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.
