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Thanks, in part, to the generous support of the NIHCM, this month we are releasing four special episodes on Opioids. We hope you enjoy them. This week's episode:

The History of Opioids - We will give a historical overview of people and opioids. We will look at when people first started using opioids, how they've changed over the years, and ways that they've been both amazingly positive as really effective painkillers and devastating to individuals and social orders. We will explore the early accounts of opiate use, addiction, and treatment, and touch on the Opium Wars in China. The evolution from raw opium latex to the powerful drugs derived from opium today traces a clear history of increasing addiction as opioids were available in more and more powerful preparations.


Those of you who want to read more can go here: http://theincidentaleconomist.com/wordpress/?p=70453

John Green -- Executive Producer
Stan Muller -- Director, Producer
Aaron Carroll -- Writer
Mark Olsen -- Graphics

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We're continuing our in-depth look at the class of drugs known as opioids.
How do they work?
What's the science behind them?
That's the topic of this week's healthcare triage.
This episode and our entire opioid series
are brought to you in part by the generous support of the
National Institute for Healthcare Management
We all know that analgesia, or pain relief is the intended use of opioids like morphine
But before we can talk about how these compounds reduce pain we need to discuss the physiology of pain perception
Let's start with some biology the brain and the nervous system are made up of cells called Neurons
each neuron consists of a cell body which runs the neurons activity the cell body has a number of
Dendrites which come off of it these are short fibers that receive signals from other neurons and transmit them to the cell body
Also attached to the cell body is an axon a long fiber that takes messages from the cell body and sends them to other
Dendrites and from there to other cell bodies
Axons can also end up in other tissues, like muscles, transmitting commands to them is needed when nerves talk to each other
It's called Neurotransmission. They do this by releasing chemical messengers called neurotransmitters
across the spaces between cells which are called synapses
the chemicals are released from the Axons and are picked up by
specific molecules called receptors in the dendrites there are different receptors all
Over the body that send messages to your brain when they're exposed to stimuli
There are temperature receptors that tell you when you're feeling something hot or cold mechanical
Receptors let you know when you're touching something or something is touching you there are even receptors that detect
Changes in Ph when stimuli are interpreters being noxious meaning that they could cause damage to our tissues specialized receptors called Nociceptors
Send signals to our brain
Nociceptors are located throughout the body
But we mostly think of them as being in the skin the walls of organs and deep within other body tissues like muscles and joints
so if you've ever mashed your finger with a hammer
splashed hot water on yourself while cooking or rolled your ankle while playing sports you can thank your
Nociceptors for sending a message to your brain all about the dumb thing you just did. We commonly refer to this message as pain
But nociceptors are kind of like the first leg of the journey that a pain signal takes to your brain
When we encounter noxious stimuli like touching a hot stove an electrical signal is sent up a primary
afferent neuron to a part of the spinal cord called the dorsal root ganglion. There. their electrical current causes a release of
Neurotransmitters. They pass the pain signal from the primary afferent neuron to a secondary, excitatory neuron there are several
neurotransmitters involved in pain signaling, but the major players are glutamate and Substance P.
The message is then sent up the spinal cord to different parts of the brain where it's
Interpreted as pain one area of the brain that receives the signal is the thalamus which helps give
Context to the message the thalamus relays the message to the hypothalamus
and limbic system which help us learn from our pain and avoid touching hot stoves in the future a
Downside to these parts of the brain receiving pain messages
Is that they can modify our behaviors and emotions about pain in ways that can be disruptive
Afraid of getting shots because of a traumatic childhood experience at the doctor's office?
Yeah, that's probably not the nurse or pediatricians fault. You can thank your limbic system for that one
So what does all of this have to do with opioids? well the cool thing about
opioids is that they inhibit the pain signal at multiple steps in the pathway they work in the brain the spinal cord and
even in the periphery in the brain
Opioids have mood altering effects cause sedation and can even decrease the emotional response to pain
