The science that changed how we study pain
From sex differences to the facial cues of mice, Dr. Jeffrey Mogil’s work transformed how researchers understand and measure pain.

Some of Dr. Jeffrey Mogil’s most influential discoveries could be considered serendipity. He may not have set out to revolutionize the field, but what he ended up finding has made a lasting impact in the world of pain research.

Dr. Mogil is a pain researcher and professor at McGill University, and his CIHR-supported work uncovered two big blind spots: the research had focused almost entirely on male pain and mostly measured one type of pain—and not the type that makes the biggest difference for patients.

As a graduate student, Dr. Mogil happened to be using both male and female mice. At the time, researchers primarily used male mice or rats, but to save money, the head of the lab Dr. Mogil worked in bred his own mice, resulting in litters that included both sexes. Dr. Mogil noted that the drug he was testing had a moderate effect overall, but when he analyzed the data by sex, he found it had a complete effect in male mice and no effect in female mice. He reported this difference, but his finding was largely ignored by the pain research community. Over time and in new studies, however, Dr. Mogil kept finding more differences between the sexes.

“I would be publishing these things periodically—this neurotransmitter is involved in males and not females and that gene is involved in females but not males,” he says. “People thought it was interesting, but I think it was dismissed by most as flukes.”

That changed in 2014 when Dr. Mogil and his colleagues published a study that proved pain biology is very different in males and females. The research showed that microglia (immune cells in the spinal cord) drive pain only in male mice while T cells drive pain in female mice—two completely different mechanisms in the body. For several years pain research operated on the premise that microglia drove pain. “We came along and said this is absolutely true in male mice and absolutely false in female mice,” recounts Dr. Mogil. “What we all thought was pain biology was male pain biology, so really only pain in men.”

This discovery helped back policies requiring researchers to use both sexes of animals in research, a practice that has since grown significantly in preclinical research. What also grew were the number of pain researchers actively looking for sex differences. “Today, this is a big subfield of pain research,” he says.

Dr. Mogil’s other research breakthrough is the Mouse Grimace Scale. His research found that mice experience empathy for pain through sight. This got him thinking: Could researchers also see pain on a mouse’s face? He collaborated with experts in infant pain to create the scale that helps a researcher gauge the level of pain a mouse is experiencing by looking at its face.

This scale, and one for rats that Dr. Mogil and his colleagues also created, were among the first tools to measure spontaneous pain in mice and rats. Spontaneous pain is pain that comes from within the body. Most previous research was measuring a type of pain called evoked hypersensitivity—pain caused by having to ‘do’ something to the research subject, such as poking. However, spontaneous pain is the main source of pain for patients. This means that a pain treatment, such as a drug, that comes from research based on evoked hypersensitivity may not be as effective as when research uses spontaneous pain as its starting point.

“The biology of evoked hypersensitivity is not the same as the biology of spontaneous pain,” Dr. Mogil says. The Mouse Grimace Scale offers a path to developing treatments that better reflect patient pain.

Together, Dr. Mogil’s discoveries show how complex and diverse pain research is and how important it is for researchers to pay attention to factors that have a real impact on patients. “The way you approach your pain research in order to come to conclusions that are valid for different populations or across populations, matters.”