Pharmacology - OPIOIDS (MADE EASY)

Summary

This lecture delves into the pharmacology of opioids, explaining their mechanism of action in pain relief and euphoria through interaction with the central nervous system. It details the transmission of pain, the role of neurotransmitters like glutamate and substance P, and the body's endogenous opioids. The video also covers opioid receptors, synthetic agonists, and the side effects and addiction risks associated with opioid use. It concludes with a discussion on partial agonists like Buprenorphine and the antagonist Naloxone, crucial in reversing opioid overdoses.

Takeaways

• 💊 Opioids are drugs that act on the central nervous system to provide pain relief and euphoria, similar to morphine.
• 🧠 Pain transmission starts at nociceptors in the peripheral nervous system and is processed through the spinal cord to the brain.
• ⚡ Pain signals are carried as action potentials and involve neurotransmitters like glutamate, substance P, and CGRP.
• 📈 Glutamate excites neurons by activating NMDA and AMPA receptors, increasing calcium and sodium ion influx.
• 🔄 Endogenous opioids (enkephalins, dynorphins, and endorphins) bind to opioid receptors (μ, δ, k) to reduce pain by inhibiting neurotransmitter release.
• 🚀 Synthetic opioids, such as Fentanyl and Oxycodone, are more potent than naturally-derived opioids.
• 🤒 Opioids can cause side effects like nausea, respiratory depression, immune suppression, and constipation.
• 🔄 Opioid addiction involves GABA-inhibitory interneurons and increased dopamine release, leading to euphoria.
• 🚨 Naloxone is an opioid antagonist used to reverse the effects of opioid overdose by blocking receptors.
• 🧬 Prolonged opioid use leads to tolerance and withdrawal symptoms, which are opposite to the drugs' effects.

Q & A

What are opioids and how do they affect the central nervous system?

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.

What is the primary function of nociceptors in pain transmission?

Nociceptors are the branching ends of sensory neurons in the peripheral nervous system that respond to body damage by transmitting the painful stimulus to second-order neurons in the dorsal horn of the spinal cord.

How does glutamate contribute to the transmission of pain signals?

Glutamate activates both NMDA and AMPA receptors, permitting the influx of positively charged calcium and sodium ions, which makes neurons more likely to fire, thereby exciting second-order neurons in the dorsal horn and propagating a sharp, localized pain signal.

What role does Substance P play in pain transmission?

Substance P binds to NK-1 receptors, leading to intracellular signaling that activates arachidonic acid pathways, nitric oxide synthesis, and NMDA receptors. This increases the pain signal and makes neurons more likely to fire.

What are the three major families of endogenous opioids, and how do they function?

The three major families of endogenous opioids are enkephalins, dynorphins, and endorphins. They exert their effects by binding to opioid receptors, which are present in the central and peripheral nervous systems, thereby inhibiting pain transmission.

How do opioid receptors inhibit the transmission of pain?

Activation of opioid receptors by an agonist causes the closing of voltage-gated calcium channels on presynaptic nerve terminals, decreasing neurotransmitter release, and opening potassium channels, resulting in hyperpolarization and reduced neuron sensitivity to excitatory inputs.

What are some examples of synthetic opioid agonists, and how do they differ from naturally derived opioids?

Examples of synthetic opioid agonists include Fentanyl, Hydrocodone, Hydromorphone, Methadone, Meperidine, Oxycodone, and Oxymorphone. They are more potent than naturally derived opioids due to refined processing.

What are the common side effects associated with opioid use?

Common side effects include nausea, respiratory depression, antitussive effect, suppression of the immune system, hypotension, dilation of cutaneous blood vessels, tachycardia or bradycardia, itching, constipation, renal function depression, and urinary retention.

How does prolonged use of opioids lead to addiction and withdrawal symptoms?

Prolonged opioid use leads to desensitization and down-regulation of receptors, decreasing sensitivity to opioids. When use is reduced or stopped, withdrawal symptoms manifest as opposite effects to those of the opioids, such as diarrhea, elevated blood pressure, dysphoria, and anxiety.

What is Naloxone and how is it used in opioid overdose situations?

Naloxone is an opioid antagonist that blocks or reverses the effects of opioids by knocking off the opioids attached to brain receptors, restoring normal breathing during an overdose.

Outlines

00:00

💊 Opioid Pharmacology and Pain Transmission

This paragraph introduces opioids, a class of drugs that mimic morphine's effects on the central nervous system to relieve pain and induce euphoria. It explains the process of pain transmission from nociceptors to the brain, involving neurotransmitters like glutamate, substance P, and CGRP. The paragraph also details the role of NMDA and AMPA receptors in pain signaling, the function of endogenous opioids like enkephalins, dynorphins, and endorphins, and the presence of opioid receptors (μ, δ, and κ) in the nervous system. The activation of these receptors by endogenous peptides or synthetic agonists like fentanyl and oxycodone modulates neurotransmitter release and neuronal excitability, contributing to pain relief.

05:02

🚑 Opioid Side Effects and Addiction

This section delves into the various side effects of opioid use, including nausea, respiratory depression, antitussive effects, immune system suppression, histamine release, hypotension, tachycardia, bradycardia, itching, constipation, renal depression, and urinary retention. It also discusses the potential for addiction due to the euphoric effects opioids have on the brain's reward system, involving the suppression of GABA and increased dopamine activity. The paragraph further explains the process of opioid dependence and withdrawal, highlighting the physiological and psychological challenges associated with cessation of opioid use. Additionally, it introduces Buprenorphine as a partial μ receptor agonist with a lower risk of abuse and Naloxone as an opioid antagonist used to reverse opioid effects in emergencies.

