Posted on Pain Management

Fighting pain through knowledge about sensory organs in the fingertips

Jianguo Gu, University of Alabama at Birmingham


Jianguo Gu . CREDIT UAB

That a finger can distinguish the texture of satin from suede is an exquisite sensory discrimination largely relying on small sensory organs in the fingertips called Merkel discs. Jianguo Gu, Ph.D., of the University of Alabama at Birmingham, has now unraveled how the sensory information is processed in the Merkel discs and further conveyed to the ending of a sensory nerve, the start of its journey to the brain.

Such molecular understanding about the sensory information transmission between Merkel cells and nerve endings may lay the foundation to treat the intense pain felt by patients with a gentle touch of their inflamed skin — a pathological pain known as tactile allodynia. This knowledge may also point to how diabetes patients lose their sense of touch. And this new knowledge may lead to preventive care.

“Cancer patients often have touch-induced pain after chemotherapy,” said Gu, the Edward A. Ernst, M.D., Endowed Professor in the UAB Department of Anesthesiology and Perioperative Medicine. “Touch-induced pain is also commonly seen in clinical conditions such as fibromyalgia, traumatic injury and in inflammation from sunburn. Our new findings may have profound implications in these conditions.”

A Merkel disc consists of a Merkel cell and a closely associated nerve ending that branches from a single sensory nerve. Until recently, it was unclear how the physical pressure of a light touch gets transduced from a mechanical force to an electrical nerve signal in Merkel discs.

In 2014, Gu’s research team overturned the common assumption that transduction from the mechanical force takes place at the endings of the sensory nerves in Merkel discs. Instead, as he reported in the journal Cell, that mechanical transduction at Merkel discs initiates primarily in the Merkel cells. His team further pinpointed that a new ion channel in the Merkel cells — called Piezo2 — is the mechanical transducing molecule.

Now Gu and colleagues have discovered how the signal transduced by Piezo2 is passed from the Merkel cells to the nerve endings. They report in Proceedings of the National Academy of Sciences that the Piezo2 transducer triggers Merkel cells to release the neurotransmitter serotonin. This serotonin crosses the tiny gap to the nerve ending, where it activates 5-HT receptors and triggers nerve impulses.

Such gaps from one nerve cell to the next are called synapses, and they are conventional in neural communication. The newly discovered Merkel cell-nerve ending synapse is unique, Gu says, “because it is the only example of a synapse formed between a non-neuronal cell and a nerve cell, and it is the first synapse that is found underneath the skin.”

Other types of sensory nerves from the skin — which detect sensations like heat, cold or pain — have their first synapse at the point where the sensory nerve meets the spinal column.

Elucidation of a Merkel disc serotonin synapse in the skin opens several areas for future investigation.

“The serotonergic transmission in the epidermis, probably like that in the central nervous system, can be regulated by factors affecting serotonin uptake and release,” Gu and colleagues write in their PNAS paper.

“This raises an interesting issue as to whether serotonin uptake inhibitors, such as cocaine, methamphetamine and other recreational drugs in this category, may act at the epidermal serotonergic synapses to alter tactile sensations. It would also be interesting to know whether the epidermal serotonergic transmission may be altered under pathological conditions in patients with diabetes, tissue inflammation and undergoing chemotherapy, because tactile dysfunctions including mechanical allodynia and reduced tactile sensitivity are commonly observed in these patients.”

In humans and other primates, Merkel discs are concentrated in the fingertips, and lesser numbers are also found in other areas of the skin.

“They can sense the wind blowing on your skin,” Gu said.

Intriguingly, Merkel discs in nonprimate mammals are concentrated in whisker hair follicles at the base of their whisker hairs. Thus, a mouse whisker can act as a model for a human fingertip.

“Nonprimate animals can use their whiskers to sense texture, shape and other physical properties of an object,” Gu said. “A manatee has whiskers over its entire body. Bats have whiskers, too, to detect aerodynamic changes in flight.”

Posted on Pain Management

Researchers find new clues in the brain linking pain and food

Plant based food
Plant based food


It has long been known that there is an association between food and pain, as people with chronic pain often struggle with their weight. Researchers at the Del Monte Institute for Neuroscience may have found an explanation in a new study that suggests that circuitry in the brain responsible for motivation and pleasure is impacted when someone experiences pain. “These findings may reveal new physiological mechanisms linking chronic pain to a change in someone’s eating behavior,” said Paul Geha, M.D., lead author on the study published in PLOS ONE. “And this change can lead to the development of obesity.”

Finding pleasure in food comes from how our brain responds to what we are eating. In this study researchers were looking at the brain’s response to sugar and fat. Using a gelatin dessert and pudding researchers altered the sugar, fat, and texture of the foods. They found that none of the patients experienced eating behavior changes with sugar, but they did with fat. Those with acute lower back pain who later recovered were most likely to lose pleasure in eating the pudding and show disrupted satiety signals – the communication from the digestive system to the brain – while those with acute lower back pain whose pain persisted at one year did not initially have the same change in their eating behavior. But chronic lower back pain patients did report that eventually foods high in fat and carbohydrates, like ice cream and cookies, became problematic for them over time and brain scans showed disrupted satiety signals.

“It is important to note, this change in food liking did not change their caloric intake,” said Geha, who first authored a previous study published in PAIN that recent research is building on. “These findings suggest obesity in patients with chronic pain may not be caused by lack of movement but maybe they change how they eat.”

