Dangerous Microbe offer a new way to Relieve pain

Anthrax has a dreadful reputation. The anthrax bacteria, which causes catastrophic lung infections in humans and unsightly, albeit painless, skin lesion in livestock and people, has even been employed as a terror weapon.

Now, according to the findings of a recent study, the nasty microorganism may also have unexpectedly good potential: one of its poisons has the ability to mute numerous forms of pain in animals.

The findings show that this particular anthrax toxin alters signaling in pain-sensing neurons and, when administered in a targeted manner into central and peripheral nervous system neurons, can provide relief to distressed animals.

The study, which was spearheaded by Harvard Medical School investigators in partnership with industry scientists and researchers from other universities, was published in Nature Neuroscience on December 20.

In addition, the researchers mixed sections of the anthrax toxin with several types of molecular cargo and delivered it to pain-sensing neurons. The method can be used to develop new precision-targeted pain medications that act on pain receptors while avoiding the systemic side effects of conventional pain relievers like opioids.

"Using a bacterial toxin to carry chemicals into neurons and modify their activity is a new strategy to target pain-mediating neurons," said research senior investigator Isaac Chiu, an associate professor of immunology at Harvard Medical School's Blavatnik Institute.

According to the experts, there is still a pressing need to enhance the present pharmacological arsenal for pain management. Opioids are still the most efficient pain relievers, but they come with a slew of negative side effects, the most hazardous of which is their potential to rewire the brain's reward system, making them highly addictive, as well as their proclivity for suffocating respiration, which can be fatal.

"Developing non-opioid pain medications that are not addictive but effective in suppressing pain is still a huge therapeutic need," said study first author Nicole Yang, an HMS research fellow in immunology in the Chiu Lab. "At least in theory, our results suggest that employing this bacterial toxin to specifically target pain neurons could be a viable method."

The researchers warn, however, that this strategy is still in its early stages of development and needs to be evaluated and fine-tuned in future animal experiments and, eventually, in humans.

The Chiu lab has long been fascinated by the interaction of microorganisms with the neurological and immune systems. Other disease-causing bacteria can interact with neurons and modify their signals to enhance pain, according to previous research headed by Chiu. However, only a few research have looked into whether certain microorganisms can reduce or eliminate pain. Chiu and Yang set out to accomplish this.

They began their research by attempting to identify how pain-sensing neurons differ from other neurons in the human body. They started by looking at gene expression data. One factor that drew their attention was the fact that pain fibres carried anthrax toxin receptors, whereas other types of neurons did not. In other words, the anthrax bacterium was structurally predisposed to interact with the pain fibres. They couldn't figure out why.

That is the subject of a new study that has just been published. The findings show that pain is silenced when sensory neurons in the dorsal root ganglia, nerves that convey pain signals to the spinal cord, interact with two proteins produced by the anthrax bacterium. Experiments indicated that when one of the bacterial proteins, protective antigen (PA), attaches to the receptors on nerve cells, it creates a pore that allows two other bacterial proteins, edoema factor (EF), and lethal factor (LF), to enter the nerve cell. The study also found that PA and EF, collectively known as edoema toxin, disrupt signalling inside nerve cells, thereby silencing pain.

The researchers discovered that the anthrax toxin affected signalling in human nerve cells in dishes, as well as in real animals, in a series of tests.

The toxin was injected into the lower spines of mice, resulting in significant pain-blocking effects that prevented the animals from sensing high-temperature and mechanical stimulations. Other important indications in the animals, such as heart rate, body temperature, and motor coordination, were unaffected, indicating that this approach was highly selective and precise in targeting pain fibres and inhibiting pain without causing extensive systemic effects.

Furthermore, injecting mice with the anthrax toxin reduced the symptoms of two other types of pain: inflammation-induced pain and pain caused by nerve cell damage, both of which are common in the aftermath of traumatic injury and viral infections like herpes zoster, or shingles, as well as as a side effect of diabetes and cancer treatment.

The researchers also discovered that as the pain decreased, the treated nerve cells remained physiologically intact, indicating that the pain-blocking effects were not caused by nerve cell injury but rather by changed signalling inside them.

Finally, the scientists created an anthrax protein-based carrier vehicle that was utilised to carry various pain-blocking chemicals into nerve cells. Botulinum toxin, a potentially fatal bacterium recognised for its capacity to alter nerve signals, was one of these chemicals. In mice, this method also blocked discomfort. The results show that this could be a revolutionary pain-targeting delivery strategy.

Yang explained, "We bonded pieces of the anthrax toxin to the protein cargo that we intended it to carry." "In the future, new types of proteins could be used to provide customised medicines."

The researchers warn that as the research develops, the toxin treatment's safety must be closely watched, especially since the anthrax protein has been linked to the disruption of the blood-brain barrier during infection.

Another intriguing topic arises as a result of the new findings: Why would a microorganism, in terms of evolution, choose to ignore pain?

Chiu believes that microorganisms have evolved ways to communicate with their hosts in order to assist their own proliferation and survival, albeit this is a highly speculative theory. In the instance of anthrax, this adaptive mechanism could be changed signalling, which prevents the host from sensing pain and thus the microbe's existence. This concept could explain why the black skin lesions caused by the anthrax bacterium are often painless.

Beyond the typical small-molecule medicines that are currently being developed, the new findings suggest to novel drug development possibilities.