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xpl0de
ḆËŦŦЯ_őƑ_Ŧwo ƹvïlz




Registered: 07/14/07
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New opioid douses pain without being addictive or deadly in primates 1
#23611256 - 09/04/16 12:32 PM (7 years, 4 months ago) |
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http://arstechnica.com/science/2016/09/new-opioid-douses-pain-without-being-addictive-or-deadly-in-primates/
Quote:
 In monkeys, the drug is a highly effective pain reliever without downsides.
While the opioid epidemic continues kill more than 40 American every day, researchers and health experts are frantically searching for ways to curtail use of the highly addictive, pain-quenching drugs. In March, the Centers for Disease Control and Prevention even released new guidelines directing doctors to simply refrain from prescribing opioids. But if a new study holds up, the health agency may be able to reverse course.
According to a report in the Proceedings of the National Academy of Sciences, an opioid drug referred to as BU08028 was able to alleviate pain in a dozen monkeys just as well as other opioid painkillers, such as morphine. Yet, unlike every other opioid drug, BU08028 showed no signs of being addictive. Even at high dose—at which other opioid drugs inhibit the respiratory and cardiovascular system, which can be fatal—BU08028 was harmless.
"Based on our research, this compound has almost zero abuse potential and provides safe and effective pain relief," Mei-Chuan Ko, a professor of physiology and pharmacology at Wake Forest Baptist Medical Center and lead author of the study, said in a statement. "This is a breakthrough for opioid medicinal chemistry that we hope in the future will translate into new and safer, non-addictive pain medications."
In pain experiments, which involved dipping monkeys' tails into hot water, BU08028 was a potent pain-killer. A single dose relieved pain for up to 30 hours. Next, in experiments in which the monkeys were trained to self-medicate, BU08028 proved no more habit-forming than a control dose of saline. Scientists forced one group of monkeys to take BU08028, while another group was forced to take morphine. When the drugs were taken away, the monkeys who had taken BU08028 showed no withdrawal symptoms, unlike the monkeys who had blazed on morphine.
BU08028's lack of nasty side-effects may hinge on its dual-action biochemistry. Like other opioids, it controls pain by targeting the nervous system's classic μ-opioid peptide receptors, called MOP receptors. But BU08028 also targets “nonclassical” opioid receptors, called NOP receptors for nociceptin receptors, in the nervous system. These receptor proteins generally don’t interact with opioid drugs, yet they share similarities with the receptors that do. NOP receptors regulate pain, like their MOP counterparts, but they are also involved in a host of other brain functions, such as memory, cardiovascular functions, and anxiety.
“To our knowledge, the present study provides the first functional evidence in nonhuman primates that BU08028 with mixed MOP/NOP agonist activities is an effective and safe analgesic without apparent abuse liability or other opioid-associated side effects,” the authors conclude.
Next, the researchers hope to test BU08028 at treating chronic pain without risks of addiction or overdoses. Regardless of BU08028's fate in subsequent trials, the researchers are hopeful that the strategy of co-activating NOP and MOP receptors will eventually lead to a safer painkiller.
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Love_spirit
Circle Of Power


Registered: 07/18/15
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Re: New opioid douses pain without being addictive or deadly in primates [Re: xpl0de]
#23611282 - 09/04/16 12:41 PM (7 years, 4 months ago) |
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Anything that actually removes suffering is addictive.
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Ogla



Registered: 02/16/04
Posts: 11,315
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Re: New opioid douses pain without being addictive or deadly in primates [Re: Love_spirit]
#23611358 - 09/04/16 01:09 PM (7 years, 4 months ago) |
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theres gonna be alot of upset dopefiends outthere
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Dark_Star
train driver pervading a desktop


Registered: 08/20/04
Posts: 31,859
Loc: Uranus
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Re: New opioid douses pain without being addictive or deadly in primates [Re: Ogla] 1
#23611379 - 09/04/16 01:20 PM (7 years, 4 months ago) |
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It would be awesome if they find an effective painkiller that isn't addictive. I have doubts though. Remember heroin was first touted as a cure for morphine addiction. People still try to tout suboxone as a non-addictive treatment for opioid addiction, despite the fact that anyone who's been on it knows better.
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Cognitive_Shift
CS actual




