In this lecture we’re gonna cover the pharmacology of opioids so let’s get right into it.
Opioids, sometimes called narcotics, are a group of drugs that act on the central nervous
system to produce morphine-like effects such as pain relief and euphoria.
Now, in order to gain better understanding of their mechanism of action first we need
to talk about the transmission of pain.
So, pain begins at the nociceptors, which are simply the branching ends of sensory neurons
found within the peripheral nervous system.
These high threshold primary sensory neurons respond to damage to the body by transmitting
the painful stimulus to the second-order neurons in the dorsal horn of the spinal cord.
From there the signal is carried through the spinothalamic tract to the thalamus, and then
to the somatosensory cortex where pain is perceived.
Now, on a microscopic level, the pain signal takes the form of a series of action potentials
that fire repeatedly depending on the intensity of pain.
To enhance movement across the synaptic cleft, transmitter chemicals are released from the
presynaptic neurons, including glutamate, substance P, and calcitonin gene-related peptide,
CGRP for short.
Glutamate is one of the most important neurotransmitters for pain and can activate both NMDA and AMPA
receptors, which permit influx of positively charged calcium and sodium ions respectively.
As you may recall, the flow of positively charged ions into the neuron, makes the neuron
more likely to fire.
In this way glutamate excites the second-order neurons in the dorsal horn, which leads to
propagation of a sharp, localized pain signal.
Substance P, on the other hand, binds to the neurokinin-1, NK-1 for short, which
leads to intracellular signaling that involves activation of arachidonic acid pathways,
nitric oxide synthesis and activation of NMDA receptors.
NMDA receptors are activated when Substance P attaches to NK-1 receptors and then gets
incorporated into the cell, activating Protein Kinase-C.
This action removes the magnesium that under normal conditions is blocking NMDA receptor.
This in turn allows glutamate to attach to the NMDA receptor and thus permit the inflow
of calcium ions, ultimately causing the pain signal to increase and fire more frequently.
Lastly, the released CGRP binds to its receptor on second order neurons leading to changes
in receptor expression and function and thereby altered neuronal activity.
This in turn contributes to the so-called central sensitization that is characterized
by lowered threshold for evoking action potentials.
Now fortunately for us, our bodies can cope with certain amount of pain by releasing so-called
endogenous opioids.
There are three major families of endogenous opioids: the enkephalins, dynorphins, and endorphins.
Endogenous opioids exert their effects by binding to opioid receptors, which are abundantly
present in the central and peripheral nervous systems.
There are three major types of opioid receptors, that is; µ (mu), δ (delta) and k (kappa).
In general, all three receptors differ in their cellular distribution, their relative
affinity for various opioid ligands and their contribution to specific opioid effects.
All opioid receptors are 7-transmembrane spanning proteins that couple to inhibitory G-proteins
and they are all present in high concentrations in the dorsal horn of the spinal cord.
Activation of these receptors by an agonist, such as the endogenous μ-opioid peptide endorphin
causes closing of the voltage-gated calcium channels on the presynaptic nerve terminals which in
turn decreases the release of neurotransmitters, such as glutamate, substance P and calcitonin-gene-related-peptide.
In addition to that, activation of opioid receptors leads to opening of potassium channels,
allowing efflux of potassium ions which in turn results in hyperpolarization, rendering
neurons less sensitive to excitatory inputs.
Now, the majority of currently available opioid analgesics act primarily at the μ-opioid
receptors essentially mimicking the effects of endogenous opioid peptides.
However, while naturally-derived opioids can only reach a certain potency, the synthetically-produced
opioids are refined and processed to be much more powerful.
The examples of synthetic opioid agonists are; Fentanyl, Hydrocodone, Hydromorphone,
Methadone, Meperidine, Oxycodone, and Oxymorphone.
As a side note here, its important to note that Methadone is not only a potent μ-receptor
agonist but also a potent antagonist of the NMDA receptor as well as norepinephrine and
serotonin reuptake inhibitor.
These properties make Methadone useful for treatment of both nociceptive and neuropathic pain.
