you that they can predict which patients will have the worst post-operative pain outcomes based on the level of anxiety and stress that a patient exhibits before a scheduled surgery. And it has been shown that women exhibit greater stress responses," said Porreca, the Cosden Professor of Pain and Addiction Studies at the U of A College of Medicine – Tucson . "Our study uncovered a link between psychological stress and nociceptor activation through prolactin, which means there are approaches we could use preemptive intervention to improve outcomes in post-operative pain in women."
Prolactin is produced and released into the bloodstream by the pituitary gland. That production is usually slowed when the hypothalamus releases dopamine, a natural prolactin inhibitor. Stress can disrupt this natural balance, resulting in increased prolactin levels.
For this study, Porreca's research team used mouse models to test the hypotheses that: high levels of prolactin enhance and prolong the degree of post-operative pain; stress can act as a priming stimulus for a prolactin mechanism leading to increased post-operative pain; and a pre-surgery intervention to reduce prolactin levels could improve post-operative pain outcomes.
In each case, they were right.
"Our findings focused on the fact that the prolactin consequence comes from the psychological stress of an anticipated surgery," Porreca said. "Now we know how stress may influence the excitability of the nociceptors that are going to produce the pain input to the central nervous system."
Porreca and the team successfully lowered prolactin levels and reduced post-operative pain in female mice using three different approaches: gene therapy; medication with cabergoline, a drug that acts at dopamine receptors to inhibit prolactin release; and administration of PL 200,019, a novel monoclonal antibody discovered by the team and optimized to inhibit prolactin.
"The concept here, in all cases, is that if you have an anticipated surgery and related psychological stress, there are approaches we can use preemptively to improve outcomes of post-operative pain in females," Porreca said.
Cabergoline is a Food and Drug Administration-approved medication that Porreca is hoping to take into clinical trials soon to test its suitability as a pre-emptive therapy for post-surgical pain.
PL 200,019 is still under development, but research suggests a high likelihood the monoclonal antibody eventually can be successfully transferred into the clinic.
Either therapy could help decrease the risk of acute pain turning into chronic pain and reduce the post-surgery use of opioids by women.
"Opioids remain the most important medications that we have for trauma-induced pain, for surgical-induced pain and for cancer pain," Porreca said. "If we can reduce the need for post-operative opioids, it's beneficial for the patient. It shortens their duration of stay in the hospital, and it gets them back on their feet faster, moving and recovering quicker. And, of course, that decreases the risk of addiction, respiratory depression, constipation, and all the things that we don't like with opioids."
This study built on some of Porreca's prior research, published in BRAIN, including a paper that showed stress-induced activation of the hypothalamus in models of migraine can affect prolactin production and lead to increased nociceptor activation; and a study that was the first to identify that nociceptors are sexually dimorphic and selectively sensitized by prolactin in women and the hormone orexin in men.
Porreca's co-authors from the College of Medicine – Tucson Department of Pharmacology include research associate and first author Harrison Stratton, doctoral student Mahdi Dolatyari, Assistant Research Professor Carol Kopruszinski, PhD, Postdoctoral Research Associate Kara Barber, PhD, Associate Professor Edita Navratilova, PhD, and former graduate student Nicolas Dumaire. The research team also included collaborators from Saint Louis University, the Atria Institute of Science and Medicine, Anabios Corporation, and Peptide Logic, the latter of which is developing the monoclonal antibody against prolactin.
This study was funded in part by the National Institutes of Health under award nos. R01NS120395 and P30DA051355, and by the Department of Defense under award no. HT9425-23-1-0853.
