Does Gender Influence Pain Sensitivity?

STOWE, VT—Mounting evidence suggests that gender affects the modulation of pain to a greater extent than has been understood, according to an overview presented at the 27th Annual Headache Cooperative of New England Stowe Headache Symposium. Data indicate that the differences are biologic, and researchers are examining whether social and psychologic differences also may influence pain.

Jeffrey S. Mogil, PhD

“If biomedicine ever comes up with a treatment, reproductive issues aside, that works and gets approval for one sex and not the other for treating the same underlying condition, it is going to happen in pain first,” said Jeffrey S. Mogil, PhD, Canada Research Chair in Genetics of Pain at McGill University in Montreal. “Maybe we are only 10 or 15 years away from seeing such a thing occur.”

A Clear Gender Difference

The first investigation of gender differences in pain was published in 1997, according to Dr. Mogil. It indicated that a greater number of chronic pain syndromes were more prevalent in women, compared with those that were more prevalent in men. Furthermore, the syndromes that were more prevalent in women were more common overall. The study also estimated that approximately 70% of patients with chronic pain are women. This result, however, could follow from reluctance among men to consult a physician, said Dr. Mogil.

When Dr. Mogil reviewed epidemiologic studies of pain, he found that women were between 5% and 10% more likely than men to endorse the symptoms of chronic pain. Although the studies used different definitions of chronic pain, each study used the same definition for men and women. A possible explanation for the result is that women are more susceptible to painful diseases.

But when he examined laboratory data from controlled experiments involving painful stimuli, Dr. Mogil found that “regardless of what type of pain you are looking at, and regardless of how it is measured, women are more sensitive to pain than men.” The difference in pain sensitivity is not great and depends on various factors, but it is clear and unmistakable, he added.

Biology Influences Pain Sensitivity

Biologic differences may explain gender differences in pain sensitivity. Research during the past 20 years has suggested that microglia play an important role in nociception. Newer data, however, indicate that microglial involvement in pain may be specific to males. Because the majority of animal research had been performed in male rodents, this observation had not been made previously, said Dr. Mogil.

He and his colleagues injured male and female mice to induce mechanical allodynia. The mice exhibited the same amount of mechanical allodynia, regardless of gender. The investigators next administered minocycline, a glial inhibitor, to the mice. The intervention reversed the allodynia in male mice, but not in female mice. Using fluorocitrate or propentofylline in place of minocycline produces the same result, said Dr. Mogil. Research into the biologic basis for pain modulation in females is ongoing.

Gender, Stress, and Analgesia

A patient’s sensitivity to pain may be influenced not only by his or her gender, but also by the gender of a person that the patient encounters. The results of certain mouse studies prompted researchers to hypothesize that the experimenters themselves may have produced analgesia, and Dr. Mogil decided to test this hypothesis.

When an investigator injected zymosan, an inflammatory agent, into a mouse’s ankle and left the room, the injection caused pain and grimacing in the mouse. When a male investigator administered zymosan to a mouse and remained in the room, the rate of grimacing decreased by approximately 40%. “In fact, experimenters are causing analgesia,” said Dr. Mogil. A female investigator did not produce the same effect, however.

Further research indicated that the effect has an olfactory origin. When injured mice are exposed to clothing previously worn by a male, or to bedding previously used by any male animal, they exhibit the same reduction in pain. “This is a stress phenomenon,” said Dr. Mogil. A mouse’s level of corticosterone, an equivalent to cortisol in humans, increases after exposure to male experimenters or their clothing.

The mice appear to be responding to axillary chemosignals (eg, androstadienone and androstenone) that males emit. The most important compound may be 3-Methyl-2-hexenoic acid, because it is “the only chemosignal that can produce this effect at reasonable concentrations in the nanomolar range,” said Dr. Mogil. He and his colleagues are studying whether these chemosignals produce the same responses in humans. “I would expect the effect to be much smaller and last for not quite as long,” he said. They also are studying the social modulation of pain in animals and humans.

—Erik Greb

Suggested Reading

Berkley KJ. Sex differences in pain. Behav Brain Sci. 1997;20(3):371-380; discussion 435-513.

Mogil JS. Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon. Nat Rev Neurosci. 2012;13(12):859-866.

Sorge RE, Mapplebeck JC, Rosen S, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci. 2015;18(8):1081-1083.

Sorge RE, Martin LJ, Isbester KA, et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat Methods. 2014;11(6):629-632.