Fascinating research from Nature dot Com delving into the depths of pain differences between the sex’s and whilst it doesn’t specifically talk of Intersex ( a third sex) it does draw on differences in female sex which can also be seen with intersex variations, particularly so of XXY, such as lessened or absent Testosterone receptors as well as the primary sex defining hormones response to pain, in this context the emphasis appears to be on endogenous PSDH which might then seem to indicate that given our 2 x X chromosomes that we would display a similar pain threshold to biological females.
If animals can switch between pain pathways, what controls the switch? Researchers have long attributed sex differences in pain perception to oestrogen, a hormone that controls the development of the uterus, ovaries and breasts, and which regulates the menstrual cycle. Oestrogen can either exacerbate or dull pain, depending on its concentration and location. Testosterone, the hormone involved in development of the penis, testes and prostate, as well as of secondary characteristics such as body hair, has received much less attention from pain researchers, although studies suggest it can reduce pain3, and some people with chronic pain take testosterone treatments4.
In the case of microglia and pain hypersensitivity, Mogil’s research points squarely at testosterone as the control switch for pain pathways. In the 2011 and 2015 studies1,2, when Sorge tested castrated male mice, which have low testosterone levels, the animals exhibited a response similar to females. And when the researchers provided testosterone to castrated males, or to females, the pain pathway switched to one dependent on microglia.
Since then, researchers have continued to find evidence shoring up the importance of microglia — and the cells’ enzymes and receptors — in male mice experiencing pain. And the phenomenon isn’t restricted to mice: one of Mogil’s collaborators, neuroscientist Michael Salter, also found microglial receptors at work in male rats that had hypersensitivity from nerve injury5. Salter, who is chief of research at the Hospital for Sick Children in Toronto, Canada, is now investigating the question in macaques, which are likely to process pain in a more similar way to humans.
It’s much harder to investigate these pain pathways in people, but clues are emerging. Neuropharmacologist Ted Price, at the University of Texas at Dallas, and his collaborators have found preliminary evidence, published this month6, of differences in how immune cells contribute to pain in people.
They’re working with nerve tissue removed from individuals with cancer, whose tumours had invaded their spines. In nerves excised from men experiencing pain, Price’s team found signs of inflammation caused by an immune cell called a macrophage. These cells serve a similar function to microglia. In women who were in pain, however, the more important players seemed to be nerve cells themselves and a short stretch of protein building blocks (called a peptide) that stimulates nerve growth. The results suggest parallels between human and rodent sex differences, says Price.
But immune cells and hormones don’t fully explain pain differences. For instance, Sarah Linnstaedt, a translational biologist at the University of North Carolina Medical Center in Chapel Hill, has found hints that some women might have a genetic predisposition to chronic pain. Her team has identified a suite of RNA molecules in the bloodstream that are more likely to be elevated in women who develop chronic neck, shoulder or back pain after a motor-vehicle accident. Many of these RNA molecules are encoded by genes on the X chromosome, of which there are two copies in most women7.
That’s useful information, says Linnstaedt. “It will enable us to develop new therapeutics that can either be used specifically in women, or at higher doses in women.”