A new study found that the anthrax edema toxin, also known as ET, has the ability to alter pain responses in both mouse and human sensory neurons. By injecting the ET toxin in the spine of mice, it blocked the pain without any systemic effects either.
The study also found that modified anthrax protein could also serve as a potential delivery vehicle for other types of pain-blocking substances in the nerves. But in order to use it to treat pain, scientists will need to conduct further studies in human and animal participants to determine both the effectiveness and the safety.
The body uses pain as a defense mechanism, alerting the body of the possible damage in order to prevent further injury.
When a person feels pain, it creates sensitivity which then triggers the transmission of pain signals through a number of afferent sensory nerve fibers to the dorsal horn of the spinal cord, then up into the brain. This pain information then travels from the brain, through the spinal cord, and into the limbs and organs.
When the pain is acute or sudden, it can resolve without long-term consequences. But when the pain lasts longer than 3 months, doctors usually classify it as a chronic case.
According to a report from the Centers for Disease Control and Prevention (CDC), they estimate that around one-fifth of adults within the United States had chronic pain back in 2016. Of this group, 8% had pain that managed to limit their social, recreational, work, and self-care activities.
While chronic pain isn’t always curable, there are typical treatment options that include the following:
- The use of pain medications like acetaminophen (Tylenol), nonsteroidal anti-inflammatory drugs like ibuprofen (Advil, Motrin), and when they are not effective, opioids.
- The use of nondrug therapies like acupuncture, electrical stimulation, biofeedback, meditation, and massage.
- The need for surgery
There Is A Need For Targeted Treatments
There is a serious opioid problem in the United States, which is why there are many serious risks that are associated with it that include overdosing, misuse, and addiction. In 2019, there was an average count of at least 38 people in the United States dying every day from prescription opioid overdosing. This is one main reason why there is a critical need to develop what they consider targeted treatment options.
In this new study, which can be found in the journal Nature Neuroscience, it was discovered that the anthrax toxin can selectively target pain neurons and alter the response in mice.
Associate professor of immunobiology at Harvard Medical School in Boston, Dr. Isaac Chiu, who is also the senior author of the study, alongside his team, set out to figure out the connection between pain and microbes.
During an interview with the online publication Medical News Today, he said, “Chronic pain is a major problem that affects at least 10% of the world’s population, and there is a strong clinical need to develop better-targeted treatments for pain. Painkillers such as opioids, for example, have off-target effects, [but] microbes are a rich source of molecules that can naturally target neurons.”
In addition, he said, “In recent years, more discoveries have been made about how certain bacterial products can act on neurons to induce pain or cough during infection. We thus set out to identify receptors for bacterial products that are expressed on pain-mediating nociceptive neurons.”
When speculating about how the anthrax possibly blocks the pain, Dr. Chiu explained, “In the case of anthrax, that adaptive mechanism may be through altered signaling that blocks the host’s ability to sense pain and therefore the microbe’s presence. This hypothesis could help explain why the black skin lesions that the anthrax bacterium sometimes forms are notably painless.”
The Pain-Blocking Effects
In the new investigation, the study authors conducted experiments to detect gene expression with RNA scope analysis in human and mouse sensory nerves within the dorsal root ganglia (DRG) which demonstrated how these pain fibers had anthrax toxin receptor 2, which was something that wasn’t present in other neurons within the central nervous system.
What they found was that anthrax bacteria produce three different proteins, which are protective antigen (PA), and lethal factor (LF). PA and EF together are referred to as the “edema toxin” (ET).
The research team then gave anthrax LF or ET to DRG cultures and observed changes in signaling within the cells. After they confirmed the effects of anthrax toxin in cells, the study authors did another experiment in mice to explore the impact on pain sensation. The mice were given injections of LF and EF with and without PA via the animals’ spinal canal.
What they found was that by administering ET to mice also decreased their ability to sense cold, heat, and pinpricks, all without affecting their heart rate, motor coordination, or body temperature.
Such experiments in mice that don’t express the anthrax toxin receptor 2 also showed that the presence of these receptors was needed for the ET-induced pain relief. Meanwhile, the ET treatment didn’t cause any cell death in DRG cultures after 16 hours, nor in the mice that had been given the treatment.
After, the researchers gave ET via injection to the mice with artificially induced inflammatory or neuropathic pain.
As for inflammatory pain, it occurs as a response to tissue injuries that come from either surgery, trauma, or arthritis. Neuropathic pain can also be caused by diseases or lesions of the sensory nerves from such health conditions as multiple sclerosis, diabetes, shingles, or cancers.
What researchers found was the ET managed to reduce the neuropathic and inflammatory pain responses in the mice as well.
As for the next set of experiments, the scientists administered LT combined with botulinum toxin, which is another potentially harmful bacteria that can affect nerve transmission and measured the analgesic effects in mice too. It was shared that essentially, the scientists used the anthrax toxin as a pathway to bring the botulinum toxin into the nerve cells.
Through this approach, it also blocked the pain in the mice.
Discussing Targeted Treatment Strategies
According to Dr. Chiu, he explained,
Dr. Chiu commented: “We were intrigued to find that pain-mediating nociceptive neurons express anthrax toxin receptor 2, the high-affinity receptor for anthrax toxin. Surprisingly, this receptor was mostly absent in the central nervous system, providing an opportunity to selectively target nociceptive neurons when the toxins are administered locally to the spinal cord.”
He goes on to share, “We were also surprised to find that one of the anthrax toxins, [ET], induces potent analgesia (pain blockade) that was broadly effective in several animal models of pain. The known biochemical and signaling pathways affected by ET classically have been […] involved in causing pain, but we found the opposite.”
Despite these early studies showing a pain-blocking effect, there is still a need for future animal and human studies in order to determine the efficacy and safety of this approach. It is also important to understand that administrating drugs through the spinal canal is both invasive and linked with a number of complications.
“One of the most exciting next steps [is] to further develop and engineer anthrax toxin as a platform for delivering molecular cargo into nociceptive neurons to block pain. […] For example, could we use this system to deliver proteins that, when activated, shut down pain? Or how about nucleic acids like RNA?,” said Dr. Chiu.
In addition, he said,“More research is needed on better characterizing and optimizing the delivery platform for in vivo use and exploring other interesting payloads. Identifying other analgesic cargo may help the development of new pain therapeutics.”
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