Opioid Drugs, Part 1: Mechanism of Action

Opioid Drugs, Part 1: Mechanism of Action

Pain is one of the worst sensations a person
can experience. Thankfully, we have access to one of the most
powerful classes of painkillers: opioid drugs. Some examples you might know of are morphine,
oxycodone, heroin, and fentanyl. While these are excellent painkillers, opioid
drugs are also one of the most widely abused and deadliest drugs, with North America currently
experiencing an opioid epidemic where the number of overdoses are at an all-time high. Since there is so much to discuss about this
class of drug, this is going to be a two-part series. Watch part 1 to learn about the mechanism of how opioids can cause pain relief. Opioid drugs include a wide range of drugs
that can be classified as opiates, which are drugs derived from the opium poppy, semi-synthetic
opioids that are made from chemically modifying opiates, and fully synthetic opioids. All these drugs work in pretty much the same
way with just slight differences that you can read more about in the video description
below. They mimic the effects of small painkilling
peptides our body naturally produces. These are called endogenous opioids and can
be classified as endorphins, enkephalins, and dynorphins, which are made of amino acids
and share a common amino acid chain motif: tyrosine, glycine, glycine, phenylalanine. All of these molecules bind and activate opioid receptors, which are scattered throughout our nervous system. Four receptor types exist with similar structures
and slightly different effects – we will be focusing on the mu receptor, which is the
main receptor that causes pain relief and other effects of opioid drugs. So what happens when you get an intravenous
injection of an opioid drug, for example, morphine, at a hospital or on the street? First, the drug must leave the blood and enter
your central nervous system. To do so, it must cross the highly selective
blood brain barrier. Smaller, lipid soluble drugs can more easily
cross this barrier and start causing their effects earlier than larger, water soluble
drugs. For example, fentanyl is much more lipid soluble
than morphine, and so crosses the barrier much faster, which is why fentanyl’s effects
are almost immediate compared to morphine. Conversely, fentanyl can just as easily leave
the central nervous system, so it has a shorter duration of action. Once inside the central nervous system, opioids
will bind to opioid receptors found on pain signalling neurons, causing molecular and
cellular changes that prevent these neurons from sending signals to each other, therefore
stopping a person’s sensation of pain. How does this signal shutdown occur? First, let’s learn how neurons communicate
with each other. Signals travel through a neuron as a flow
of positive charge called an action potential, while signals travel between neurons through
the release of neurotransmitters. Let’s take a closer look at neurotransmitter
release. Neurons have special ion channels called voltage-gated
ion channels, which open to let ions through when there is increased positive charge. When an action potential reaches the end of
the presynaptic neuron, the increased positive charge causes voltage-gated calcium channels
to open and allow calcium to flow in. Increased calcium levels inside the neuron
triggers the fusion of neurotransmitter-containing vesicles with the neuronal membrane, causing
release of neurotransmitters, in this case, the excitatory neurotransmitter glutamate. Glutamate then binds to receptors on the postsynaptic
neuron to activate channels that allow positively charged ions like sodium to flow in. This increases the positive charge within
the neuron, a process called depolarization. This positive charge activates nearby voltage-gated
sodium channels, which allow more positive charge to flow in. This in turn activates other nearby voltage-gated sodium channels, resulting in a domino effect to create an action potential in the postsynaptic
neuron. If the neurotransmitter released is instead
inhibitory, like GABA, it binds to postsynaptic receptors that activate chloride channels. Chloride, a negatively charged ion, will flow
in, making the inside of the cell more negatively charged. This process is called hyperpolarization, and the negative charge makes it difficult to activate the voltage-gated sodium channels,
which open when there is positive charge. Therefore, the action potential does not form
and the signal is no longer continued. Essentially, in order for an action potential
to form in the postsynaptic neuron to continue the signal, it needs to depolarize and become
more positively charged inside. If it hyperpolarizes, it becomes more difficult
for an action potential to form, and no signal is produced. Now, how do opioid drugs stop this communication
from occurring? When opioid drugs bind to opioid receptors
on neurons, they can prevent the presynaptic neuron from releasing neurotransmitters, called
presynaptic inhibition, and prevent the postsynaptic neuron from depolarizing, called postsynaptic
inhibition. To understand how these two processes work,
let’s take a closer look at opioid receptors. These receptors are a special kind of receptor
called a G protein-coupled receptor, meaning that a G protein is attached to the receptor. When an opioid drug binds to the receptor,
a variety of structural and molecular changes occur that activate the G protein. The G protein separates into two subunits
