Your body makes it’s own, natural opioids as a way to regulate pain, reward, and addictive behaviors. One example is the endorphin rush after a hard workout — a runner’s high. This is also how the body shuts down too much pain.
Genetic variants, though, mean that we don’t all feel the same amount of pain, and we don’t all react the same way to opiate-based drugs.
OPRM1 gene codes for the mu opioid receptor. These receptors are on the outer membranes of neurons. When something binds to that receptor, it triggers a chemical change that starts a cascade of events leading to pain relief and feelings of pleasure due to an increase in dopamine.
More specifically, mu opioid receptors are found in the neurons of the spinal cord, the brain, and in the intestines. Nociceptors are what initially signals 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). The opioid receptors, when activated, partially block the activation of the neurons that are relaying the pain signal.
There are two other opioid receptors in the body, as well. They are known as delta and kappa (perhaps the topic of future articles).
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. It reduces the production of substance P, which transmits pain via your neurons.
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 vagarities of the potency of the raw opium. Merck pharmaceutical company was founded on the sale of morphine.
There are several important medications and illegal recreational drugs that bind to the mu opioid receptors that are derived from opium. Among these are oxycodone, fentanyl, buprenorphine, methadone, oxymorphone, codeine, morphine, hydrocodone, and heroin.
When any of those drugs bind to the mu opioid receptor, it reduces the excitability of the neurons through 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 something to take into consideration.
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 overdose.
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.
The variant known in studies as A118G has reduced signaling efficiency and reduced expression of the receptor. [ref] This is a very well studied genetic variant, with hundreds of studies on it over the last two decades.
Here are some of the recent studies on the A118G (rs1799971- G) variant:
Check your 23andMe data for rs1799971(v4, v5)
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 23andMe results for rs10485057 (v4 only)
Check your 23andMe results for rs2281617 (v4, v5)
Check your 23andMe results for rs510769 (v5 only)
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 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 agonist. One is kratom, which is still legal in the US (I think) but may soon be a schedule I substance. Kratom is a plant that is native to Southeast Asia, and consuming the leaves gives a stimulant effect at lower levels and opioid-like effect at higher levels through binding to the mu opioid receptor.[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.