opioids block the signaling from the primary Nociceptors to the secondary Neurons
Opioids also work on neurons that descend from the brainstem to the spinal cord that function to modulate pain signals those
Descending Pathways have fibers that either amplify or inhibit pain signals being sent to the brain
opioid compounds suppress the fibers amplifying the signal and enhance the fibers that
Inhibit the signal there's even evidence that opioids can work peripherally to decrease activation of primary neurons and inhibit immune and inflammatory
Responses to noxious stimuli the fact is, opioid medications are so effective at treating acute pain because they attack it from every
Neurological angle let's get even more sciencey and technical for a second and talk about how opioids work with the neurons in the spinal cord
we'll focus on the area where the primary neuron is passing the pain signal to the secondary neuron
remember, the space where the neurons meet is called the synaptic cleft the influx of calcium ions causes the release of
neurotransmitters into the synapse those
Neurotransmitters will float across the synapse and then bind with receptors on the postsynaptic neuron
This initiates a chain of events within the secondary neuron that further
Propagates the pain signal to the brain there are specific opioid receptors on both the presynaptic and postsynaptic
Neuron when an opioid compound attaches to a receptor on the presynaptic neuron it
Decreases the amount of calcium ions that can enter the cell ultimately decreasing the amount of excitatory
Neurotransmitters that are released into the synapse opioids binding to their receptors on the postsynaptic
neuron function to Decrease the response to any of the
neurotransmitters being released from the presynaptic neuron the end result less pain
But wait a second why do our nerves have receptors that respond to a compound that miraculously diminishes pain?
After all it doesn't really make sense that mammals would evolve a specific receptor for the sap of the poppy flower
Humans have known about the analgesic effects of opium for Millennia
But we wouldn't really be able to explain exactly why we had opioid receptors until the 1970s
It turns out that we have a built-in or endogenous
Analgesic system that modulates pain signals these endogenous opioids like beta endorphins and enkephalins and dynorphins are
Collectively known as endorphins a name derived from Endogenous morphine. See what they did there, so things are going to get
Superduper sciencey here the beta endorphins, enkephalins, and dynorphins
Interact with different opioid receptors to varying degrees, but one thing they all have in common is the tetra-peptide sequence
Tyrosine, Glycine, Glycine, and Phenylalanine or
tyr, gly, gly, phe. this sequence is really important because it's needed for the endogenous opioid to interact
Chemically with the opioid Receptor on a neuron if this is hard to visualize
think of the opioid Receptors as the car's ignition and the
Tetra-peptide
Sequence is the key if the key fits in the ignition
Just right then the opioid Receptor will be activated and cause a series of changes in the neuron that decrease the pain signal
opioid drugs and medications take advantage of this structure-activity relationship
They bind to our opioid receptors in much
The same way that
Endogenous opioids do but with much more powerful consequences there are three types of opioid receptors Mu receptors Kappa
Receptors and Delta Receptors when activated with an opioid agonist like morphine hydrocodone or heroin they will all produce
Analgesia
but each one comes with an unpleasant suite of side effects that we often associate with opioid use Kappa Receptor stimulation is
Associated with hallucinations and dysphorias an overwhelming sense of dissatisfaction
anxiety and restlessness
Delta and Mu receptors agonism can cause respiratory depression because opioid stimulation in the midbrain
suppresses the body's ability to
Appropriately detect Carbon dioxide levels in the body this can cause a person to simply stop
Breathing for a period of time other unpleasant side effects of opioid drugs are sedation urinary retention
Nausea vomiting dizziness
And really really
Really bad
Constipation one might argue that the most catastrophic side effect of opioids is tolerance meaning that higher and higher doses are required
To get the same level of pain relief the exact cellular mechanism behind tolerance is unclear though
There are many plausible theories in any case opioid tolerance is the harbinger of physical dependence and addiction
And that's the topic of next week's healthcare triage healthcare triage is supported in part by viewers like you
through Patreon.com, the service that allows you to support the show through a monthly donation
We'd especially like to thank our research associates Joe Sevits, MT, and our surgeon admiral, Sam. Thanks, Joe MT
And Sam! more information can be found at patreon.com/healthcareTriage