10:06

🆘 Naloxone: The Opioid Antidote

The final paragraph focuses on Naloxone, an opioid antagonist that can counteract the effects of opioids by displacing them from their receptors due to its higher receptor affinity. This action is crucial in emergency situations, such as opioid overdose, where Naloxone can rapidly restore normal breathing and potentially save lives. The paragraph concludes the lecture with an acknowledgment of the importance of understanding opioid pharmacology and the role of Naloxone in emergency medicine.

Keywords

💡Opioids

Opioids are a class of drugs that include both natural and synthetic substances that mimic the effects of opium. They are primarily used for pain relief and can induce a sense of euphoria. In the video, opioids are discussed as acting on the central nervous system to produce morphine-like effects, highlighting their mechanism of action and their role in pain management.

💡Nociceptors

Nociceptors are specialized nerve endings that detect potentially damaging stimuli and send signals to the brain to initiate a pain response. The script explains that pain begins at these sensory neurons, which are found within the peripheral nervous system and are crucial for the transmission of pain signals to the spinal cord.

💡Spinothalamic Tract

The spinothalamic tract is a pathway in the spinal cord that carries sensory information related to pain and temperature from the body to the brain. The video describes how the signal from nociceptors travels through this tract to the thalamus and then to the somatosensory cortex, where pain is perceived.

💡NMDA Receptors

NMDA receptors are a type of ionotropic glutamate receptor that plays a significant role in synaptic plasticity and is involved in the transmission of pain signals. The script mentions that Substance P binding to NK-1 receptors can activate NMDA receptors, leading to an increase in pain signals.

💡Endogenous Opioids

Endogenous opioids are naturally occurring peptides within the body that bind to opioid receptors to produce pain relief and other effects. The video lists three major families of endogenous opioids: enkephalins, dynorphins, and endorphins, and explains their role in the body's natural pain relief mechanisms.

💡Opioid Receptors

Opioid receptors are a group of G-protein-coupled receptors found in the central and peripheral nervous systems that respond to opioids. The video details three major types of opioid receptors: µ (mu), δ (delta), and κ (kappa), and discusses their distribution, affinity for ligands, and contribution to opioid effects.

💡Synthetic Opioid Agonists

Synthetic opioid agonists are man-made substances that are more potent than naturally-derived opioids. The script provides examples such as Fentanyl, Hydrocodone, and Oxycodone, and explains that these drugs act primarily at the μ-opioid receptors, mimicking the effects of endogenous opioid peptides.

💡Methadone

Methadone is highlighted in the video as a potent μ-receptor agonist with additional properties, including being an antagonist of the NMDA receptor and a reuptake inhibitor of norepinephrine and serotonin. This makes Methadone useful for treating both nociceptive and neuropathic pain.

💡Addiction

Addiction is a complex condition characterized by compulsive engagement in rewarding stimuli despite adverse consequences. The video discusses how opioids have the potential to cause addiction by inducing both physical and psychological dependence, and explains the neurobiological mechanisms behind the euphoric effects and withdrawal symptoms.

💡Buprenorphine

Buprenorphine is described in the video as a partial µ receptor agonist with a ceiling effect on its maximal effects, reducing the risk of abuse, addiction, and side effects compared to full agonists. It is also noted for its antagonist activity at δ and κ receptors, making it a mixed agonist-antagonist.

💡Naloxone

Naloxone is an opioid antagonist used to block or reverse the effects of opioid drugs. The script explains how Naloxone displaces opioids from their receptors, which can be critical in emergency situations involving opioid overdose, as it can quickly restore normal breathing.

Highlights

Opioids are a group of drugs that act on the central nervous system to produce morphine-like effects such as pain relief and euphoria.

Pain begins at the nociceptors, the branching ends of sensory neurons in the peripheral nervous system.

Glutamate is a key neurotransmitter for pain that activates NMDA and AMPA receptors, leading to increased neuronal firing.

Substance P binding to NK-1 receptors activates intracellular signaling pathways involved in pain perception.

Endogenous opioids like enkephalins, dynorphins, and endorphins bind to opioid receptors to alleviate pain.

There are three major types of opioid receptors: µ (mu), δ (delta), and κ (kappa), each with distinct functions.

Opioid receptors are 7-transmembrane spanning proteins that inhibit neurotransmitter release when activated.

Synthetic opioids like Fentanyl and Oxycodone are more potent than naturally-derived opioids.

Methadone has unique properties as a potent μ-receptor agonist, NMDA antagonist, and norepinephrine/serotonin reuptake inhibitor.

Opioids can cause side effects like nausea, respiratory depression, and immune system suppression.

Opioids are associated with addiction due to their euphoric effects and potential for physical and psychological dependence.

Prolonged opioid use leads to receptor desensitization and withdrawal symptoms when use is reduced or stopped.

Buprenorphine is a partial µ receptor agonist with lower abuse potential and maximal effects compared to full agonists.

Buprenorphine also acts as an antagonist at δ and κ receptors, making it a mixed agonist-antagonist.

Naloxone is an opioid antagonist used to block or reverse the effects of opioid overdose by displacing opioids from receptors.

Naloxone can quickly restore normal breathing in emergency situations involving opioid overdose.

Transcripts

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.