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A painful experience is not one you are likely to forget—you don’t need to a trunk slammed onto your finger multiple times to realize that it’s a situation you’d like to avoid. According to a study published Thursday (January 10) in Current Biology, one painful ordeal in a particular setting is enough to make pain less tolerable in that same place in the future—but only if you’re male.

A growing body of evidence suggests a close link between pain and memory. For example, scientists have found that the molecular mechanisms underlying the two processes in the neurons of the spinal cord and brain share striking similarities. And in rodents, scientists have used drugs that manipulate memory-like processes in the spinal cord to reduce persistent pain. “The idea that chronic pain is an issue of memory is increasingly gaining traction,” says Jeffrey Mogil, a neuroscientist at McGill University and a coauthor of the new study.

At the same time, researchers have struggled to demonstrate Pavlovian (classical) conditioning of pain, that is, if you feel pain in the same location where you’ve been in pain before, it should feel more agonizing, Mogil says. “But it turns out that’s not a common finding at all—there’s only a few studies in humans and almost none in animals.”

The reason for the absence of Pavlovian pain memory might be study design, rather than biology. Mogil and his colleagues now developed an experiment that demonstrated this effect, although they stumbled on it by accident. While working on another study looking at the social effects of pain, they discovered that injecting a diluted solution of acetic acid into the bellies of mice—a procedure that causes temporary stomach pain—immediately increased their sensitivity to thermal pain. Twenty-four hours later, the effect remained.

The field has completely ignored the study of females for decades, and only now are people starting to switch. —Jeffrey Mogil, McGill University

This finding made Mogil and his team wonder whether that the hypersensitivity was due to classical conditioning. To test this theory, they tried placing mice in a different room a day after the acetic acid injection and discovered that the pain hypersensitivity did not occur.

The researchers subsequently conducted a larger study with more mice. This revealed a fascinating finding: only males were more sensitive to heat pain on day two, and only in the same cage where they received the injection. Heat tolerance in female mice did not change after the injection.

To see whether humans had the same experience, the team recruited 79 people and repeated the experiments using the so-called ischemic tourniquet test, in which a blood pressure cuff is squeezed tightly around a participant’s arm and the resultant loss of blood supply causes pain. (This procedure is safe, but according to Mogil, “it hurts like hell.”) Again, they found that just the men showed a heighted response to heat pain the next day—and only in the room where they previously took part in the agonizing task. In a different room, men’s tolerance for heat pain remained unchanged after the tourniquet test. Women rated heat pain similarly on both testing days, and in both locations.

Closer examinations revealed that, at least in mice, the context-dependent pain hypersensitivity was dependent on testosterone. The pain memories disappeared in castrated male rodents, and it emerged in ovariectomized female animals infused with testosterone.

The team also found that stress was crucial for this effect. Blocking the synthesis of corticosterone—a key hormone in the hypothalamic-pituitary-adrenal (HPA) stress axis—prevented the hypersensitivity from occurring in mice. And in men, the researchers found a correlation between stress levels in the second test session and the increase in pain rating from day one to day two.

Anne Murphy, a neuroscientist at Georgia State University who did not take part in the work, says she was surprised that the researchers only found this effect in males. “I would really like to see this in a clinically relevant situation,” Murphy adds. “For example, if you know you’re going into repeated surgery, is the pain experienced by the second surgery more intense than the first one?”

Several important questions remain, such as what effect the testosterone is having on the pain-related stress—for now, the study has only shown that both testosterone and stress response are required to produce pain memories. But for Mogil, the most important takeaway from this study is that these findings “reinforce the fact that sex differences are important in pain, and females deserve to be studied,” he says. “The field has completely ignored the study of females for decades, and only now are people starting to switch.”

Theodore Price, a neuroscientist at the University of Texas at Dallas who wasn’t involved in this research but has collaborated with some of the study’s authors in the past, agrees. “We’ve been learning a lot about sexual dimorphism in pain mechanisms from mouse studies. . . . This is the first example that I’m aware of where you can draw a direct line from a mouse study to a human study where the same sexual dimorphic result was observed,” Price says. “I think it’s a bit unfortunate that yet again we’ve discovered something that’s male-specific—the mystery of how pain plasticity is driven in females is still an open, extremely important, question.”

L. Martin et al, “Male-specific conditioned pain hypersensitivity in mice and humans,” Curr Biol, doi:10.1016/j.cub.2018.11.030, 2019.