The hormone prolactin is known for and named after its role in breastfeeding. But that is far from its only role.

There are more than 300 identified functions of prolactin, which is present in both men and women, though women have higher levels, and extremely high levels late in pregnancy and during breastfeeding.

Now, scientists at the University of Arizona have identified another function of prolactin signaling. In the Feb. 5, 2020, issue of Science Translational Medicine, they reported one form of the prolactin receptor sensitized pain receptors, and played a role in the induction of hyperalgesia by opioids, in female but not male mice.

Scientifically, corresponding author Frank Porreca told BioWorld, the work identified “a mechanism that may help to explain why women have more pain syndromes than men,” while on the practical side it could lead to ways to improve the treatment of pain in women.

Porreca is associate department head of pharmacology and a professor of anesthesiology, cancer biology, pharmacology and neuroscience at the University of Arizona College of Medicine in Tucson.

His lab’s overarching goal is “to understand the circuits that are associated with pain, and in particular, we have been trying to understand… functional pain syndromes,” he said.

The positive, though not pleasant, aspect of pain is that it signals tissue injury – the body’s warning system that it’s time for a change.

Pain syndromes, though, are just the bad parts. “There is a large percentage of patients that suffer from pain that don’t actually have any injuries,” Porreca said. Such pain is referred to as functional (perhaps ironically, since it is certainly not serving pain’s regular function).

Common functional pain syndromes include migraine, irritable bowel syndrome and fibromyalgia.

Such syndromes have a gender imbalance. “Being female is a risk factor… and why that is has never been fully understood,” Porreca said.

But functional pain conditions are associated with stress, which can precipitate episodes of pain, and stress triggers the release of prolactin, prompting Porreca and his team to take a look at a possible link between the two.

The researchers studied opioid-induced hyperalgesia, a paradoxical functional pain syndrome that can occur as a result of both drug abuse and pain medication. Because they were interested specifically in functional pain syndromes, they compared mice with opioid-induced hyperalgesia to a group of animals with neuropathy, that is, pain that resulted from nerve damage.

Unexpectedly, they found that opioids affected the balance of two different forms of prolactin receptor, the long and the short form.

The signaling of prolactin at its receptor is “kind of complicated,” Porreca said. There is one gene for the prolactin receptor, but due to alternative splicing, that gene produces two protein chains, a long and a short chain.

For a receptor to form, two long or two short chains must combine to form what’s called a homodimer.

Heterodimers, made of one long and one short chain, don’t signal, and the two homodimers have different functions.

Signaling at the short form promotes pain by sensitizing pain receptors (nociceptors) in the spinal cord, while long form homodimers lead to transcriptional changes.

“The balance of the long and the short form determines how readily the [pain] fibers can be activated,” Porreca explained. And in the work now published in Science Translational Medicine, they showed that opioids down-regulated the production of long form prolactin receptors in female mice.

In follow-up work, the team showed that CRISPR editing of the prolactin receptor also influenced pain perception in the animals. Mice lacking long form prolactin were more sensitive to pain than those missing the short form, or both forms.

“The idea that we would selectively regulate expression of isoforms with opioids… was completely surprising,” Porreca said. “It identifies a mechanism that shows a difference in the fibers that transmit the pain signal.”

Porreca’s lab has also been studying central pain circuits in the amygdala. The researchers plan to look at possibly mechanistic links between the effects of prolactin on nociceptors in the spinal cord, as well as exactly how stress promotes the changes that can lead to hyperalgesia.

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