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We all know that we feel pain, but why do we? And how does our brain send pain responses through our bodies? Join Hank Green for a fascinating new episode of SciShow where he explains not only the biochemistry of pain, but exactly how painkillers work to take it away. Let's go!

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Pain is generally considered to be an unpleasant thing, no one likes the sensation of a pounding headache or a broken collarbone, so there's always been a market for analgesics, or pain-killing remedies. Ancient Egyptians munched on myrtle leaves and smoked opium, and Native Americans chewed up strings of willow and birch bark to dull their pain. Today there are all sorts of pills that can make painful situations more bearable, but to understand how these things do their job, it helps to first get a handle on why we have physical pain at all- how it works, and why we feel it so often.
Like right now- the lights, my eyes- it's been a long day.


Although most of us go to great lengths to avoid it, pain is good for us, because it helps us protect ourselves from the world. Pain means the body is damaged or under distress. It keeps us from doing stuff that is not in our self-interest by making that lack of self-interest very obvious. "Ouch!" is your brain saying, "Stop, back away from the flame, or porcupine, or wasp nest before you suffer further damage." And it's often the earliest sign of when our bodies are under attack by disease. This is why one of the most dangerous, but extremely rare, conditions can be an inability to feel pain. Take, for example, Georgian teenager Ashlyn Blocker. She has a mutation on a gene called SCN9A that has left her with the congenital insensitivity to pain. She's run around on a broken ankle for days, fished dropped spoons out of pots of boiling water, and nearly chewed her own tongue off accidentally! Sometimes, other medical conditions can interfere with the body's ability to feel pain. The bacterial infection leprosy, for example, leaves infected nerves and tissue dead, so, contrary to lore, lepers' fingers don't just fall off, rather, they sometimes sustain great damage because they're numb and have to be amputated. Thankfully, conditions like this are exceptionally rare, because our whole nervous system is set up to make sure that pain is the first response to any damage to our bodies.

Our nerve receptors are constantly picking up all kinds of sensations, but we've got specialized receptors, called nociceptors, that, unlike those receptors that help you enjoy kitten kisses, only fire to indicate pain. For example, if you hold a needle lightly into your palm you can feel the point, but it doesn't hurt, because only your normal nerve receptors are reading the needle. But, if you start slowly pushing on the needle, at some point it'll hit the nociceptive threshold, and then, ow. The pain hopefully makes you stop digging the needle into your flesh.

Now if the pain is the result of something more severe, like tissue or cell damage from falling on your tailbone or slicing your finger on the can opener, your body starts sending waves of tuning chemicals to your bruised bum or bloody finger. These chemicals lower your nociceptive pain-receiving threshold even more. That's why if you touch a cut or other open wound barely, it hurts more. Those tissues have higher levels of tuning chemicals that warn against further damage. Kinda like adding insult to injury, I know, but these chemicals are not only the root causes of our pain, they're also the targets that scientists look for to kill the pain. Think of these compounds as locks and keys. One of the main chemicals that damaged cells release in your body is called arachidonic acid. Its job is to interact with two enzymes known as COX-1 and COX-2. When the arachidonic acid combines with enzymes, they form compounds that do things like cause swelling, raise your body temperature and heart rate, and lower that pain threshold- everything we associate with being hurt. So if we can keep the arachidonic acid from being the key that fits into those enzymes' locks, we can control the effects that these chemicals cause. To do that, we send in painkillers to block those locks, and they fall into two main categories; first, you've got your friendly, hard-working over-the-counter variety. You'll find them in your medicine cabinet, purse, or tiny package of two pills at a gas station for like five freakin' bucks. The second family is made up of the big gun opioid drugs, the kind that only doctors can prescribe, like morphine, and oxycodone (the ones that people keep getting addicted to these days). You're not popping these babies for a little headache. They're for severe, nail-through-the-foot, hernia surgery, crap-oh-crap pain.

