When you bite into a spicy chili pepper, a sharp, burning sensation fills your mouth. For some, this sensation is a mild kick; for others, it’s an intense fire. The difference isn’t just due to personal tolerance but also stems from biological factors like sex and hormones. Similarly, the experience of pain varies between males and females, influenced by hormonal fluctuations across reproductive cycles. In mammals like humans and rodents, this creates a complex picture of how different sexes uniquely experience pain due to varying biological factors.
Sara Luz Morales-Lázaro, a professor at Universidad Nacional Autónoma de México (National Autonomous University of Mexico), has been interested in the molecular mechanisms behind pain generation. More specifically, her research team studies the interaction of sex hormones and receptors that participate in pain signaling and the sexual dimorphism of pain. “I’m interested in understanding why men and women experience pain differently by looking at the varying experiences of the burning sensation after eating something spicy like chili peppers,” Morales-Lázaro said.
Morales-Lázaro’s research team honed in on a specific chemical compound for their recent project: capsaicin. Found in all chili peppers, ranging from jalapeños to habaneros, this chemical compound is responsible for causing a burning sensation when in contact with pain receptors in the mouth. By examining the responses to capsaicin in different hormonal stages, her research team can determine how pain sensitivity changes based on varying biological factors like sex.
Capsaicin triggers a burning sensation by binding to a specific protein known as Transient Receptor Potential Vanilloid 1 (TRPV1) in certain nerve cells specialized for sensing and transmitting pain. This interaction causes the familiar burning feeling we experience when eating spicy foods. Morales-Lázaro’s research team closely examined how capsaicin interacts with TRPV1, discovering that a larger presence of the protein in nerve cells amplifies sensitivity to the burning sensation. This led the research team to consider how hormonal fluctuations could influence protein levels, potentially explaining the differences in pain sensitivity between men and women. “For example, the regulation of the transcription of this protein could be affected by sexual hormones like estrogen,” Morales-Lázaro said.
Specifically, Morales-Lázaro and her team compared male mice to female mice in different stages of their estrous cycle. During the estrous cycle, female mice have different sex steroid hormones present in varying concentrations. During one part of the cycle known as the proestrus phase, estrogen is present in high levels. Hormones like estrogen have the potential to regulate proteins in multiple ways; Morales-Lázaro and her team performed multiple experiments to demonstrate whether differing hormone levels affected the pain perception of capsaicin and the regulation or function of its receptor, TRPV1.
In the behavioral part of the experiment, the researchers injected the paws of male and female mice with capsaicin and evaluated their acute pain response, known as a nociceptive response, by observing how often the mice licked their paws. “Mice spend time licking their paws since that is where they perceive pain. This is how we evaluated acute pain resulting from capsaicin,” Morales-Lázaro said. They discovered that female mice had a greater nociceptive response when injected with capsaicin during their proestrus phase than when they were in other phases of their estrous cycle. This pain response during the proestrus phase was also greater than the response for male mice; responses for male and female mice were similar when they were in other parts of their estrous cycle.
Further support for the idea that estrogen affects the pain response comes from the fact that ovariectomized rats, or rats who make less estrogen due to the removal of their ovaries, respond less to capsaicin, but their response returns when they are given estrogenic replacement. Similar dimorphism in response to pain, according to the researchers, has also been found in humans via observation of physiological responses, thereby indicating a possibility for across-species sexual differences in pain perception that are specifically regulated by the female hormonal cycle.
For the second stage of their investigation, the researchers sought to determine the specific molecular mechanism behind the apparent relationship between sex hormones and pain tolerance. They found differences in the regulation of TRPV1 gene expression during different phases of the estrous cycle, supporting the idea that sex hormones affect how TRPV1 is expressed. “Since these phases involve varying levels of estrogen and progesterone, we compared the pain responses to capsaicin between males and females in the different stages of the estrous cycle,” Morales-Lázaro said. In addition, they found differences in the amount of TRPV1 protein present in neurons from specific nervous system regions. Higher levels of the TRPV1 protein were found in female mice during the proestrus phase than in other phases of their cycle; this fits with the above results since more receptors can allow for a greater effect of capsaicin.
Additionally, the researchers artificially mimicked the conditions of proestrus and other phases in the estrous cycle by culturing neurons with various levels of 17β-estradiol, a hormone abundant during proestrus. They found that the amplitude of the pain response was the same, but faster response times were seen with the neurons that mimicked proestrus. This again supports the behavioral observations, indicating that female mice in the proestrus phase of their estrous cycle would feel the pain produced from capsaicin faster.
These results present exciting future targets of research into sex hormones, pain perception, and the sexual dimorphism of pain. They might even help to explain why women experience certain painful conditions such as orofacial pain and migraines at higher rates than men. However, further research is needed to see if the same hormonal patterns can be replicated in humans. This research also only explored acute pain. Chronic pain engages a different system within the brain and thus would need to be studied with a different method.
According to the research team, the results of this project led to more questions rather than answers. “The molecular mechanism behind the interaction between capsaicin and the hormone-regulated receptor protein is still unknown, and we want to try to continue to demystify this pain pathway. Additionally, hormones like estrogen could also regulate gene transcription of other proteins, alongside the receptor protein,” Morales-Lázaro said.
Based on their work, the research team has since broadened their focus to explore how hormonal fluctuations might regulate other gene transcription factors. At the same time, they have continued investigating the connection between capsaicin, pain signaling, and the influence of hormonal changes on these biological pathways.
Morales-Lázaro’s research highlights the complex relationship between biological factors—such as sex, hormones, and chemical compounds like capsaicin—and the experience of pain. By examining how capsaicin interacts with specific proteins and how hormonal fluctuations may regulate these pain-signaling pathways, the team has opened a new avenue for understanding the molecular differences in pain sensitivity based on sex. Continued research in this area could not only enhance our understanding of pain mechanisms but also inform more personalized approaches to pain management, potentially benefiting those who experience pain more intensely.