An opioid receptor mutation that makes ladies feel the pain

Aug 22 2012 Published by under Behavioral Neuro

Note: I was thinking about writing up some refutations on the idea that “if it’s a legitimate rape, the female body has ways to try to shut that whole thing down,”, because that is NONSENSE and that kind of claim makes me ragey. However, Kate Clancy over at Context and Variation has written up a BRILLIANT summary on the topic. I cannot recommend it enough. So I think any thoughts I might have are superfluous. Head over there. Read it. Read the follow up. And then come back here to learn about mu-opioid receptors. :)

We all know of someone who says they are impervious to pain. That they have higher pain threshold. Maybe we know someone who is acutely sensitive to pain.

When you hear that someone is more or less sensitive to pain, what do you attribute it to? Me, I always default to someone being told to toughen up as a child. I always thought that people were all roughly equally sensitive to pain, and some were just bigger divas about it than others (and I've always worried that one of those divas was me!).

And sure, maybe there's some nurture, but there may also be some nature. A naturally occurring mutation that may make some people (particularly women) more sensitive to pain than others.

Olsen et al. "Pain Intensity the First Year after Lumbar Disc Herniation Is Associated with the A118G Polymorphismin the Opioid ReceptorMu 1 Gene: Evidence of a Sex and Genotype Interaction" J. Neuroscience, 2012.


(Does anyone else wonder why people with lower back pain are always topless in photos? Can't you have lower back pain through clothing? Source)

Ah, single nucleotide polymorphisms. Using that phrase around non-scientists almost always results in either glazed-over faces or total incomprehension. But it shouldn't!! Cause the words are long, but they're not hard! At least, not if you have a basic understanding of DNA (and most of the time, you do, really!).

So here's DNA.


(Source)

Two strands, paired up against each other. Four bases. A pairs with T, C pairs with G. So on each strand you get something that looks, say, like this: AAGGGCGCGTATAAGTGCTCAGA. The DNA gets transcribed to RNA. The RNA then gets translated to protein. During translation, each triplet of the bases listed above will be translated to a single amino acid, and those amino acids together make up a protein, like, say, a receptor.

Now, what about single nucleotide polymorphisms? A single nucleotide polymorphism (SNP) is when one of those bases above is...not what it's supposed to be. Say you have a sequence of AGA. Suddenly, it's AGG. That A -> G is a single nucleotide polymorphism, a change in a single nucleotide of a single triplet in the whole, long gene. It might seem like a really small change, but small changes can have big effects. If, for example, that SNP changes the "translation" of that triplet so it doesn't mean anything, the whole making of the protein may just get hacked off, as the translating machinery doesn't know how to get around it. Alterntively, the SNP may change the "translation" to make another amino acid, which could alter the structure and function of the end protein. Or...the SNP couldn't matter at all.

But in this paper, it matters. The SNP of the day is the A118G (meaning that A -> G at position 118 in the gene) in the mu-opioid receptor. The mu-opioid receptor is most famous due to being the target of drugs like morphine and heroin, but it also plays a big role in daily life, especially in how we feel pain.

And of course, the mu-opioid receptor has it's SNPs. Like this one, which is present in humans. I heard of this SNP due to its potential role in addiction, it looks like the G version could also have implications for pain. Previous studies have shown that men with at least one G (remember, you have to have two copies of everything, so in the case of this SNP you can be A/A, A/G, or G/G) are less sensitive to pain than those with A/A.

But it looks like women aren't so lucky. Previous studies have shown that women with one G allele or more show more pain following Caesarian section deliveries. But of course, that's surgical pain, and could have something to do with the surgery itself and the meds given for it. Not only that, you can't look for sex differences, as there are very few men who've had Caesarean section deliveries. You need a type of pain that both sexes suffer from.

The authors of this study were interested in this particular SNP in chronic pain. In this case, lower back pain. They recruited 258 patients who were being treated for lumbar disc herniation or sciatic pain. They followed them for a year during treatment and asked how much pain they were in.

And what they got was an interesting sex-specific effect:

What you can see here is pain ratings over time on a visual scale. All patients had a decrease in pain with treatment (and a good thing!), but the G allele carriers had less of a decrease than the A allele carriers. And this change was specific to women. Women with a G allele suffered more pain than women with A/A or men with any genotype.

And even more interesting, men with G alleles had the opposite effect! They were LESS sensitive to pain! One SNP, opposite effects. It makes me wonder how the mu-opioid receptor is interacting with other things in the body (say, sex hormones) to have these sex-specific effects.

