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Genetically modified mice reveal the secret to a painless life

  1. RoboCodeine7610

    People born with a rare genetic mutation are unable to feel pain, but previous attempts to recreate this effect with drugs have had surprisingly little success. Using mice modified to carry the same mutation, UCL researchers funded by the MRC and Wellcome Trust have now discovered the recipe for painlessness.

    'Channels' that allow messages to pass along nerve cell membranes are vital for electrical signalling in the nervous system. In 2006, it was shown that sodium channel Nav1.7 is particularly important for signalling in pain pathways and people born with non-functioning Nav1.7 do not feel pain. Drugs that block Nav1.7 have since been developed but they had disappointingly weak effects.

    The new study, published in Nature Communications, reveals that mice and people who lack Nav1.7 also produce higher than normal levels of natural opioid peptides.

    To examine if opioids were important for painlessness, the researchers gave naloxone, an opioid blocker, to mice lacking Nav1.7 and found that they became able to feel pain. They then gave naloxone to a 39-year-old woman with the rare mutation and she felt pain for the first time in her life.

    "After a decade of rather disappointing drug trials, we now have confirmation that Nav1.7 really is a key element in human pain," says senior author Professor John Wood (UCL Medicine). "The secret ingredient turned out to be good old-fashioned opioid peptides, and we have now filed a patent for combining low dose opioids with Nav1.7 blockers. This should replicate the painlessness experienced by people with rare mutations, and we have already successfully tested this approach in unmodified mice."

    Broad-spectrum sodium channel blockers are used as local anaesthetics, but they are not suitable for long-term pain management as they cause complete numbness and can have serious side-effects over time. By contrast, people born without working Nav1.7 still feel non-painful touch normally and the only known side-effect is the inability to smell.

    Opioid painkillers such as morphine are highly effective at reducing pain, but long-term use can lead to dependence and tolerance. As the body becomes used to the drug it becomes less effective so higher doses are needed for the same effect, side effects become more severe, and eventually it stops working altogether.

    "Used in combination with Nav1.7 blockers, the dose of opioid needed to prevent pain is very low," explains Professor Wood. "People with non-functioning Nav1.7 produce low levels of opioids throughout their lives without developing tolerance or experiencing unpleasant side-effects. We hope to see our approach tested in human trials by 2017 and we can then start looking into drug combinations to help the millions of chronic pain patients around the world."

    The findings were made possible by the use of 'transgenic' mice, meaning they were modified to carry genetic material from another organism -- in this case, the mutation that prevents humans from feeling pain. Precise physiological experiments showed that the nervous systems of the transgenic mice contained around twice the levels of naturally-produced opioids as unmodified mice from the same litter.

    "Our results reaffirm the clinical relevance of transgenic mouse models for human diseases," says Professor Wood. "Studying the mice showed us what was going on in the nervous system that led to painlessness and our findings were directly translatable to humans, as confirmed by the painless patient. Without the work in transgenic mice, none of this would have been possible and we still wouldn't know how to replicate the effects to help people suffering from chronic pain."

    University College London.
    ScienceDaily, 4 December 2015.


  1. detoxin momma
    i enjoy your reads robo.

    but, am i the only person whos ever thought, why do we get compared to mice?

    we are far superior to mice.

    if you think about it, we've all been guinea pigs for years....and we're alright.
    well, some of us.
  2. Shampoo
    Mice (and other rodents) are used in research because their nervous systems are extremely similar to us (including their brains and therefore minds). They are also easy to breed, have a relatively short life (so longitudinal studies are easier) and at least for mice, have a completely mapped genome so we can manipulate their genetic composition to simulate aberrant states like disease. For other types of research, different animals may be more advantageous (for example, pig hearts are nearly identical to human hearts and therefore cardiovascular research is often done with pigs).

