The Role of Animal Research in Understanding and Alleviating Pain
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Many of the conditions and functions studied by animal researchers are too specific or esoteric to be easily understood by the general public, but there’s one area of study everyone can relate to: pain.
Occasional pain is an expected part of life, but when it becomes chronic—defined as pain that persists beyond normal tissue healing time, which is usually about three months—it can have devastating consequences, including restriction of mobility and activities, reduced quality of life, anxiety, depression, poverty, and opioid addiction.
More than 50 million U.S. adults—approximately one out of five—suffer from chronic pain, and the condition costs the U.S. up to $635 billion annually. As the population ages, those numbers are only expected to increase, so finding a safe, effective way to treat or alleviate chronic pain is crucial to improving the health and quality of life of millions of people.
Using CRISPR to Silence Pain Signals
Researchers at the University of California, San Diego, have successfully alleviated chronic pain in mice with a new CRISPR-based gene inhibitor.
Pain signals are transmitted to the brain via ion channels in neurons, which open and close to create a current along the nerve. Recent studies have found that one specific ion channel—sodium channel NaV1.7—could play a major role in chronic pain.
Previous research has shown that a hereditary loss-of-function mutation in the sodium channel NaV1.7 causes insensitivity to pain. To mimic this outcome, the research team used CRISPR to artificially repress NaV1.7 using a method called long-lasting analgesia via targeted in vivo epigenetic repression (LATER).
When used in mice, the LATER method reversed chronic pain from chemotherapy. The mice didn’t lose any non-pain-related sensations or suffer from any side effects, as has been the case with previous efforts to target NaV1.7.
The method is a long way from being used in humans, but researchers plan to continue developing the treatment, with the goal of eventually entering human trials.
Repurposing Old Antibiotics to Fight Nerve Damage Pain
In their quest to find a non-opioid-based solution for chronic pain, researchers at the University of Texas Southwestern Medical Center looked not forward, but backward, to a trio of antibiotics that have been in use for decades.
Used together, the three antibiotics can block a type of pain triggered by nerve damage, as with chronic pain related to cancer, diabetes, or injury. In their research, the UT team targeted EphB1, a protein found on the surface of nerve cells that has been shown to play a key role in producing neuropathic pain. Mice that have been genetically altered to remove all EphB1 don't feel any neuropathic pain, and mice with half the amount of EphB1 are resistant to neuropathic pain.
While no existing drugs are known to inactivate EphB1, the team scanned the list of FDA-approved drugs to see if any might have the right molecular structure to bind to EphB1. They found three: demeclocycline, chlortetracycline, and minocycline. All three are tetracyclines, a type of antibiotic that has been used since the 1970s to treat a wide variety of bacterial infections and that has shown few side effects.
In mouse models of neuropathic pain, all three drugs inhibited EphB1 at low doses. When combined, the effect was even greater—the mice showed significantly reduced reactions to painful stimuli, and an examination of the brains and spinal cords of the treated mice confirmed that EphB1 on their nerve cells had been deactivated.
The next step in the research is to test the drugs on humans, a process that may prove easier than usual since all three drugs have proven safe and effective for humans over decades of use.
Shutting Off Pain in the Brain
A team of researchers at Duke University has identified an area of the brain that can help shut off pain responses. The group of neurons, called CeAga neurons, is located in the amygdala, which is also the location of anxiety and the fight or flight response and has not previously been associated with pain.
Researchers discovered the role of CeAga neurons by giving mice a mild pain stimulus and mapping all the regions of the brain that were activated by the pain. They discovered that more than a dozen brain centers already known to process the sensory or emotional aspects of pain were receiving inhibitory signals from the CeAga neurons.
The team found that by activating the CeAga neurons, the mice immediately stopped displaying the self-soothing behaviors they typically exhibit when in discomfort, such as paw-licking and face-wiping. In effect, inhibiting CeAga neurons can act as a single off switch for multiple pain-related centers in the brain.
The next step is to look for a drug that can activate just CeAga neurons, which could lead to a new treatment for pain in humans.
Redheads Provide a New Clue About Pain
Red-haired people experience pain differently, and researchers at Massachusetts General Hospital now know why.
People with red hair (and animals with red fur) display a loss-of-function variation of the melanocortin 1 receptor (MC1R) in the skin’s pigment-producing melanocyte cells. This variation results not only in the inability to darken the skin, but also in a higher pain threshold and increased sensitivity to opioid pain drugs.
To better understand the connection between MC1R and pain, a team of researchers at Massachusetts General Hospital studied a strain of red-haired mice with a dysfunctional MC1R variant. The team found that loss of MC1R function in the mice caused a chain reaction in the body that resulted in an increase in opioid signals, which raised the threshold for pain.
This new knowledge may help the medical community better treat humans with differing pain sensitivities.
Targeting a Different Opioid Receptor
Traditional opioids treat chronic pain by targeted the mu opioid receptor, but an international team of researchers has discovered that targeting the delta opioid receptor instead may offer an attractive alternative to treating chronic inflammatory pain.
By studying cells from humans and mice with inflammatory bowel disease, researchers showed that delta opioid receptors have a built-in mechanism for pain relief that can be precisely targeted with drug-delivering nanoparticles.
Opioid medications such as oxycodone and morphine, which target the mu opioid receptor, can cause side effects such as constipation and difficulty breathing, not to mention their diminishing effectiveness over time and risk of addiction and overdose.
Using the delta opioid receptor’s natural ability to block pain, the researchers used nanoparticles to test a painkiller called DADLE that binds to the delta opioid receptor. The treatment caused a long-lasting reduction of pain. The team is now working on coming up with a combination of particles that uses the new mechanism to maximize pain relief.
Chronic pain is one of the most stubborn conditions to understand and treat. With some pain medications causing serious side effects and potential for abuse, several new research breakthroughs offer hope for a treatment for chronic pain that is safe, effective, and long-lasting.