Registered: 12/11/07
Posts: 29,591
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Re: New opioid douses pain without being addictive or deadly in primates [Re: Dark_Star] 1
#23611595 - 09/04/16 02:31 PM (7 years, 4 months ago) |
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If it's an opiate/opiod habituation will lead to physical dependency which is what makes opiates so notoriously addictive. This article sounds to good to be true.
-------------------- L'enfer est plein de bonnes volontés et désirs
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musiclover420
psychonaut



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Re: New opioid douses pain without being addictive or deadly in primates [Re: Cognitive_Shift]
#23611637 - 09/04/16 02:46 PM (7 years, 4 months ago) |
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Even if it works as good as they say I wonder how much they will end up charging for it... If it lasts "30 hours" they won't make much $ selling it cheap.
-------------------- Don't worry about me, I've got all that I need. And I'm singing my song to the sky You know how it feels, With the breeze of the sun in your eyes. Not minding that time's passing by I've got all and more, My smile, just as before. Is all that I carry with me I talk to myself, I need nobody else. I'm lost and I'm mine, yes I'm free
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fapjack
Title



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Re: New opioid douses pain without being addictive or deadly in primates [Re: musiclover420]
#23611924 - 09/04/16 04:40 PM (7 years, 4 months ago) |
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If anyone is interested on the difference between this and buprenorphine
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durian_2008
Cornucopian Eating an Elephant


Registered: 04/02/08
Posts: 16,693
Loc: Raccoon City
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Re: New opioid douses pain without being addictive or deadly in primates [Re: fapjack]
#23611973 - 09/04/16 04:49 PM (7 years, 4 months ago) |
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But, what happens to the monkeys' tails?
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QT3BFLEE
ส้


Registered: 02/17/13
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Re: New opioid douses pain without being addictive or deadly in primates [Re: durian_2008]
#23612277 - 09/04/16 06:40 PM (7 years, 4 months ago) |
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Please. Give me a double-blind with hardened heroin addicts already stable on high-dose bupe and then tell me this is a step towards the Holy Grail.
-------------------- My Public Key
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grower182
Stranger


Registered: 01/11/13
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Re: New opioid douses pain without being addictive or deadly in primates [Re: QT3BFLEE]
#23612293 - 09/04/16 06:44 PM (7 years, 4 months ago) |
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So is BU08028 just kratom in pill form?
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morrowasted
Worldwide Stepper



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Re: New opioid douses pain without being addictive or deadly in primates [Re: grower182]
#23612344 - 09/04/16 07:01 PM (7 years, 4 months ago) |
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Opiates that antagonize delta-opioid receptors in addition to agonising mu-opioid receptors, or that do not bind to delta-opioid receptors only to mu-opioid receptors, show promise in mitigating tolerance and thus the physical addiction because opioid-induced tolerance appears to be linked to the upregulation of delta-opioid receptors.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943346/
One promising currently available herbal candidate is Akuammine from Akuamma seeds.
Edited by morrowasted (09/04/16 07:06 PM)
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morbiddoctor
Frilly fungal fruiter



