Morphine and Social Rejection

Overly sensitive? It may be partly genetic

by Andrew Hellman, Stanford University

September 4, 2009

A single DNA difference
may make some people
more sensitive
to rejection.

Anybody who has been picked last for a team or turned down for a date knows that it can hurt. But some people are more sensitive to rejection than others. One person may laugh it off while another may be devastated.

A new study suggests that part of the reason may be due to a person’s genes. Less sensitive people tend to have one version of the mu-opioid receptor gene (OPRM1). More sensitive people tend to have a different version.

At first it might seem odd that this gene turned up in this study. OPRM1 is involved in how people react to the pain killer morphine. People with the “sensitive to rejection” version of OPRM1 need more morphine to dull physical pain than people with the other version.

This result makes sense in light of some previous animal studies that showed that morphine can dull the effects of social rejection. In many species, young animals send out distress calls when separated from their parents. When the young animals are given a little bit of morphine (but not enough to make them drowsy), they don’t cry out as much. Morphine seems to dull the effects of the rejection just like it does for physical pain.

Of course, the body doesn’t naturally produce morphine. Instead, it makes endorphins that do something similar. So maybe being less sensitive to endorphins (and morphine) makes someone more sensitive to social rejection.

The idea is that these endorphins lessen the pain that comes with rejection. And people with the “sensitive to rejection” version of the OPRM1 gene don’t respond as well to these natural endorphins. Thus, they may experience more pain when turned down or left out.

The study suggests that our genes contribute to how we handle social rejection. It also suggests that the same molecules, like the mu-opioid receptor, are involved in both insult and injury.

How Sensitive Are You?

The researchers in this study set out to sort people into “sensitive to rejection” and “less sensitive to rejection” groups. To make things simpler, these groups will be referred to as “sensitive” and “less sensitive” from here on out.

First, the researchers had 122 people fill out a survey. The answers from that survey allowed scientists to measure how sensitive each person was to social rejection.

Then the researchers compared the DNA between the groups and looked for something that was more common in one group than the other. They focused on the OPRM1 gene.

The two most common versions of this gene have one small difference. People who need more morphine for pain have the “G” version, while other people have the “A” version.

It turned out that people with two copies of the “G” version (G/G) were more sensitive to social rejection than people with two copies of the “A” version (A/A). And people with one copy of each version (G/A) were in between—more sensitive than A/A but less sensitive than G/G*.

Based on what people said about their own sensitivity to social rejection, it appeared that the OPRM1 gene was involved in dealing with social rejection. And the “G” version, which makes a person need more morphine for dealing with pain, also makes them more sensitive to rejection.

But self-reporting isn’t always the most reliable way to collect data. Sometimes people aren’t quite sure what a question means or have a skewed view of themselves. So scientists took the study a step further and looked directly at the subjects’ brains.

* Remember that everybody has two copies of each gene, one from mom and one from dad.

Rejection and Brain Activity

Scientists compared the brain activities of the sensitive and less sensitive groups using a functional MRI (fMRI) machine. An fMRI is like a live X-ray machine that measures brain activity.

Scientists didn’t want to have to search through the entire brain. Instead, they focused on regions of the brain that normally respond to social and physical pain.

While scientists watched a person’s brain, they had him or her play a ball-tossing game on a computer. Participants were told that they were playing with two other people via the internet. In reality, they were playing with a computer program that would eventually not toss them the ball. The idea was to make them feel rejected.

Scientists found that people with a “G” version of the OPRM1 gene had higher activity in the pain region than those with an “A” version when they were rejected. In this case, higher activity means more pain. So people with a “G” version were more sensitive to being rejected in a social situation.

These experiments suggest that the OPRM1 gene version that a person has affects how sensitive that person is to social rejection. So, physical and social pain may be using the same molecules to tell the body that something is wrong. And the sequence of OPRM1 may affect how sensitive a person is to that pain.

What is really interesting is that scientists have a pretty good handle on why this DNA change affects a person’s pain (and presumably social rejection) reaction. Basically, the DNA difference causes less of a receptor to be made. That means that morphine and endorphins have less of an effect.

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Different DNA, Less MOR

Genes contain the instructions for making proteins. And proteins do specific jobs in our body.

The OPRM1 gene has the instructions for making a protein called the mu-opioid receptor, or MOR. Morphine relieves pain by binding to this protein.

The “G” and the “A’” versions of the OPRM1 gene have slightly different instructions. In fact, the G actually refers to a single letter change in the OPRM1 gene.

Remember the protein instructions in genes are written in a simple genetic code. This “language” has four letters, A, G, T, and C. (The letters are actually abbreviations of small chemicals called nucleotides.)

Two ways a single difference
in a gene might affect
sensitivity to rejection.

People with the “G” version have a G at position 118 of the OPRM1 gene instead of an A. The image to the right shows a couple of ways that this change in the instructions might make morphine less effective.

One is if the “G” version makes a receptor with a slightly different shape. The red triangles don’t fit the rounded receptor as well as the triangular one leading to less of an effect (fewer arrows). In this case, less morphine binds because it doesn’t fit the receptor well.

Another way is if the changed instructions cause less receptor to be made. There is now less of the triangular receptor around to bind the receptor. Less receptor means a smaller signal (fewer arrows).

People with a G at position 118 make more receptor than people with an A at the same position. This is why people with the “G” version respond less well to morphine. And why they may not be able to deal as well with rejection.

So sticks and stones can break your bones. And words may also hurt you. How much partly depends on the version of your OPRM1 gene.

Andrew Hellman

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Content provided by the Department of Genetics, Stanford University.