Now, in addition to producing analgesia, activation of the opioid receptors in other parts of
the body can bring about many side effects.
For example, all opioids produce some degree of nausea, which is due to direct stimulation
of the chemoreceptor trigger zone in the medulla.
All opioid receptor agonists also produce a dose-dependent respiratory depression.
Opioids primarily cause respiratory depression by reducing brain stem respiratory center
responsiveness to carbon dioxide.
They also depress the respiratory centers in the pons and medulla, which are involved
in regulating respiratory rhythmicity.
In addition to that, opioids produce an antitussive effect by depressing the cough center in the medulla.
Opioids are known to be associated with suppression of the immune system, as opioid receptors
are involved with regulation of immunity.
Morphine as well as Meperidine may provoke release of histamine, which plays a major
role in producing hypotension.
Furthermore, when given by injection Morphine and Meperidine can cause dilation of cutaneous
blood vessels, which results in the flushing of skin of the face, neck, and upper thorax.
Meperidine in particular produces tachycardia due to its structural similarity to Atropine.
Other opioids generally produce a dose-dependent bradycardia by increasing the centrally mediated
vagal stimulation.
All opioids can cause itching via central action on pruritoceptive neural circuits.
Opioids also decrease gastric motility and prolong gastric emptying time, which may cause constipation.
Likewise, opioids depress renal function and produce antidiuretic effects.
They also increase sphincter tone and thus may cause urinary retention.
Now, the biggest problem with opioids is that they have the potential to cause addiction
by causing both physical and psychological dependence.
The euphoric effect appears to involve GABA-inhibitory interneurons of the ventral tegmental area of the brain.
Normally, GABA reduces the amount of dopamine released in the nucleus accumbens, which is
a brain structure that is part of our pleasure and reward system.
However, when opioids attach to and activate the µ receptors in that area, the release
of GABA becomes suppressed.
This in turn increases dopamine activity and thereby increases the amount of pleasure felt.
Now, on the other hand, prolonged, regular use of opioids leads to desensitization of
receptor signaling and down-regulation of the receptors and thus a decrease in sensitivity
to the effects of opioids.
As a result, when regular opioid use is reduced or suddenly stopped, the lack of receptor
activity is manifested as withdrawal symptoms.
These symptoms generally are opposite to the pharmacological effects of the opioid drugs.
So, now rather than causing constipation and slowing respiration, the brain stem triggers
diarrhea and elevates blood pressure.
Instead of triggering happiness, the nucleus accumbens and amygdala reinforce feelings
of dysphoria and anxiety.
All of this negativity feeds into the prefrontal cortex, further pushing a desire for opioids.
Now, before we end I wanted to briefly discuss couple more agents that interact with opioid
receptors but in a different way than the agents that we discussed so far.
The first one is a partial µ receptor agonist called Buprenorphine.
So, while a full opioid agonist binds to the µ receptor, activates it by changing its
shape and thus induces a full receptor response, a partial agonist binds to the receptor and
activates it with a smaller shape change which leads to only a partial receptor response.
In other words, the effects of partial agonists increase only until they reach a plateau.
Like all opioids, Buprenorphine can cause respiratory depression and euphoria, but its
maximal effects are much smaller than those of full agonists.
The benefits of this are lower risk of abuse, addiction, and side effects.
One last thing to keep in mind is that Buprenorphine is also an antagonist at the δ and
κ receptors and because of that it is referred to as mixed agonist-antagonist.
However, the contributions of these actions to its analgesic profile are currently unclear.
Now, let’s move on to our last agent that is Naloxone.
So, Naloxone is an opioid antagonist that can be used to block or reverse the effects
of opioid drugs.
Naloxone works by knocking off the opioids attached to the receptors in the brain, thereby
temporarily stopping the opioid effect.
This is possible because Naloxone has a stronger affinity for opioid receptors and thus is
able to kick the opioids out and block them from attaching again.
So during an emergency situation when a person’s breathing has slowed down or stopped due to
an opioid overdose, Naloxone can quickly restore normal breathing and save the life.
And with that I wanted to thank you for watching, I hope you found this video useful and as
always stay tuned for more.