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Re: New opioid douses pain without being addictive or deadly in primates [Re: morrowasted]
#23612857 - 09/04/16 09:36 PM (7 years, 4 months ago) |
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If opiates kill over 40 people a day, and kratom has killed maybe 40 people ever, how is Kratom worse?
-------------------- Trade list Updated 12/20/15 Ranco temperature controller and Wagner steamer for pasteurization in trade list! I'm looking for eyecatching, colorful, unique and interesting fungi. Not limited to edible or medicinal. Print them when you're on foray and pm me please!
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LuSiD enthusiast
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Re: New opioid douses pain without being addictive or deadly in primates [Re: grower182] 1
#23613074 - 09/04/16 10:48 PM (7 years, 4 months ago) |
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Quote:
grower182 said: So is BU08028 just kratom in pill form?
Of course not if it actually got people off heroin, then that would be a cause for concern and a imminent public health threat with no medical benefits, and we would have to ban it.
I mean, that's just what the DEA has taught me the last few days.
-------------------- I'm addicted to coke, weed, booze, ludes and speed. Not LSD, you can't get addicted to LSD, it was built by scientists. I ain't got no demons that gonna get woke. In erowid we trust. Just take your damn pills and don't ask any questions, you'll be fine.
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LuSiD enthusiast
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Re: New opioid douses pain without being addictive or deadly in primates [Re: morbiddoctor] 1
#23613081 - 09/04/16 10:50 PM (7 years, 4 months ago) |
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Quote:
morbiddoctor said: If opiates kill over 40 people a day, and kratom has killed maybe 40 people ever, how is Kratom worse?
Don't you get it? If people get off heroin that's bad. We need to get people back on heroin because that's not a public health crisis. Hell they got heroin now with fentanyl analogs so strong they could wipe out entire cities with an 8 ball.
BUY HEROIN, BAN KRATOM, PRAISE THE GREAT LEADERS OF OUR NATION THE DEA!!!
-------------------- I'm addicted to coke, weed, booze, ludes and speed. Not LSD, you can't get addicted to LSD, it was built by scientists. I ain't got no demons that gonna get woke. In erowid we trust. Just take your damn pills and don't ask any questions, you'll be fine.
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morbiddoctor
Frilly fungal fruiter



Registered: 07/05/09
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Re: New opioid douses pain without being addictive or deadly in primates [Re: LuSiD enthusiast]
#23613658 - 09/05/16 03:31 AM (7 years, 4 months ago) |
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Of course I get it. These twats and alll related groups are just vouchers for public domineering and slavery. I was just hoping to link the insane kartom ban to this bs. I've given up hope. There's nothing to do. Let this world crumble so we can rebuild. To hell with those in power, and a bullet to their heads, please.
-------------------- Trade list Updated 12/20/15 Ranco temperature controller and Wagner steamer for pasteurization in trade list! I'm looking for eyecatching, colorful, unique and interesting fungi. Not limited to edible or medicinal. Print them when you're on foray and pm me please!
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travelleler
a horse-fart in a hurricane



Registered: 08/30/08
Posts: 3,955
Loc: yonder mountains
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Re: New opioid douses pain without being addictive or deadly in primates [Re: morbiddoctor]
#23614027 - 09/05/16 08:03 AM (7 years, 4 months ago) |
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Sounds like the same shit they told everyone when they developed Demerol, which turned out not to be very effective against pain but still causes dependence. Then again when they came out with Oxycodone and Hydrocodone.... a pain killer safer than morphine with very little withdrawl risk... Riiiiiiight. Now they got the Suboxone which is a fantastic tool to get people off heroin, right? Except people who use it find that they can't sleep unless they take the pills... so dependence all over again.
I can't forsee this new drug will be any different. It's more than likely a tool of leverage big pharm is using to advance the Kratom and herbal medicine ban agenda.
a bullet to the head isn't good enough for these shit-heads, they need severe banishment from the Earth... proceeded by a "difficult interview" with re-education, a lil something they can take to eternity.
--------------------

"Whales have deep thoughts"
Dreams are the fuel of the soul
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AllGreyThumbs
Storage Container Aficionado


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Re: New opioid douses pain without being addictive or deadly in primates [Re: fapjack]
#23614056 - 09/05/16 08:14 AM (7 years, 4 months ago) |
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Quote:
fapjack said: If anyone is interested on the difference between this and buprenorphine

So let me guess, they need a new cash cow? Maybe the patent is expiring? Because to me it looks like almost exactly the same thing.
Just tack a tiny extra piece on the molecule, tout it as the next miracle drug, and sell it as premium prices, despite being almost exactly the same as something we already have.
I really doubt that they even give a damn about it being better than other options. They just mixed up a new product is all.
-------------------- I only use drugs medicinally. If I don't my knees hurt from kneeling down.
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travelleler
a horse-fart in a hurricane



