Male and Female Mammals Have Different Pain Receptors And We Don’t Know Why

Male and Female Mammals Have Different Pain Receptors And We Don’t Know Why

When men and women in heterosexual relationships complain their partners do not understand their pain, they might be right. A study of pain receptors in rodents and primates has found that in every case, male and female members of the species are primed by different molecules. 

Physical pain, be it excruciating or merely unpleasant, may not be experienced the same way. Besides raising deep evolutionary questions, the finding indicates we may need to drastically adjust many diagnoses and treatment processes, particularly, but not exclusively, for females.

Evolution can be quite conservative when it comes to sexual dimorphism, minimizing differences unless there is a benefit for survival or reproduction. It’s probably the reason males have nipples – they may not be useful, but it would take more work to make the sexes different in that way than the same.

That doesn’t mean everything will be identical, but as the male nipple example reveals, it’s easier to differentiate by degree rather than develop a whole new model. Consequently, differences in males’ and females’ experiences of pain were thought to reflect variations on a theme. When it was found that microglia transmit pain among male mice, but not females, the results astonished even the researchers involved.

Now it seems it is not just the way pain is transmitted that differs by sex, but the receptors themselves, known as nociceptors,  are sensitized by different hormones. Moreover, this time it has been demonstrated in macaque monkeys and humans, as well as in mice. 

“Our data support the remarkable conclusion that nociceptors from multiple species, including humans, can be functionally classified as male or female,” a team led by Dr Frank Porreca of the University of Arizona report.

Specifically, the hormone prolactin sensitizes dorsal root ganglion neurons (clusters of neurons in the spine) in females of all three species, but not in males, turning mild pain into something much more debilitating. On the other hand, the neurotransmitter orexin B performs a similar sensitization role in males, but not females.

The team studied neurons in vitro from human organ donors and animals. Only one macaque of each sex was used, because the neurons could only be used after death, but the samples of humans and mice were large enough that the team are confident in their findings.

Other pain-sensing neurons were found to show stronger sensitization to the same hormones in one sex, without a complete absence in the other.

“Until now, the assumption has been that the driving mechanisms that produce pain are the same in men and women,” Porreca said in a statement. “What we found is that the basic, underlying mechanisms that result in the perception of pain are different in male and female mice, in male and female nonhuman primates, and in male and female humans.”

The evolutionary basis for this, as well as the mechanisms, remain mysterious. Prolactin is the hormone that triggers the development of breast tissue and lactation, so it is not quite so surprising its influence on pain is restricted to females. 

However, orexin B helps keep all of us awake – there’s no obvious reason why it should produce different responses by sex. Both hormones do, however, also have other roles in the body that have been overlooked until recently.

However, the implications for medicine are more obvious. As Porcerra and co-authors note; “Patient sex is currently not a common consideration for the choice of pain therapy. Precision medicine, based on patient sex could improve therapeutic outcomes by selectively targeting mechanisms promoting pain in women or men.” 

For example, drugs that prevent the sensitization of the relevant neurons should work as pain relievers, but only in one sex. Porreca recently helped discover a prolactin antibody, so the quest for such a drug may have a big head start.

They also note that clinical trials with skewed sex ratios among the participants need to be treated with care, rather than considered to apply to everyone.

The researchers were not looking for this finding when they found it, instead investigating the connection between chronic pain and sleep.

“Conceptually, this paper is a big advance in our understanding of how pain may be produced in males and females,” Porreca said. “The outcomes of our study were strikingly consistent and support the remarkable conclusion that nociceptors, the fundamental building blocks of pain, are different in males and females. This provides an opportunity to treat pain specifically and potentially better in men or women, and that’s what we’re trying to do.”

There are probably bigger reasons why painful conditions that primarily or exclusively affect females, such as migraines, fibromyalgia, and endometriosis, have been underplayed by the medical establishment. Nevertheless, this work shows how much needs to be done, particularly since the authors note that “[r]ecent advances in our understanding of preclinical pain neurobiology have generally failed to translate to improved treatment of pain in patients.”

The study is published in Brain.

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