There is an unfortunate irony for people who depend on morphine, oxycodone and other painkillers opioids: the drug that is supposed to offer you relief can actually make you more sensitive to pain over time. This effect, known as hyperalgesia name, could make these progressively less effective drugs for chronic pain, leading people to rely on higher and higher doses. A new study in rats, the first to examine the interaction between opioids and nerve damage for months after the treatment was stopped analgesic-paints a particularly bleak picture. An opioid triggers a chain of immune signals in the spinal cord that amplifies pain rather than tarnish even after the drug leaves the body, the researchers found. However, drugs already under development may be able to reverse the effect.
There is no secret that powerful analgesics have a dark side. Overdose deaths from prescription opioids have nearly quadrupled over 2 decades in near the same pace as the increase of prescription. And many researchers consider hyperalgesia as part of this equation a force that compels people to take more and more medicine, while prolonging exposure to addictive drugs known to sometimes dangerously slow breathing at high doses. Regardless of their interaction blocking pain with receptors in the brain, opioids appear to reshape the nervous system to amplify pain signals, even after the original illness or injury decreases. Animals given opioids become more sensitive to pain, and people who are already taking opioids before surgery tend to report more pain later.
But how opioids actually interact with pre-existing pain was poorly studied, says Peter Grace, a neuroscientist at the University of Colorado (CU), Boulder. His team tried to trace hyperalgesia how opioids affect the immune system. In the new study, he and colleagues used a rat model to mimic chronic neuropathic pain in people, the kind many might feel a traumatic injury to the nerve, stroke or nerve damage caused by diabetes. They sliced in rat thighs and tied a thin wire around a major nerve. The wire swelled over time, which causes the nerve constriction painfully and then dissolved after about 6 weeks.
Ten days after the injury, half of the rats received a 5-day treatment of morphine. Then, in about 3 months, the researchers periodically measured the pain threshold rodents pushing their hind paws with stiff nylon bristles of different thicknesses. (The finer hair that causes the rat to withdraw its paw, the logic goes, the more sensitive to pain.) After 6 weeks, the injured rats that received no morphine have withdrawn from the same kind of pokes that rats free witness. But the morphine treated rats remained susceptible to pokes with much finer hairs. It took 12 weeks to return to the same sensitivity to pain than control rats, the team reports today in Proceedings of the National Academy of Sciences . Even after the physical injury was probably cured, they were in pain.
"Just the primary observation itself I think is incredible," said Vania Apkarian, a neuroscientist at Northwestern University, Chicago, Illinois, who was not involved in 'study. The result "should have a revival of impact on the ground."
Control rats without injury also saw their pain tolerance dip if they have received morphine, but they returned to their original level after about a week. So what made the jump sensitivity to pain much more dramatic in rats with injury?
The authors propose that nerve damage and morphine delivered a kind of one-two punch cells in the spinal cord called sentinel microglia- the nervous system that scout for infection. Microglia release inflammatory molecules in the spinal cord, which activate neurons that fire pain signals to the brain signaling. Previous studies showed that opioids are more sensitive to microglia activation. In the new study, the authors found that the active morphine a specific protein in microglia group, collectively known as an inflammasome signaling.
This is not likely to be the only mechanism behind hyperalgesia, Apkarian notes. But in the study, the inhibition of microglia by insertion of a gene of a receptor which makes them sensitive to an inverted drug deactivating the effect of the pain extend in the morphine treated rats, like the blocking of certain proteins in inflammasome.
researchers already are exploring drugs that disrupt this pathway to treat pain or improve the performance of opioids. A clinical trial recently launched at Yale University, for example, will test whether an antibiotic that inhibits glial cells prevents inflammatory effects of opioids. And Linda Watkins, a neuroscientist CU Boulder and lead author of the new study, co-founded a company to develop a treatment for chronic pain that blocks a signaling proteins in the inflammasome, called Toll-like receptor 4.
in the meantime, the conclusion certainly should not be the basis of the chosen opioid people in pain, said Catherine Cahill, a neuroscientist at the University of California, Irvine. These drugs also act to block the emotional component of pain in the brain, she noted-a form of relief this study ignores. And opioids may not prolong the pain in humans as they did in these rats, she said, because the dosage of morphine and rapid cessation probably caused the repeated withdrawal can increase stress and inflammation . Humans generally do not experience the same withdrawal because they take extended release formulations and gradually taper off opioids.
Through said the wrong field needs a human study that systematically tests the pain thresholds over time among users of opiates. His team is working to confirm the results of the animals to the pain of other injuries, and in female rats, which are not included in this study. Meanwhile, he said, "I hope it will get people to really matter what the benefit of therapy for long-term opioids could be."
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