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Early study suggests new opioid is non-addictive, works only where it hurts

‘With a straightforward chemical tweak, the addictive—and often deadly—opioid painkiller, fentanyl, may transform into a safe, non-addictive, targeted therapy. Researchers reported this on Thursday in Science.

In rats, a chemically modified form of the opioid could only work on inflamed, hurting tissue—not the rest of the body. Plus, it wasn’t deadly at high doses, like the original, and it didn’t spur addiction-forming behavior in the rodents, researchers at Freie Universität Berlin reported.

“This yielded a novel opioid analgesic [pain reliever] of similar efficacy to conventional fentanyl, however, devoid of detrimental side effects,” the authors concluded.

For their chemical makeover, the researchers noted that when tissue is damaged and hurting, it becomes inflamed and more acidic. The pH drops from approximately 7.4—what’s seen in normal, healthy tissue—to between 5 and 7. Fentanyl can work regardless of the pH, so it’s active throughout the nervous system no matter what. But, if it was altered to only work at the lower pH, then it could target just the pain source at the peripheral nerves, the researchers hypothesized. And with no activity in the central nervous system, it would dodge opioid’s serious side-effects, including addiction and systemic responses that can be lethal during overdoses.

Using computer simulations, the researcher figured out how modify fentanyl so that it only worked in more acidic conditions. The resulting molecule is (±)-N-(3-fluoro-1-phenethylpiperidin-4-yl)-N-phenyl propionamide, or NFEPP for short. NFEPP has an added fluorine, which attracts protons and allows the drug to become active only in low pH.
In experiments with human cells, the researchers found that NFEPP could still activate the classic μ-opioid receptor in the nervous system—but only at low pH.

In experiments in rats with foot injuries, the drug dampened pain responses in just the foot that was injured. In rats given fentanyl, pain responses were dampened in all feet. Next, rats on either fentanyl or NFEPP, were given a drug that blocks opioids but can’t cross the blood-brain barrier. In rats on fentanyl, the opioid blocker partially reversed the pain-relieving effects of fentanyl—which makes sense because fentanyl can target opioid receptors in the brain. But, in rats given NFEPP, the opioid blocker totally reversed pain relief. This suggests that NFEPP’s effects weren’t due to any activity in the brain, rather they were due only to activity at the site of the injury…’

Source: Ars Technica

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Sleepwalking: survival mechanism gone awry

‘Recent research from Stanford University shows that up to 4 per cent of adults [sleepwalk]. In fact, sleepwalking is on the rise, in part due to increased use of pharmacologically based sleep aids – notably Ambien.

Often, the episodes are harmless. Sometimes, of course, sleepwalking is dangerous. Somnambulists are in an irrational state during which they could harm themselves or others…

Why do some enter into such a potentially harmful state during sleep? One answer comes from studies suggesting that ‘sleepwalking’ might not be an appropriate term for what is going on; rather, primitive brain regions involved in emotional response (in the limbic system) and complex motor activity (within the cortex) remain in ‘active’ states that are difficult to distinguish from wakefulness. Such activity is characterised by ‘alpha wave’ patterns detected during electroencephalogram (EEG) recordings. At the same time, regions in the frontal cortex and hippocampus that control rationality and memory remain essentially dormant and unable to carry out their typical functions, manifesting a ‘delta wave’ pattern seen during classic sleep. It’s as though sleepwalking results when the brain doesn’t completely transition from sleep to wakefulness – it’s essentially stuck in a sleep-wake limbo.

‘The rational part of the brain is in a sleep-like state and does not exert its normal control over the limbic system and the motor system,’ explains the Italian neuroscientist Lino Nobili, a sleep researcher at Niguarda Hospital in Milan. ‘So behaviour is regulated by a kind of archaic survival system like the one that is activated during fight-or-flight.’..

Scientists now agree that bouts of localised wakeful-like activity in motor-related areas and the limbic system can occur without concurrent sleepwalking. In fact, these areas have been shown to have low arousal thresholds for activation. Surprisingly, despite their association with sleepwalking, these low thresholds have been considered an adaptive trait – a boon to survival. Throughout most of our extensive ancestry, this trait may have been selected for its survival value.

‘During sleep, we can have an activation of the motor system, so although you are sleeping and not moving, the motor cortex can be in a wake-like state – ready to go,’ explains Nobili, who led the team that conducted the work. ‘If something really goes wrong and endangers you, you don’t need your frontal lobe’s rationality to escape. You need a motor system that is ready.’ In sleepwalking, however, this adaptive system has gone awry. ‘An external trigger that would normally produce a small arousal triggers a full-blown episode.’ …’

Source: Aeon Ideas

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Trump’s “Moderate” Defense Secretary Has Already Brought Us to the Brink of War

‘Did you know that the Trump administration almost went to war with Iran at the start of February? Perhaps you were distracted by Gen. Michael Flynn’s resignation as national security adviser or by President Trump’s online jihad against Nordstrom. Or maybe you missed the story because the New York Times bizarrely buried it in the midst of a long piece on the turmoil and chaos inside the National Security Council.

Defense Secretary James Mattis, according to the paper, had wanted the U.S. Navy to “intercept and board an Iranian ship to look for contraband weapons possibly headed to Houthi fighters in Yemen. … But the ship was in international waters in the Arabian Sea, according to two officials. Mr. Mattis ultimately decided to set the operation aside, at least for now. White House officials said that was because news of the impending operation leaked.”

Get that? It was only thanks to what Mattis’s commander in chief has called “illegal leaks” that the operation was (at least temporarily) set aside and military action between the United States and Iran was averted.

Am I exaggerating? Ask the Iranians. “Boarding an Iranian ship is a shortcut” to confrontation, says Seyyed Hossein Mousavian, former member of Iran’s National Security Council and a close ally of Iranian President Hassan Rouhani. Even if a firefight in international waters were avoided, the Islamic Republic, Mousavian tells me, “would retaliate” and has “many other options for retaliation.” …’

Source: Intercept

And Mattis is the Trump appointee to whom some pundits point as the moderate voice of reason…

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Panpsychism is crazy, but it’s also most probably true

‘Common sense tells us that only living things have an inner life. Rabbits and tigers and mice have feelings, sensations and experiences; tables and rocks and molecules do not. Panpsychists deny this datum of common sense. According to panpsychism, the smallest bits of matter – things such as electrons and quarks – have very basic kinds of experience; an electron has an inner life.

The main objection made to panpsychism is that it is ‘crazy’ and ‘just obviously wrong’. It is thought to be highly counterintuitive to suppose that an electron has some kind of inner life, no matter how basic, and this is taken to be a very strong reason to doubt the truth of panpsychism. But many widely accepted scientific theories are also crazily counter to common sense.

…I maintain that there is a powerful simplicity argument in favour of panpsychism. The argument relies on a claim that has been defended by Bertrand Russell, Arthur Eddington and many others, namely that physical science doesn’t tell us what matter is, only what it does. The job of physics is to provide us with mathematical models that allow us to predict with great accuracy how matter will behave. This is incredibly useful information; it allows us to manipulate the world in extraordinary ways, leading to the technological advancements that have transformed our society beyond recognition. But it is one thing to know the behaviour of an electron and quite another to know its intrinsic nature: how the electron is, in and of itself. Physical science gives us rich information about the behaviour of matter but leaves us completely in the dark about its intrinsic nature…’

Source: Phillip Goff, associate professor in philosophy at Central European University in Budapest. His research interest is in consciousness and he blogs at www.conscienceandconsciousness.com. Writing in Aeon.