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.