– α and βγ – which interact with other proteins of the cell. In presynaptic inhibition, opioids bind to
opioid receptors on the presynaptic neuron terminal. The Gβγ subunit is released and interacts
with nearby voltage-gated calcium channels, preventing them from opening. Now, even when there is an action potential,
these channels can no longer open. Without calcium influx, no neurotransmitters
are released. In postsynaptic inhibition, opioids bind to
opioid receptors on the postsynaptic neuron. Once again, the Gβγ subunit is released
and interacts with potassium channels. However, in this case, this interaction opens
the channels and positively charged potassium ions flow out through the channel. So, if neurotransmitter was released and depolarization
was occurring, the loss of positive charge from potassium ions leaving the neuron negates
the positive charge from sodium ions entering the neuron, making it difficult for an action
potential to form. So you might be wondering, what does the Gα
subunit do? Different G proteins have different classes
of Gα subunits with different functions. The opioid receptor’s Gα is of the inhibitory
Gi/o class, whose function is to stop cyclic AMP, or cAMP, synthesis. So what is cAMP? cAMP is a very important signalling molecule
in neurons. It is synthesized from ATP by the enzyme adenylyl
cyclase. cAMP activates the cAMP dependent protein
kinase, which phosphorylates multiple neuronal proteins and channels to activate or inhibit
them, starting various signalling pathways and stopping others. The Gαi/o subunit stops cAMP synthesis by
interacting with and inhibiting adenylyl cyclase. This results in a decrease in cAMP levels
which can also result in structural, enzymatic, and molecular changes due to various signalling
pathways no longer being activated or inhibited. These changes likely affect neurotransmitter
release and opioid tolerance, and can happen on both the presynaptic and postsynaptic neuron. So now we know how opioids can stop signal
transmission between neurons. How does that result in less pain? Our body has two pain pathways: the ascending
and the descending pathways. The ascending pain pathway is used to transmit
pain signals to the brain, letting us know that we are hurt. The descending pain pathway’s job is to
shut down the ascending pathway, allowing us to no longer feel pain. So, the two main effects of opioids are to
shut down the ascending pathway and activate the descending pathway, providing pain relief. Keep in mind that this diagram and the following
explanation are very simplified – in reality, there are many more neurons, synapses, and
neurotransmitters involved in these complex and not yet fully understood pathways of pain. Let’s say you injure your hand. Primary sensory neurons in your hand are activated
and send the signal to the spinal cord where they meet secondary neurons. The signal continues up the spinal cord and
brainstem through the secondary neurons to reach the thalamus, which processes sensory
information. In the thalamus, the secondary neurons synapse
with tertiary neurons that activate other regions of the brain cortex, allowing us to
give meaning to the pain – where it is, how painful it is, and how to feel about it. This is the ascending pathway. Our body can also decrease how much pain we
feel by activating of our body’s natural painkilling system – the descending pathway. Normally, neurons in the descending pathway
are inactive because they receive GABA from inhibitory interneurons in the brainstem. Recall from earlier that GABA, an inhibitory
neurotransmitter, prevents a neuron from depolarizing, which means it can’t start an action potential
and continue a signal. However, certain neurons in the brain can
be activated in response to pain to release endogenous opioids into the brainstem. Let’s take a closer look at this brainstem
synapse. These endogenous opioids can bind to opioid
receptors on the inhibitory interneuron. Since opioids can stop neurotransmitter release
through presynaptic inhibition, GABA is no longer released. Without GABA, the neurons in the descending
pathway are no longer inhibited. Now, these neurons can send signals to activate
opioid-releasing interneurons in the spinal cord near the primary and secondary neuron
synapse. Let’s take a closer look at this spinal
cord synapse. These interneurons release endogenous opioids
that cause both presynaptic and postsynaptic inhibition, preventing communication between
the primary and secondary neurons. Thus, the ascending pathway is shut down,
pain signal no longer reaches the brain and pain relief is achieved. So, when we administer opioid drugs to people,
they will act the same way as our endogenous opioids and result in pain relief. Opioid drugs will bind to receptors on the
inhibitory interneurons in the brainstem, which stops inhibition of descending pathway
neurons, which stops the ascending pathway and pain signal transmission. They will also stop pain signal transmission
by binding to receptors in the spinal cord. Finally, they can bind to other areas in the
brain such as the ventral tegmental area to cause addiction, or the respiratory centre
to stop breathing. But more on that in part 2 of this 2 part series, as well as why overdoses occur, how to reverse an overdose, and what society can do to stop the opioid epidemic ravaging our cities. Thanks for watching, and see you next time
on Medicurio.