But it also makes me wonder if this SNP has another role to play. The G allele at this locus has been the subject of a lot of studies on drug addiction, and some of the effects appear to be sex-specific. In the general population, it appears that G allele carriers are at higher risk for addiction, but...is it sex specific? Is this effect carried by men? Mouse studies with this gene suggest that the G allele may be protective in females. Does this work in humans? Are G carrying males more susceptible? And what does this have to do with sensitivity to pain?

A good study always raises more questions than it answers.

Maria Belland Olsen, LineMelå Jacobsen, Elina Iordanova Schistad, LindaMargareth Pedersen, Lars Jørgen Rygh, Cecilie Røe, and Johannes Gjerstad1 (2012). Pain Intensity the First Year after Lumbar Disc Herniation Is
Associated with the A118G Polymorphismin the Opioid ReceptorMu 1 Gene: Evidence of a Sex and Genotype Interaction Journal of Neuroscience : 10.1523/JNEUROSCI.1742-12.2012

5 responses so far

  • Mike Little says:

    I have always had what I think of as a large tolerance for pain. A few years ago I had cardiac bypass surgery. When I was coming out of the anesthesia, they gave me morphine for pain. Unfortunately we found out that I am non-responsive to morphine for pain alleviation. In sufficient quantities it will suppress my breathing but doesn't help for pain. I found out later that morphine did not work on my mother as well. In addition to this, I used to smoke from age 18 till age 30. I decided that smoking was stupid and decided to quit. I found quitting pretty easy. The only difficulty was the association of smoking when I was driving. Other than that, easy breezy. After reading the article, I wonder how much of all of this is related to the single opioid receptor. Just one little mutation....

  • HFM says:

    Just out of curiosity...Mike, are you and your mother redheads? I used to work in a derm department with someone who studied the tanning response and endogenous opiates. IIRC, since redheads don't tan properly, they have naturally high levels of the endorphin that comes with the tanning signal - meaning they have higher pain tolerance, but are also resistant to synthetic opiates.

  • D. C. Sessions says:

    It may be necessary to distinguish different types of pain. I'm a total wuss on several fronts (I do not tolerate localized heat and cold at all, for instance) but postoperative pain? Zero. Nada. As in, never fill the prescriptions because there's no discomfort. Anasethesia wears off and I'm nothing but cheerful. And this, after a knee replacement -- I'm told not a normal response, at all at all.

    Strangely, this bothers me. It's actually embarrassing to admit that I'm lucky that way. On the other hand, I sincerely and profoundly wish someone would figure out how this works so they could maybe do the same for others.

  • S Donnell says:

    This article is absolutely fascinating. I have been diagonosed with three different chronic pain disorders in my lifetime and I 'm only 48. I have TMJ (twosurgeries and a lot of pain from 17 - 22), Fibromyalgia (36- current) after a minor fender bendera when my car was rearended at low speed and had chronic neck pain that eventually became full body pain. Then I slipped and broke my leg that turned into CRPS (Chronic Regional Pain Syndrome) and have a pain pump and a spinal cord stimulator. I have always felt so guilty like I was not tough enough but I have actually have had my pain get so bad that I do not even remember what has been going on at the time or conversations that have been had due to the severity of my pain alone. I literally cannot think or process thoughts from short term to long term as the pain can override my brain functions. I will even forget to take medication. Reading this helps explain how genetics cause this. I have a cousin who seems to have similar issues to me too although my siblings do not. It is like lifting off a cement block of self blame from my shoulders. Thank you.

  • S Donnell says:

    This article is absolutely fascinating. I have been diagonosed with three different chronic pain disorders in my lifetime and I 'm only 48. I have TMJ (twosurgeries and a lot of pain from 17 - 22), Fibromyalgia (36- current) after a minor fender bendera when my car was rearended at low speed and had chronic neck pain that eventually became full body pain. Then I slipped and broke my leg that turned into CRPS (Chronic Regional Pain Syndrome) and have a pain pump and a spinal cord stimulator. I have always felt so guilty like I was not tough enough but I have actually have had my pain get so bad that I do not even remember what has been going on at the time or conversations that have been had due to the severity of my pain alone. I literally cannot think or process thoughts from short term to long term as the pain can override my brain functions. I will even forget to take medication. Reading this helps explain how genetics cause this. I have a cousin who seems to have similar issues to me too although my siblings do not. It is like lifting off a cement block of self blame from my shoulders. Thank you.