Registered: 08/30/08
Posts: 3,955
Loc: yonder mountains
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Re: New opioid douses pain without being addictive or deadly in primates [Re: AllGreyThumbs]
#23614068 - 09/05/16 08:18 AM (7 years, 4 months ago) |
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Quote:
AllGreyThumbs said:
Quote:
fapjack said: If anyone is interested on the difference between this and buprenorphine
Just tack a tiny extra piece on the molecule, tout it as the next miracle drug, and sell it as premium prices, despite being almost exactly the same as something we already have.
I really doubt that they even give a damn about it being better than other options. They just mixed up a new product is all.
I believe you hit the nail on the head... It's leverage against Kratom and a false security blanket for lawmakers who might feel otherwise guilty about hindering people in their personal healing process... so now "oh look here's an amazing "new" drug that does the same thing as kratom!" and the idiot law men will believe it because they have been programmed en situ to accept "professional opinion" without the burden of proof or legit 3rd party corroboration.
makes me wanna puke
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"Whales have deep thoughts"
Dreams are the fuel of the soul
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bigbitch
Stranger

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Re: New opioid douses pain without being addictive or deadly in primates [Re: morrowasted]
#23614117 - 09/05/16 08:43 AM (7 years, 4 months ago) |
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Quote:
morrowasted said: One promising currently available herbal candidate is Akuammine from Akuamma seeds.
That's interesting, I'm always for a more natural route. I am skeptical of BU08028 being a miracle drug as well. It just doesn't seem sensible for big pharma, to push something like that on the market. They want people to be addicted to addictive drugs, so they can make fat stacks off the addicts.
It would be nice to have something like this available if I'm ever injured badly. I think the people who take the other opiates for pure recreational use are blind addicts. It's like cigarettes. They are addicted to a shitty drug. I've experimented very lightly with opiates, and cigarettes. The high and feeling from them isn't even enjoyable. The only reason to enjoy something like that is because you're an addict.
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durian_2008
Cornucopian Eating an Elephant


Registered: 04/02/08
Posts: 16,693
Loc: Raccoon City
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Re: New opioid douses pain without being addictive or deadly in primates [Re: morbiddoctor]
#23615074 - 09/05/16 03:09 PM (7 years, 4 months ago) |
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Quote:
morbiddoctor said: If opiates kill over 40 people a day, and kratom has killed maybe 40 people ever, how is Kratom worse?
I'm not a prohibitionist. I have no intention of protecting intelligent, moral people from themselves but believe those with a death wish will use whatever is most convenient, whether it's a plant, a pharm, or research chemical.
I'm seeing potent, black, tarry substances and refined extracts, do not consider myself a fool, am asking whether these things are fool proof.
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LuSiD enthusiast
Stranger

Registered: 03/14/13
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Re: New opioid douses pain without being addictive or deadly in primates [Re: AllGreyThumbs]
#23616630 - 09/05/16 11:29 PM (7 years, 4 months ago) |
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Quote:
AllGreyThumbs said:
Quote:
fapjack said: If anyone is interested on the difference between this and buprenorphine

So let me guess, they need a new cash cow? Maybe the patent is expiring? Because to me it looks like almost exactly the same thing.
Just tack a tiny extra piece on the molecule, tout it as the next miracle drug, and sell it as premium prices, despite being almost exactly the same as something we already have.
I really doubt that they even give a damn about it being better than other options. They just mixed up a new product is all.
Looking at this was like one of those "spot the differences" puzzle they give you as a kid.
Hell it was harder to find than fucking waldo.
-------------------- I'm addicted to coke, weed, booze, ludes and speed. Not LSD, you can't get addicted to LSD, it was built by scientists. I ain't got no demons that gonna get woke. In erowid we trust. Just take your damn pills and don't ask any questions, you'll be fine.
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bigbitch
Stranger