    I'm not interested in a debate on animal "superiority" but keep in mind that we are animals, just like mice and rats, and the intelligence of a rat is actually remarkably high. Humans have opposable thumbs, advanced language and a very well-developed cortex which allows for a great deal of complex thought - however, we're not as different as one might think. Rats are certainly as intelligent, empathetic and cognitively adept as dogs, cats and many other animals which we might think of as "superior" as well.
  3. Alien Sex Fiend
    I don't think inability to feel pain is a good ability. thats how intoxicated people injure themselves and bleed to death, or get tazed by police so many times they die when it takes one zap to stop a sober person. pain is the way we feel the world
  4. 5-HT2A
    Scientists May Have Found Formula For A Painless Existence

    [IMGR="WHITE"]https://drugs-forum.com/forum/attachment.php?attachmentid=47385&stc=1&d=1450159239[/IMGR]Physical pain is a near universal problem, whether its sudden pangs or chronic aches. Yet, researchers’ efforts to quash it completely have fallen short—possibly due to a moonlighting channel in nerve cells. But that may be about to change.

    The sodium ion channel, called Nav1.7, helps generate the electrical signals that surge through pain-related nerve cells. It’s known to play a key role in pain, but researchers’ past attempts to power-down its charged activities did little to soothe suffering. In a bit of a shocking twist, researchers figured out why; the channel has a second, un-channel-like function—regulating painkilling molecules called opioid peptides. That revelation, published in Nature Communications, provided researchers with the know-how to reverse painlessness in a woman with a rare condition, plus make mice completely pain free.

    The link between Nav1.7 and opioid painkillers is “fascinating,” Claire Gaveriaux-Ruff, a pain researcher and professor at the University of Strasbourg, told Ars. And, she added, “this discovery brings hope to the many patients suffering from pain that are not yet adequately treated with the available pain medications.”

    That source of hope has been a long time coming, John N. Wood, lead author of the study and a neuroscientist at University College London, told Ars. Researchers have been interested in Nav1.7 for years, he said. Excitement peaked in 2006 when scientists reported finding a family who lacked the channel and could feel no pain at all. After that, researchers excitedly scrambled to relieve pain with Nav1.7-blocking drugs. But the drugs inexplicably failed, Wood said. “So we thought, well maybe this channel isn’t just a channel, maybe it’s got some other activities as well.”

    Using genetically engineered mice, Wood and colleagues found that completely shutting off Nav1.7 not only made mice pain-free, it cranked up their amount of opioid peptides in nerve cells. These molecules are natural painkillers that help the body moderate pain responses. In these Nav1.7-lacking mice, opioid levels were extremely high, blunting all twinges and throbs. When the researchers gave the mice a drug that blocks those opioids, the animals could feel pain normally. (The opioid-blocking drug, naloxone, treats overdoses of opioid drugs, such as morphine and codeine.)

    Even more promising, Wood and colleagues saw the same result in a person. The test subject, a 39-year-old woman with a rare mutation that shuts off Nav1.7, had been pain-free all her life. But, when the researchers gave her a dose of the opioid-blocking naloxone, she felt pain for the first time—the sting of a tiny laser. She was happy to go back to her normal, painless state after the drug wore off, Wood reported. But, she hopes that the drug treatment can be used in children with the pain-free condition to keep them from unknowingly injuring themselves.

    Now that Wood and his team could conjure pain in the painless, they aimed to do the reverse. They gave normal mice a combination of a Nav1.7-blocker and a very low dose of an opioid drug. Individually, the drugs did little to nothing to eliminate pain. But, together, they seemed to mimic what was going on in Nav1.7-lacking mice and people, producing a blocked ion channel and boosted levels of opioid molecules. With the drug combo, the mice felt no pain.

    Wood thinks that the Nav1.7-blocking drugs can’t eliminate pain alone because they may not block the channel’s opioid-regulating role completely—thus the level of opioid peptides might not get high enough to block pain. But, it’s still unclear how the channel regulates the opioid peptides in the first place. Preliminary data suggest that the amount of sodium the channel lets into the cell may play a role, Wood said.

    Still, the one-two-punch of the drug duo may do the trick for making people pain-free. Wood has filed a patent on the therapy in hopes that a pharmaceutical company will be interested in developing a treatment. He is also pleased that only a very low dose of opioid drugs seems necessary, thus lowering the dangers of addiction. It could still all fall apart, Wood cautioned, because the combination therapy has only been tested in animals. But, he said, “at the moment, it looks very, very encouraging.”

    by Beth Mole

    December 14, 2015

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