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One Gene Makes Me Painfully Sensitive to Rejection. Now What?

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Lisa Cantrell, ready for a run at San Francisco's Dolores Park. (Lauren Hanussak/KQED)

Originally published on Sept 27, 2018

A few months ago, I ordered a home genetic testing kit. I didn’t do it because I wanted to know about my ancestry. I did it because I’d heard about a genetic variation that can make people more sensitive to rejection — and I was convinced I had it.

I have always been a bit overly sensitive. I remember a particularly devastating moment in fourth grade. Ms. Brown had asked a question I knew the answer to. I raised my hand, stretching my whole body up so she would notice. She made eye contact with me, commented that I had already gotten to answer a question that day, and then called on a student behind me.

I could feel my face flush with embarrassment. A knot started to form in my throat as, almost in a whisper, I asked to be excused, the tears welling up in my eyes. Once I was safe behind the bathroom door, I used my shirt to muffle the sounds of my crying. Simply because the teacher hadn’t called on me.

A few years later in middle school, my friend Jennifer slipped a note into my locker saying that she wanted to play with another kid at recess, not me. That night — and for many nights after — I lay curled up in my bed for hours, the note on my nightstand.


As I got older, it got worse. The emotional pain I experienced in social situations changed how I felt about myself and how I behaved with other people. As an adult, if a friend didn’t respond to a text, I would pull away and avoid them. When someone I barely knew ghosted me, I convinced myself that I wasn’t desirable to anyone.

Friends told me I was overreacting. Sure, everyone feels a little hurt by these things, but to become so debilitated each time was a bit over the top, they told me. Finally, in my late 20s, I started to wonder if maybe there was something wrong with me.

Is Oversensitivity Biological?

In 2009, a ground-breaking study investigated the link between emotional sensitivity and our genetics. Scientists already knew that a particular gene, the OPRM1 gene, could influence our sensitivity to physical pain. Previous studies had shown that people with a G allele on this gene required higher doses of morphine to curb pain, suggesting they experience pain more intensely than others. Because physical pain and emotional pain are processed in similar regions of the brain, researchers wondered if G-allele carriers might also experience more intense emotional pain.

To test the question, neuroscientists at the University of California Los Angeles recruited 122 people, 49 of whom were G-carriers, the rest of whom were not. Participants came into the lab and played a computer game intended to evoke feelings of rejection. In the game, each participant would toss a ball back and forth to two other virtual players on a screen. The two players would, at some point, exclude the participant. Meanwhile, the participant lay in a functional magnetic resonance imaging (fMRI) brain scanner that measured blood flow to the pain regions of the brain.

Brain scan showing yellow dots
fMRI scan of brain showing activation of pain regions (including the dorsal anterior cingulate cortex). The image comes from a study in which participants played “Cyberball” while lying in the fMRI scanner—a game designed to induce feelings of rejection. (Baldwin Way)

“What the researchers found was that there was an exaggerated response [in G carriers],” says Jon-Kar Zubieta, a psychiatric researcher at the University of Utah. “Individuals who were G-allele carriers had greater responses to the negative emotional challenge, which was associated with greater activation of the anterior cingulate cortex,” a pain region of the brain.

I had called up Zubieta to get his take on the research for this story — but my questions were also personally motivated.

“G-carriers seem to have less capacity to compensate for negative emotion,” he told me. And it doesn’t matter whether that negative emotion is in response to physical pain or the social pain of rejection, like what study participants experienced during the ball-tossing game.

Zubieta also told me that G-carriers — who make up 15 to 20 percent of the general population — not only feel more hurt in everyday social interactions, “these individuals have traits that make them more prone to developing conditions such as depression and anxiety.”

A man speaks in front of a white board.
Jon-Kar Zubieta, Chairman of the Department of Psychiatry and Psychiatrist-in-Chief of the University of Utah Neuropsychiatric Institute. (University of Utah Health)

Listening to Zubieta recount such findings, I found myself nodding my head. All of it resonated with me. I have long struggled with bouts of depression; my relationships are typically a roller coaster of anxieties. If I were a G-carrier, it could explain so much of what I was experiencing.

