Pain helps us to learn not to do something, like touching a hot stove. But we have built in ways to turn off the pain at some point. One way is through natural opioids the body makes as a way to regulate pain, reward, and addictive behaviors.
Genetic variants, though, mean that we don’t all feel the same amount of pain. Some feel pain more strongly or for longer times than others. These same variants also impact our reactions to opioid-based medications, impacting our susceptibility to opioid addiction.
How does the mu-opioid receptor work?
The OPRM1 gene codes for the mu opioid receptor.
The opioid receptors are located on the outer membranes of neurons. When something binds to that receptor, it triggers a chemical change that starts a cascade of events. This cascade leads to pain relief and feelings of pleasure due to an increase in dopamine.
Diving a little deeper:
Mu opioid receptors are found in the neurons of the spinal cord, the brain, and in the intestines.
To understand how mu-opioid receptors work, we need to talk about how the pain signal reaches the brain…
Initiating the signal: Nociceptors are the receptors that initially signal to the brain that there is pain. For example, when you hit your thumb with a hammer, the nociceptors in your thumb will trigger a signal that it hurts.
This initiates a multistep process to relay the signal, and then the brain also is involved in learning from the pain (e.g. don’t hit your thumb with a hammer).
Activating the opioid receptors partially blocks the activation of the neurons that are relaying the pain signal from the nociceptor. This activation can come from substances naturally created in the body (endogenous ligands) or opioid drugs (exogenous ligands).
Endogenous ligands (a.k.a. stuff your body makes that activates the receptor):
One natural opioid that your body produces is β-endorphin. They are produced by the pituitary and hypothalamus to maintain homeostasis and reduce stress.
β-endorphins can be released into the body and decrease pain through the neurons in the peripheral nervous system. They can also be released in different brain regions. When β-endorphins bind to the opioid receptor, this inhibits GABA, which then allows for a greater release of dopamine.[ref] Dopamine is associated with pleasure and reinforces learning, rewarding you.
Another natural opioid peptide that your body produces in enkephalin. This neuropeptide is found in the brain and the adrenal medulla, and it can bind to the mu-opioid receptor.[ref] Enkephalin reduces the production of substance P, which transmits pain via your neurons.
Exogenous ligands (a.k.a. drugs that bind to the receptor):
Opium has been used for thousands of years for pain relief and to treat dysentery. It comes from the dried latex that is exuded from a cut on a poppy seed pod. Historically, opium has been smoked or made into a tincture called laudanum. Wars have been fought over it. The purification of opium into morphine was a historical breakthrough in that it allowed doctors to treat patients with a known dose, rather than relying on the vagaries of the potency of the raw opium. Merck Pharmaceutical Company was founded on the sale of morphine.[ref]
There are several important medications and illegal recreational drugs that bind to the mu opioid receptors that are derived from opium.
Opioid drugs include:
When opioid drugs bind to the mu-opioid receptor, it reduces the excitability of the neurons via inhibiting GABA. In addition to decreasing pain, this also causes more dopamine to be released.
Opioid addiction (heroin or other opioids) is thought to be partially due to genetic vulnerability. Twin studies show 40 – 60% heritability. [ref] Obviously, genetics isn’t the whole picture here, but it is important.
The studies on opioid addiction show varied results for the genetic variants associated with it. This underlines the fact that there are probably several different genes involved as well as the many complex variables and environmental factors.
Naloxone, or Narcan, binds to the mu-opioid receptor and blocks it. This stops the action of opioids, and Narcan is used for opioid overdoses.
A recent study in the journal Pain Physician found that patients with both dysfunctional CYP2D6 variants and OPRM1 variants were at the highest risk for opioid addiction (estimated to be 14% of people). Patients with ‘subnormal’ or somewhat impaired variants of CYP2D6 or OPRM1 were considered to be at a medium risk (~48% of people). The rest, with functional CYP2D6 and OPRM1 variants, were considered at low risk. (~38% of the population). The study based OPRM1 functionality on the rs1799971 variant listed below. You can check your CYP2D6 variants here.