About the author


  1. I found this channel because of tier zoo and I love how thoroughly explained each topic is. Would be cool if you could cover some genetic / inherited diseases or even something like patau syndrome or cyclopia

  2. I just saw the notification that you have a new video after two weeks. WTF youtube! I check my sub feed basically everyday.

  3. It is tragic that this video has so few views. This video has the perfect level of complexity, and is surprisingly comprehensive. The superb animations are almost equally as impressive as the succinct explanations of the main concepts in the video. Your videos would be beneficial to anyone who is even slightly interested in biochemistry. Your channel deserves many more viewers than it currently has. I really can't praise your channel enough. Please continue to make content.

  4. Thanks you!!!!! you have made things easy for me………….But i need part 2, i cant seem to find it. Need help please even from anyone else.


  6. Your videos are amazing! You really know how to break down the material to make it understandable! I have a midterm on this on Thursday! Really hoping for Opioids Part II 🙂 Thanks again!

  7. Hello Medicurio, I am currently a first year pharmacy student at the University of the Pacific and was wondering if I can use a few of your graphics in this video for my class presentation on the opioid crisis. Please let me know as soon as possible. Thanks!

  8. Great video, great.
    I have a question though, our professor says that the activation of potassium channels to cause hyperpolarization occurs in both neurons of the spinal cord and in the primary afferent neurons. But what i understood here is that the primary afferent neuron is subject to inhibition by closing calcium channel which makes sense because it is the presynaptic neuron here.

  9. O, man!! Such a great video!! Was looking for some source to refresh my knowledge, but most of youtube videos are so superficial, or opposite to detailed in a harm way, or just full of trash talking. Your submission of the information is amazing! Thank you so much.

  10. Hey, so, it's been 5 months since this video, are you still working on videos for this chanel? I guess you have a job and thus not much time for youtube and I don't mind having few videos if they are such good content, just wanted to ask 🙂

  11. You are so awesome bro, it is so good and I want you to continue doing this, very very good, I loved it, and today i am using it for my exam😍😍

  12. hey, i know you havent made a video in a while, but could you make one talking about seizures and how the medicine stops seizures from happening again.

  13. You have such an amazing medicine channel. I wish you can keep making more of these high quality education videos! Your animation and graphics are so clean and thorough. These are videos I would want to learn from as a primary source of information for diseases, medications.

  14. does anyone know what software creates this type of animations?

    I have a school topic I would like to cover in this manner.

  15. Still, i don't understand why the body after feeling pain won't stop the pain. for example, I burned my hand and I felt pain… why does the pain persist for many hours after that? why won't the body system send pain blockers lets say … after 15 minutes of burning my hand so i can feel better?

