You finally got a new novel that you want to read. You are turning the crisp paper from the page when suddenly you are asked to cut the paper. Pain shot through your fingers. An unpleasant sensation spread throughout his body shouting, “Brain, we have a problem!”
An unwanted but necessary sensory experience that most living things experience is pain. It is an important component of the body’s warning system that directs attention to potential external or internal damage.
The International Association for the Study of Pain defines pain as follows: “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or the description of such damage.”
The way people perceive pain is very personal and subjective. In fact, scientists have suspected for some time now that the perception of pain can be sexually dimorphic: that is different between (biologically) men and women. But the details are a mystery.
The study, led by University of Arizona Health Sciences researchers, was recently published in the journal brain, showed for the first time sexual dimorphism of function in nociceptors, nerve cells responsible for perceiving pain.
Why do we feel pain?
Nociceptor cells have bare nerve endings and are found in the skin, bones, joints, and muscles. Receptors detect extreme pressure, temperature, and chemical signals released by the body when injured, convert these signals into electrical signals, and transmit them to the brain via the spinal cord. The brain finally reads the message and perceives pain
In a new study, researchers investigated how nociceptors first light up. “Activation of nociceptors can cause the same pain in men and women. What differs is how the nociceptors are activated.
“While nociceptors are usually activated by high-intensity stimuli, in some situations the threshold for activation can be reduced so that low-intensity and physiological stimuli usually activate and produce pain,” Frank Porreca, associate head of the Department of Pharmacology, University of Arizona Health Sciences Center, told this author in email.
Nociceptor response threshold
Previous studies have reported that the nociceptor response threshold in women is lower than in men. One of the biological mechanisms underlying this difference could be peripheral nociceptor sensitization: a phenomenon where the pain threshold is lowered by external factors, causing receptors to respond to stimuli that will not be rejected. But researchers still need to understand how this variation in sensitization arises.
To understand the sexual dimorphism in the sensitization of nociceptors, the research team investigated how easily pain receptors in the dorsal root ganglion – a group of nerve cells located near the spinal cord – can be excited. They collected samples from three male and female mice, two macaque monkeys (one of each sex), and donor nerve cells from four males and three females.
Laboratory Dr. Porecca has explored the relationship between sleep and chronic pain. In an April 2022 study, the team found that prolactin, the hormone responsible for breast tissue growth, also selectively increased the pain response in female mice. Later, researchers discovered that the receptor for prolactin is overexpressed in female-specific pain disorders such as endometriosis.
Studies of sleep and chronic pain have also shown that orexin B, a neurotransmitter that regulates wakefulness, produces sensitization in male but not female rats.
‘Differential sensitivity’
In a recent study, researchers studied how prolactin and orexin-B affect the threshold of nociceptor activation in nerve cell samples obtained. They cultured nerve cells overnight in the presence of mouse prolactin for mice and human prolactin for monkey and human samples. For orexin-B, they applied the neurotransmitter to cultured nerve cells of all three species.
In a cohort of mice, techniques to separate and identify proteins revealed that prolactin has increased the firing of nociceptors in females and orexin-B has done the same thing in males. Immunohistochemical analysis of monkeys and humans also showed similar effects.
The team’s observations here are consistent with older findings. “Our paper shows that the nociceptors of male and female animals or humans can be differentially ‘sensitized’, ie have a lower activation threshold,” Dr. Porecca, the corresponding author of this study, said.
The devil is different
When doctors prescribe drugs for pain relief, they usually do not take the patient’s gender into account. In fact, apart from female-specific hormonal therapy, health workers generally treat pain in the same way between men and women – although we also know that the degree of pain conditions varies between the sexes.
For example, pain arising from conditions unrelated to visible tissue damage, such as irritable bowel syndrome, migraines, and painful bladder syndrome, is more common in women along with female-specific problems such as endometriosis and dysmenorrhea.
On the other hand, cluster headaches and gout are more common in men, along with male-specific diseases like prostatitis.
Unraveling the different mechanisms that drive sensitization and nociceptor activation will bring us closer to understanding qualitative gender differences in pain perception, which is also important for designing precise and specific pain therapies.
“We study different species because we know some data in rodents and human cells from the differential expression of transcripts for proteins, and we do not know if this can translate into functional differences in sensitization/activation,” said Dr. Porecca.
Nociceptors can be male or female
Dr. Porecca says that this mechanism is widespread among species suggesting that it is evolutionarily relevant.
Moreover, the ability to interfere with the activation or sensitization of these mechanisms has the potential to be exploited for the development of targeted therapeutics.
The study presented a unique concept: nociceptors are male or female. The researchers expect their findings to have two implications for medical research.
First, it will encourage medical practitioners to determine the type of patient when making decisions about pain therapy.
Second, if in clinical trials of therapies with new pain treatment mechanisms, researchers should be more careful about the number of men and women in the trial in order to be warned about effects that occur only in one sex.
Dr. Porecca also said it was time to re-examine some of the ‘failed’ clinical trials to check if there were sex-specific effects for the drug.
Sanjukta Mondal is a chemist turned science writer with experience writing popular science articles and scripts for the STEM YouTube channel.