The first over-the-counter group is know as nonsteroidal anti-inflammatory drugs, or NSAIDs. They block the flood of pain chemicals, but they don't know exactly how to find the exact site of the pain, so they just block all of those pain-signalling COX enzymes, preventing them from sounding the pain alarm. Aspirin, also known as acetylsalicylic acid, was first isolated by German chemist Felix Hoffman in 1897, for the Bayer company, and its key pain-relieving compound is salicin, and that is found in that willow bark that our ancestors were munching on back in Hippocrates's day. Salicin metabolizes into salicylic acid, which disables the COX-1 enzyme particularly well.  Here aspirin's working like a key that breaks off in the lock that blocks all other keys from getting in. This means no pain-increasing arachidonic acid gets into the enzymes, which means no pain for as long as those blocked enzymes are in your system. Ibuprofen, often marketed as Advil and Motrin, was first derived from propionic acid in the 1960s as a treatment for rheumatoid arthritis, and it works a little differently from other NSAIDs. It block arachidonic acid from getting into the enzymes' sites responsible for pain, but rather than permanently breaking off like aspirin, ibuprofen just sort of sits there for a while and is eventually spit out by the enzyme lock. Naproxen sodium, including the drug Aleve, is another class of NSAID that also works by inhibiting COX enzymes. Finally, acetaminophen or paracetamol, commonly branded as Tylenol, is an over the counter drug that is not an NSAID. It only takes effect after the tuning chemicals have binded with the enzymes, and it inhibits some, but not all, of the effects caused by the compounds they form. That's why it helps relieve pain and fever but doesn't reduce inflammation. Acetaminophen is made from coal tar, and is mostly metabolized in the liver, so, yeah, if you have too much of it, it can do some liver damage, so be careful.

But sometimes pain might transcend anything your medicine cabinet can ease, after say your friend accidentally backs over your foot in their Mini Cooper. That's when you might wanna see a doctor about some prescription painkillers. Opioids do business in a completely different way from NSAIDs. They're kinda like silver-tongued pep talkers, and humans have been using them medicinally and recreationally for thousands of years. Truth be told, they don't actually kill pain. They just make you forget about it as you drift off into a cloud of numb. They relieve suffering by blocking the transmission of pain signals to the brain, and then by massaging the brain's opioid receptors to alter its perception of pain, whispering, "Everything's cool, man, just relax. Sure you're bleeding all over the place, but it's no big deal!"

There are three types of opioids: natural opiates, the semi-synthetics, and synthetics. Natural opiates, like morphine and codeine, are derived right from the old opium poppy plant. Not a coincidence, by the way, that Dorothy and her friends got all sleepy and chill in that poppy field outside the Emerald City in Oz. Morphine is the active ingredient in opium, and it was first extracted in its purest form in the early 1800s to become a commonly used painkiller during the Civil War. Before that, fainting ladies sipped laudanum, or opium diluted in alcohol, to calm their nerves. But lots of people were enjoying the mellowing effects of morphine a little too much, so, in the 1870s, chemists started working on an alternative, and they came up with a doozy, about twice as potent and equally addictive, heroin! Heroin lives in the semi-synthetic opioid branch of painkillers, right next to other highly addictive prescription bad boys like oxycodone. Chemist C.R. Alder Wright created heroin by adding two acetyl groups to a naturally occurring morphine molecule. When used medicinally to treat extreme pain, it's known as diamorphine. When it's used illegally on the street, it's called smack, dope, H, junk, et cetera, and you can watch The Wire to learn all about it. By 1905 things were bad enough that the US Congress banned opium and soon passed the Pure Food and Drug Act, which required medicines to list their contents on a label! Crazy!

Still searching for a powerful but less addictive painkiller, in 1937 German chemists synthesized methadone. Methadone works by hitting up the same opioid receptors as the morphine and heroin and belongs to the fully synthetic arm of the opioid family, which also includes stuff like Demerol and fentanyl. So methadone is used to treat addicts easing off heroin, but many believe believe it is equally - if not actually more - addictive. So while opioids definitely have their place in pain management, they can be a slippery slope. Their side effects may include nausea, drowsiness, constipation, and, if abused, your life going down the toilet. For this reason, among others, researchers keep looking for alternative ways to ease our pain. One unusual source of a new potential painkiller: snake venom. Like Beatrix Kiddo wielding a Hanzō sword, black mamba is one of the world's deadliest assassins; its super-potent venom could handily kill you in less than an hour. But recent research has found that the black mamba is actually a gentleman killer, because its deadly neurotoxin is spiked with mambalgins - I don't know how to pronounce that. But it is a painkiller as potent as morphine that eases the exquisite pain of impending death! Consider it.

But mambalgins use a different mechanism than anything we've covered so far. While morphine binds to opioid receptors, mambalgins zero in on the pain-sensing nociceptors themselves, right there at the source. There are several advantages to this, like whereas opioids have dramatic side effects like slowing down your breathing, mambalgins don't, and, they're less addictive. A French pharmaceutical company is currently developing a mamba drug, and more power to 'em.

As quick as we are to reach for the aspirin, without the sensation of pain the world becomes a dangerous place; pain is, in many ways, a gift. So next time you're running up the down escalator and you fall and slice your knee open, put aside your humiliation and thank that escalator and your angry pain receptors for reminding you to watch your step and work on your self-preservation.

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