Why Do G-Carriers Feel More Pain?

When the genetic kit finally arrived at my house, I opened it and pulled out the clear test tube. I collected my saliva, sealed it back up, and shipped it off to the lab to be tested.

In the weeks I spent waiting for my results, I looked up more research on how the OPRM1 gene could lead to a heightened sense of pain.

As it turns out, the gene controls the number of opioid receptors in the brain. In a typical brain, when a person is experiencing pain, neurons fire in regions such as the anterior cingulate cortex. In response, the body releases endorphins — our natural pain killers. The endorphins rush into the brain and attach to neuron receptors, inhibiting those cells from firing, effectively stopping the pain signal. This process is actually what happens during the “runner’s high,” and the same process occurs for most people when they experience the pain of rejection.

However, if a person doesn’t have enough opioid receptors or doesn’t release a sufficient amount of endorphins, they could experience more suffering than others. Zubieta says this is likely what happens to G-carriers; they appear to have fewer receptors in critical areas of the brain and, he adds, “they may have less capacity to release natural opioids in general.” This means, Zubieta says, that G-carriers “have less capacity to suppress responses to pain.”

So … Am I A G-Carrier?

Several weeks after shipping off my saliva, I was at home when an email popped up in my inbox; my results had come in. My stomach dropped and I sat staring at the unopened email for a few minutes.

What would it mean if I were a G-carrier? It would feel validating, of course. For so long I had felt like I was emotionally weak. If I were a G-carrier then it would mean there was a biological explanation for my feelings. It would mean that I hadn’t been overreacting all these years; rather, I had been reacting proportionally to the pain I was feeling — pain that 80 to 85 percent of the population simply doesn’t feel.

On the other hand, if I weren’t a G-carrier, I wasn’t sure where that would leave me. I could feel my heart beating faster. My hands shook slightly as I struggled to steady my breathing.

I opened the email and scrolled through lines of the genetic code until I found the OPRM1 gene on chromosome 6. Typed in small font was a “G.”

Lisa Cantrell stretches prior to running at Dolores Park in San Francisco, Calif., on Monday, June 11, 2018. (Lauren Hanussak/KQED)

What Now?

So am I stuck with unbearable pain forever? A prisoner to my genetics? On the phone with Zubieta, I ask him if a G-carrier like me could do anything about it.

“You have to remember that the opioid system becomes active when there are things like exercise or stressors,” so when you do physically demanding sports or activities that in some way cause pain “you are training the system.” In other words, Zubieta says, you can modify your brain’s response.

The advice makes sense. Exercise not only releases endorphins that decrease pain in the moment, regularly challenging your body with physical activity can strengthen the overall functioning of the opioid system, potentially prompting your brain to create new receptors and urging your body to increase the amount of endorphins released each time you experience a stressor.

All of this could make the system more optimal, more prepared to kick into full gear when it encounters pain, be it physical or emotional. Interestingly, chocolate and laughter may also help — they bump up endorphin release, which could alleviate pain in the moment as well as have longer term effects.

Zubieta continued with his suggestions. “So you could do yoga… or run marathons.” Something physically demanding, he says.

“I’m not sure about a marathon,” I laugh.

But the idea stuck with me as I hung up the phone.

I do envision a life for myself someday in which I have slightly thicker skin — a life in which I don’t cry because a friend forgets to return my text. So, after a few days of mulling it over, I decide to take Zubieta’s advice.


For the past two months I have been on a strict running schedule, gradually increasing my miles, preparing for a half marathon I’m signed up to run next month. Is the physical training helping me tame my emotions? It’s hard to say. I have definitely experienced moments of rejection over the last few weeks that I feel have been easier to deal with. But it’s hard to know if the marathon training is the cause of my increased ability to cope, or if it’s just the power of having a label. Maybe just knowing I’m a G-carrier — knowing that my pain might be more intense than others — is what I have needed all along. My own self-awareness might just be the first real step in changing how I react to the world.

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