Registered: 04/17/14
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Re: New opioid douses pain without being addictive or deadly in primates [Re: fapjack]
#23616642 - 09/05/16 11:39 PM (7 years, 4 months ago) |
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Quote:
fapjack said: If anyone is interested on the difference between this and buprenorphine
lol, I knew this was too good to be true. It's basically suboxone. Which even though is less narcotic/recreational, it stays in your system longer. I've heard that at the year mark, you are still very mildly detoxing off of suboxone. So let us get all of the addicts hooked on a shittier drug that is more difficult to abstain from, because the detox is longer.
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morbiddoctor
Frilly fungal fruiter



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Re: New opioid douses pain without being addictive or deadly in primates [Re: bigbitch]
#23616697 - 09/06/16 12:18 AM (7 years, 4 months ago) |
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I'm not going after you durian. I'm on board. Just perplexed at the idiocy of those running the show.
-------------------- Trade list Updated 12/20/15 Ranco temperature controller and Wagner steamer for pasteurization in trade list! I'm looking for eyecatching, colorful, unique and interesting fungi. Not limited to edible or medicinal. Print them when you're on foray and pm me please!
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travelleler
a horse-fart in a hurricane



Registered: 08/30/08
Posts: 3,955
Loc: yonder mountains
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Re: New opioid douses pain without being addictive or deadly in primates [Re: morbiddoctor]
#23617109 - 09/06/16 06:18 AM (7 years, 4 months ago) |
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Fapjack,
I can't see any difference at all. For all intents and purposes it's Subutex, or at the very least a subutex analog.
Buprenorphine or whatever... I dont use the stuff. Have friends who need it unfortunately.
--------------------

"Whales have deep thoughts"
Dreams are the fuel of the soul
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durian_2008
Cornucopian Eating an Elephant



Registered: 04/02/08
Posts: 16,693
Loc: Raccoon City
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Re: New opioid douses pain without being addictive or deadly in primates [Re: morbiddoctor]
#23617954 - 09/06/16 11:59 AM (7 years, 4 months ago) |
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Quote:
morbiddoctor said: I'm not going after you durian. I'm on board. Just perplexed at the idiocy of those running the show.
Over 3,000 posts, I am still not in the habit using the bracketed replies.
My comment was not intentionally directed at anyone, in particular. 
While I am not presently in possession of any controlled substances, my stance on public medicine, as opposed to private practice, is akin to my stance on public transportation, as opposed to vehicle ownership.
I believe the medical treatment should be priced for maximal demand, or there should be none. If it is not well liked, by the people using it, it should command an even lower price.
The free market can contend with side effects or miraculous benefits.
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rider420
Ghost in the machine


Registered: 02/11/16
Posts: 659
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Re: New opioid douses pain without being addictive or deadly in primates [Re: durian_2008]
#23618115 - 09/06/16 12:50 PM (7 years, 4 months ago) |
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And heroin was invented and sold as a less addictive form of morphine. SSDD same shit different day.
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Greg
always learning




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Re: New opioid douses pain without being addictive or deadly in primates [Re: AllGreyThumbs]
#23618400 - 09/06/16 02:08 PM (7 years, 4 months ago) |
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Quote:
AllGreyThumbs said: So let me guess, they need a new cash cow? Maybe the patent is expiring? Because to me it looks like almost exactly the same thing.
Just tack a tiny extra piece on the molecule, tout it as the next miracle drug, and sell it as premium prices, despite being almost exactly the same as something we already have.
I really doubt that they even give a damn about it being better than other options. They just mixed up a new product is all.
I mean no disrespect but this is wrong from a pharmacology/chemistry viewpoint.
Take for example epinephrine and albuterol, two very different drugs with totally different uses. Here are the molecules:


Or sucralose and sucrose. Again two very different substances (table sugar and splenda):