  16. I found this channel yesterday and i am totally in love with it! I love you man and your effort in making these videos. Please do not stop making these kind of videos and i hope you sponsor your channel to become more popular on YouTube! ❤️❤️❤️❤️❤️❤️❤️❤️❤️

  17. Great video! You explained it very clearly!
    I just started my own medical youtube channel, and I also made a video on Morphine.
    However I still find it hard to find the balance between informational content and a fun way to explain it.
    You do this in a very natural way, which inspired me to make my videos more visual.
    Keep it up!

  18. I've began studying this mechanism out of necessity when a 1990 TBI, back of head meets concrete, resulted in a 40 minute nap and a son to follow anterior pituitary hormone regulation nightmare many years too early to simply explain your symptoms and get a diagnosis requiring only a few blood tests to confirm. So a very long story later I found a treatment to stimulate growth hormone release and treat chronic pain and fatigue using high dose morphine with a Mu receptor stimulant. Using igf-1 as a delayed indicator my HGH release returned to normal and I lived a pain free stable life and suffered none of the mind altering effects that the powers that be expect everyone to be feeling with a linear relationship to dosage. The opioid insanity hit and my rights were ignored as a knowledgeable patient to accept or reject any changes my doctor might suggest. That was 5 years ago and I was forceably tapered at 10% per month without much if any reseting of receptors taking place. I've been fluctuating in opioid withdrawal and only managing to get by because of the Mu stimulant trick. I've noticed many additional improvements over the years to the mechanism you've so carefully shared and I'll check out your other videos. I'm wondering if the current understanding can offer possibilities to explain my stable withdrawal symptoms over so many years. I'm growth hormone deficient once again and certainly suffering from that. I lost my sense of hunger and most of my thirst sensation too with my TBI. I would be diagnosed as having Centralized Pain Syndrome if Dr. Tennant was operating north of the 49th.

    Enjoyed your video with an interest and respect that I have not been able to before. Your collaboration of process details is appreciated. I'm an industrial automation electrician with several chemical treatment inventions in my past and a concept for a medication to eliminate most of the opioid induced constipation people get plugged up over. The idea came after taking Naltrexone to try a receptor restart. Actually the idea came in the short time I was graying out and my head was heading for the floor but just prior to said head hitting the floor. Somewhat ironically the medication, Relistor, offers no improvement for my plumbing. A one year free trial as the final addition to the list of patients giving Relistor a shot.

    Well back to withdrawal.

  19. MIND BLOWING! This video explains its clearly form the endogenous mechanism of norciceptive and antinorciceptive pathways and also the MOA of opiod 🤯🤯🤯🤯🤯 thanks

  20. Super interesting, but not terribly surprising: Your explanation of hyperpolarisation as a means of blocking neurotransmission is similar to how a semiconductor transistor 'switches off' and blocks current. Search 'flow of holes in transistor' for the analog.

    Depolarisation, being the opposite, is analog to flow of electrons in the transistor which then 'switches on' and allows flow of current.

  21. this was awesome! Thank you for making this video! 4 hours in my therapeutics class and it wasn't even close to being this clear!

  22. Thanks for such formidable explanation. But I have two questions if you please;
    The first, can we use GABA mimetics as pain analgesic? I mean for their inhibitory effect in the descending pathway.
    The second, as the descending neuron also seretonergic/adrenorgic, do sertonin & adrenaline have inhibitory effect on pain transmission?

  23. You make me feel like a machine, that lives for the sake of the machine, and myself just a component made to serve.
    … Not that I am complaining or anything.

  24. These are in All Narcotic Medications that can change the moods to bad behaviors & make a High Sex Drive. I know, cause I had to use my ID to get the Narcotic Medication from the Pharmacy for pain after having a baby & during a Toothache. Yes, it does ease pain & I was also moody & very Horny too. 😔

  25. The pain pills with Tylenol you will overdose on tylenol before you you overdose on opiates dont take my word for it that is just wht i was told

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