OPRM1 (opioid receptor, mu 1) Genetic Variants:
The most well-studied mu opioid variant is rs1799971. The variant (G) has reduced signaling efficiency and reduced expression of the receptor. [ref]
Check your genetic data for rs1799971 (23andMe v4, v5; AncestryDNA)
- A/A: Normal
- A/G: reduced opioid receptors
- G/G: reduced opioid receptors, more pain, decreased response to opioids (see below)
Members: Your genotype for rs1799971 is —.
Here are some of the recent studies on the A118G (rs1799971- G) variant:
- Increased pain or fear of pain.[ref]
- Decreased postoperative vomiting (less than half the risk)[ref]
- On average, a higher opioid dose needed for pain[ref][ref]
- Less likely to have a response to placebo for pain.[ref]
- The studies on alcohol-dependence risk give varied results.[ref] But naltrexone more successful for alcoholism in G-allele carriers[ref]
- Meta-analysis shows an increased risk of opioid dependence.[ref] Some studies show a large increase in risk, but others show little to no statistical increase in risk.
While the A118G variant is the most well-studied mu-opioid receptor variant, there are many other variants that may also affect the function. Here are a few:
Check your genetic data for rs10485057 (23andMe v4 only)
- A/A: normal
- A/G: increased risk for alcohol consumption
- G/G: increased risk for alcohol consumption[ref]
Members: Your genotype for rs10485057 is —.
Check your genetic data for rs2281617 (23andMe v4, v5; AncestryDNA)
- C/C: (normal) euphoria with amphetamines
- C/T: less euphoria with stimulant drugs, lower body fat
- T/T: less euphoria with stimulant drugs (amphetamine) [ref], lower body fat and lower fat intake[ref]
Members: Your genotype for rs2281617 is —.
Check your genetic data for rs510769 (23andMe v5; AncestryDNA):
- T/T: less euphoria, less energy with 10mg amphetamines, higher euphoria, energy with 20 mg
- C/T: euphoria and energy with amphetamines
- C/C: (normal) euphoria, energy with amphetamines[ref]
Members: Your genotype for rs510769 is —.
Avoiding opioid addiction:
The study from the journal Pain Physician is eye-opening in that it estimates that only 38% of us are not at an increased risk of opioid dependence.
While the research is not entirely conclusive, I think that it is strong enough to promote caution in people who are OPRM1 variant carriers when faced with a choice of an opiate-based vs. non-opiate based pain medication — especially if coupled with CYP2D6 variants.
Researchers and doctors can argue about the nuances of when to recommend what, but I think that patients should also be involved in making an informed decision. Understanding your genetic variants is the first step in figuring out what is right for you.
I hope that this article also drives home the point that some people quite literally have a lower pain tolerance than others. And some people are more susceptible to opioid dependence than others. Instead of judgment, we need to work towards finding solutions.
Other than narcotics that originate from the poppy, there are few other mu-opioid receptor agonists. One is kratom, which is still legal in most US states (check to make sure for your state / city / country since laws change). Kratom is a plant that is native to Southeast Asia, and consuming the leaves gives a stimulant effect at lower levels and an opioid-like effect at higher levels through binding to the mu-opioid receptor. Some use kratom to wean themselves off opioids.[ref][ref]
Poppy seeds do contain a trace amount of morphine, and newer drug testing standards have been raised so that consuming poppy seeds doesn’t result in a positive drug test.
Melatonin has analgesic effects, and the body produces more melatonin in response to acute pain. Researchers have found that melatonin increases endogenous opioids such as beta-endorphin. [ref]
You can increase melatonin levels at night by blocking blue-light after dark (wearing 100% blue light blocking glasses). Exposure to sunlight during the morning also increases melatonin the following night.
More to learn:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.