A single functional group can completely change the way a molecule acts in the body.
There are even more extreme examples such as enantiopure drugs which one form of the molecule is a useful drug and another is a poison despite being essentially mirror images of each other.
Don't get me wrong though, I don't personally place much trust in the pharma industry either and I don't blame you for being skeptical.
Edited by Greg (09/06/16 02:19 PM)
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sh4d0ws
LSx


Registered: 02/26/08
Posts: 12,086
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Re: New opioid douses pain without being addictive or deadly in primates [Re: Dark_Star]
#23619814 - 09/06/16 09:14 PM (7 years, 4 months ago) |
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Quote:
Dark_Star said: It would be awesome if they find an effective painkiller that isn't addictive. I have doubts though. Remember heroin was first touted as a cure for morphine addiction. People still try to tout suboxone as a non-addictive treatment for opioid addiction, despite the fact that anyone who's been on it knows better.
This. I even seem to remember hydromorph (possibly oxy) also touted as being a "less addictive" pain killer than morphine.
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CLIT
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Re: New opioid douses pain without being addictive or deadly in primates [Re: morrowasted]
#23627866 - 09/09/16 03:06 AM (7 years, 4 months ago) |
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so Akuammine from Akuamma seeds is opioidergic? Anyone tried it?
Quote:
morrowasted said: Opiates that antagonize delta-opioid receptors in addition to agonising mu-opioid receptors, or that do not bind to delta-opioid receptors only to mu-opioid receptors, show promise in mitigating tolerance and thus the physical addiction because opioid-induced tolerance appears to be linked to the upregulation of delta-opioid receptors.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943346/
One promising currently available herbal candidate is Akuammine from Akuamma seeds.
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howsyournaggerdoin
Happy


Registered: 02/04/16
Posts: 1,600
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Re: New opioid douses pain without being addictive or deadly in primates [Re: CLIT]
#23627885 - 09/09/16 03:20 AM (7 years, 4 months ago) |
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https://www.researchgate.net/figure/49701691_fig2_Fig-2-Acute-thermal-antinociceptive-effect-of-BU08028-A-and-buprenorphine-B-alone
Quote:
yl)piperidinl-4-yl)-indolin-2-one (SR16835), which are not in the oripavine family, but bind with greater affinity to the NOP receptor, also have -mediated antinociceptive activity that is attenuated by the NOP component (Khroyan et al., 2009). Like- wise, buprenorphine enhances alcohol consumption at low doses, presumably through opioid receptors, but reduces alcohol consumption at higher doses. This reduction in alcohol consumption is blocked by the NOP receptor antagonist [Nphe 1 ,Arg 14 ,Lys 15 ]nociceptin-NH 2 (UFP-101), suggesting that the buprenorphine-induced reduction in alcohol consumption is caused by activation of NOP receptors (Ciccocioppo et al., 2007). An NOP-mediated reduction in CPP and self-administration of a variety of abused drugs by N/OFQ is already well documented (Murphy et al., 1999; Kotlin ́ ska et al., 2002; Ciccocioppo et al., 2003; Zhao et al., 2003). Therefore, it is possible that increasing the NOP agonist efficacy in buprenorphine, or other opioid ligands, may produce an effective nonaddicting analgesic and may be more efficacious than buprenorphine for drug abuse pharmacotherapy.
The buprenorphine analog BU08028 was designed to have increased affinity and efficacy at the NOP receptors. BU08028 is the first reported “universal opioid ligand” that binds with high affinity (under 10 nM) to each of the receptors in the opioid receptor family. BU08028 is almost 10 times more potent at NOP receptors than buprenorphine and also has higher functional efficacy at NOP compared with buprenorphine in vitro (Table 2). Because BU08028 has similar receptor activity to buprenorphine but increased NOP activity, we expect diminished -receptor-mediated effects such as antinociceptive activity, tolerance development, and reward. In acute antinociception assays, BU08028 seems less potent than buprenorphine, showing virtually no antinociceptive activity at 0.1 mg/kg and little activity at 0.3 mg/kg (Fig. 2), possibly suggesting NOP-mediated suppression of -mediated antinociception. However, the antinociceptive activity of BU08028 is potentiated only by the NOP receptor antagonist SB612111 at higher doses of BU08028, suggesting NOP receptor agonist activity has little or no dis- cernable effect on antinociception at low doses of BU08028.
Alternatively, the lack of antinociceptive activity at low doses might suggest that the higher logP of BU08028 is hindering its access to the central nervous system. Even though the partial agonist activity of BU08028 at receptors in vitro is similar to that of buprenorphine, the dose-response curve of BU08028 for antinociception is much steeper than that of buprenorphine, where the higher doses of BU08028 produced near maximal effects. As demonstrated in many reports, the dose-response curve for buprenorphine is very shallow, never approaching 100% MPE (Cowan et al., 1977; Ide et al., 2004).
In addition, animals dosed with BU08028 exhibit a very profound Straub tail (T. Khroyan, unpublished observation), indicative of -like excitatory activity, and an obvious increase in locomotor activity, also a -mediated effect in mice (Cowan et al., 1977). BU08028 produces antinociceptive effects that are longer- lasting than buprenorphine, consistent with BU08028’s higher logP. BU08028 antinociception is still strongly evident 24 h postinjection with virtually 100% activity remaining at 10 mg/kg, whereas buprenorphine antinociceptive activity is no longer evident at this later time (Fig. 2). Furthermore, it was anticipated that a compound with higher NOP efficacy, similar to the mixed NOP/ agonist SR16435, would likely have a reduced tolerance development (Khroyan et al., 2007). However, as shown in Fig. 5, administration of BU08028 over 9 days resulted in tolerance to its antinociceptive effects, similar to that seen with morphine and buprenorphine.From these experiments it is evident that BU08028 produces a very long-lasting antinociceptive effect, but tolerance to this effect develops at a similar pace compared with the parent compound buprenorphine. Initial assessment of the rewarding effects of BU08028 was conducted using the one-trial PC paradigm with a 48-h period between drug and vehicle sessions (Fig. 6). This behavioral protocol was used to avoid any interference with the long- lasting effects of BU08028.
Similar to morphine, BU08028 produced CPP. BU08028 was also directly compared with its parent compound buprenorphine using this same protocol. Buprenorphine produced an inverted U-shaped dose-response curve where the 3 mg/mg dose produced a significant CPP and 1 and 10 mg/kg did not, a phenomenon that has previously been observed in rats (Brown et al., 1991; Rowlett et al., 1994). In mice, CPP to buprenorphine has been reported after repeated injections at the 3 mg/kg dose, whereas one-trial conditioning with this dose did not result in CPP (Marquez et al., 2007, 200. Using the more common repeated-injection PC protocol, BU08028 also produced CPP after four drug pairings, when drug sessions were not separated by 48 h (Fig. 7). Apparently, the effect of BU08028, with respect to “reward,” is not as long- lasting as its antinociceptive effect, lasting less than 24 h, being associated only with the drug-paired compartment and not in- terfering with the production of a CPP. 18,19-Dehydrobu- prenorphine (HS 599), a didehydro derivative of buprenorphine that is also long-lasting, did not produce CPP in the traditional PC training regimen (Lattanzi et al., 2001). It is possible that, unlike BU08028, HS 599 may have longer-lasting effects that influence the development of CPP, and that the drug effects could have carried over to the vehicle session. In any case, the present findings show that BU08028 produces CPP alone and suggest that its NOP agonist activity is not attenuating its receptor-mediated behavior with respect to antinociception, tolerance development, or reward.
Although buprenorphine is approved for maintenance for heroin addiction, it has been considered as a potential pharmacotherapy for other abused drugs. Previous research has examined the effects of buprenorphine on cocaine-induced behaviors. Chronic buprenorphine administration can decrease cocaine intake during self-administration, drug-in- duced reinstatement of extinguished cocaine seeking, and cocaine-induced locomotor activity (Sorge et al., 2005; Sorge and Stewart, 2006; Placenza et al., 200. In the PC paradigm, buprenorphine has been reported to both attenuate and potentiate cocaine-induced CPP (Brown et al., 1991; Kosten et al., 1991). These discrepant findings are probably caused by the experimental parameters including the drug regimen used. We were hoping that BU08208 would reduce cocaine-induced CPP. Not surprisingly, however, because BU08028 produced CPP, it was unable to attenuate cocaine- induced CPP.
The goal of this project was to synthesize and characterize compounds with significant NOP receptor activity to supple- ment (and potentially ␦ and ) activity found in the buprenorphine scaffold. The behavioral results obtained with BU08028 can also be compared with other bifunctional /NOP receptor ligands that we have characterized previously. We have demonstrated previously that SR14150 and SR16435, both with high affinity and partial agonist activity at NOP and receptors, have antinociceptive activity that is inhibited by naloxone and potentiated by the NOP receptor antagonist SB612111 (Khroyan et al., 2009; Toll et al., 2009). SR16435, which has an in vitro profile strikingly similar to BU08028, produces antinociception and CPP, indicating that, like BU08028, the NOP component is not sufficient to block the rewarding effect of the component. It is interesting to note that SR16435 has one behavioral feature diamet- rically opposed to that of BU08028. Although BU08028 causes a large increase in locomotor activity, SR16435 does the opposite, resulting in reduced activity levels, a behavior attributed to NOP receptor activation.
This difference in global activity observed with SR16435 and BU08028 is diffi- cult to explain because these compounds have a similar in vitro profile with respect to NOP, , and receptors, but suggest once again that the -mediated activities are strongly represented in BU08028. Alternately, it is possible that the very weak ␦ component of BU08028, which is not present at all in SR16435, might contribute to the increased global activity seen in BU08028. As we have shown previously, it is possible to overcome potential -, -, and ␦ -mediated behavior by increasing the relative NOP activity of a compound. For example, we have shown that SR14150, which has increased NOP affinity and is 20-fold selective for NOP over receptors, is not rewarding on its own (Toll et al., 2009). To go one step further, SR16835 is a full agonist at NOP receptors and a weak partial agonist at receptors. This compound is not analgesic on its own and is able to attenuate morphine CPP (Toll et al., 2009). To- gether, all of these data suggest that the balance of NOP and components of mixed-profile compounds such as these can have significant impact in modulating the antinociceptive and rewarding aspects of the compounds. With BU08028, which is a partial agonist at both NOP and receptors, -mediated activity masks effects that could be mediated by the NOP receptor. It is possible that a different buprenorphine analog with high affinity at all the opioid receptors but with full agonist activity at NOP may counteract other traditional opioid-mediated effects such as reward and antinociception.
Doesnt really sound like a miracle drug to me. Its apparently just less euphoric due to high activity at NOP receptors but that doesnt mean its not abusable.
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morrowasted
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Re: New opioid douses pain without being addictive or deadly in primates [Re: CLIT]
#23628690 - 09/09/16 10:58 AM (7 years, 4 months ago) |
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Quote:
CLIT said: so Akuammine from Akuamma seeds is opioidergic? Anyone tried it?
Quote:
morrowasted said: Opiates that antagonize delta-opioid receptors in addition to agonising mu-opioid receptors, or that do not bind to delta-opioid receptors only to mu-opioid receptors, show promise in mitigating tolerance and thus the physical addiction because opioid-induced tolerance appears to be linked to the upregulation of delta-opioid receptors.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943346/
One promising currently available herbal candidate is Akuammine from Akuamma seeds.
There are some reviews online if you google it
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morrowasted
Worldwide Stepper



Registered: 10/30/09
Posts: 31,377
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Re: New opioid douses pain without being addictive or deadly in primates [Re: morrowasted]
#23628693 - 09/09/16 10:59 AM (7 years, 4 months ago) |
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I'm holding out hope.
Bupe is less abusable than oxycontin, there is no doubt about that, even if the withdrawals are worse. I think it's possible to make progress in a better direction. Which isn't to say that plant-based alternatives shouldn't also be legal.
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