Brain scans of the study participants revealed that the nucleus accumbens – a small area of the brain mostly known for its role in decision-making – may offer clues to who is at risk to experience a long-term change in eating behavior. Researchers found the structure of this area of the brain was normal in of patients who initially experienced changes in their eating behavior but whose pain did not become chronic. However, patients whose eating behavior was normal, but whose pain became chronic had smaller nucleus accumbens. Interestingly, the nucleus accumbens predicted pleasure ratings only in chronic back pain patients and in patients who became chronic after an acute bout of back pain suggesting that this region becomes critical in motivated behavior of chronic pain patients. Previous research by Geha, found a smaller nucleus accumbens can indicate if someone is at a greater risk of developing chronic pain.

Posted on Infectious Diseases

Discovery could enable broad coronavirus vaccine

Scripps Research discovery could enable broad coronavirus vaccine


Scripps Research scientists identified a site on SARS-CoV-2, the virus that causes COVID-19, that could be useful in developing a vaccine against a broad set of coronaviruses. CREDIT Scripps Research

The COVID-causing virus SARS-CoV-2 harbors a vulnerable site at the base of its spike protein that is found also on closely related coronaviruses, according to a new study from Scripps Research. The discovery, published Feb 8 in Science Translational Medicine, could inform the design of broad-acting vaccines and antibody therapies capable of stopping future coronavirus pandemics.

The scientists had previously isolated an antibody from a COVID-19 survivor that can neutralize not only SARS-CoV-2 but also several other members of the family of coronaviruses known as beta-coronaviruses. In the new work, they mapped at atomic scale the site, or “epitope,” to which the antibody binds on the SARS-Cov-2 spike protein. They showed that the same epitope exists on other beta coronaviruses, and demonstrated with animal models that the antibody is protective against the effects of SARS-CoV-2 infection.

“We’re hopeful that the identification of this epitope will help us develop vaccines and antibody therapies that work against all beta-coronaviruses, including coronaviruses that may jump from animals to humans in the future,” says study co-senior author Raiees Andrabi, PhD, an institute investigator in the Department of Immunology and Microbiology at Scripps Research.

Beta-coronaviruses have emerged recently as major, ongoing threats to public health. These coronaviruses include SARS-CoV-1, which killed about 800 people, mostly in Asia, in a series of outbreaks in 2002-04; MERS-CoV, which has killed about 900 people, mostly in the Middle East, since 2012; and, of course, SARS-CoV-2, which by now has killed over 5 million people worldwide in the COVID-19 pandemic. Two other beta coronaviruses, HCoV-HKU1 and HCoV-OC43, cause only common colds, but are suspected of having caused deadly pandemics centuries ago, when they first jumped from animals to humans. Researchers widely believe that future coronavirus pandemics initiated by animal-to-human spread are inevitable.

That prospect has spurred efforts towards the development of a pan-beta-coronaviral vaccine or antibody therapy. Scripps researchers took an initial step in that direction in 2020 when they identified an antibody, in a blood sample from a COVID-19 survivor, that could neutralize both SARS-CoV-2 and SARS-CoV-1. Although neutralizing tests weren’t available for all other beta-coronaviruses, they found that the antibody at least bound to most of these viruses.

In the new study, the team used X-ray crystallography and other techniques to precisely map the antibody’s binding site on the SARS-CoV-2 spike protein. They showed that the same site is found on most other beta coronaviruses—which helps explain the antibody’s broad effect on these viruses.

“The site is on the stem of the viral spike protein and is part of the ‘machinery’ the virus uses to fuse with cell membranes in its human or animal hosts after the virus has initially bound to a cell-surface receptor,” says study co-senior author Dennis Burton, PhD, Chair of the Department of Immunology and Microbiology at Scripps Research. “Fusion allows the viral genetic material to enter and take over host cells, and the crucial role of this machinery explains why the site is consistently present across beta-coronaviruses.”

By contrast, the receptor binding site at the top of the viral spike protein mutates relatively rapidly and thus tends to vary greatly from one beta-coronavirus to the next—making it a poor target for broad beta-coronavirus vaccines or antibody therapies.

The researchers now are following up with efforts to find other, perhaps even more broadly effective antibodies, in their search for optimal antibodies and vaccines against coronaviruses.

Posted on Autism

Insight into the genetics of autism offers hope for new drug treatments

Autism


Some of these genetic changes cause neurodevelopmental problems and dramatically increase someone’s risk of developing disorders such as autism, schizophrenia and Tourette’s syndrome CREDIT Lancaster University

Drugs to increase insulin signaling may be effective for treating autism say Lancaster University researchers, who have discovered how a genetic change impacts on insulin signaling and glucose metabolism in the brain.

In the human genome small sections of DNA have been found to be duplicated or deleted in some people, a phenomenon known as Copy Number Variation.

Some of these genetic changes cause neurodevelopmental problems and dramatically increase someone’s risk of developing disorders such as autism, schizophrenia and Tourette’s syndrome.

For example, people with a DNA deletion at chromosome 2p16.3, which results in deletion of the Neurexin1 gene, commonly experience neurodevelopmental delay and cognitive problems.

People with the 2p16.3 deletion are also around 14 to 20 times more likely to develop neurodevelopmental disorders including autism, schizophrenia and Tourette’s syndrome than people without the deletion.

There are an estimated two to three million people worldwide who have this type of DNA deletion but there are currently no effective drug treatments for their resulting cognitive problems.

For the first time, in research funded by The Royal Society, scientists have demonstrated that Neurexin1 gene deletion reduces glucose metabolism in the prefrontal cortex, a key brain region involved in higher-level cognitive functions including cognitive flexibility and paying attention. Neurexin1 deletion was also found to reduce insulin receptor signaling in the prefrontal cortex, which likely underlies the reduced glucose metabolism seen in this region.

The research, published in the journal Autism Research, give valuable new insight into how this leads to cognitive deficits, behavioural changes and dramatically increases the risk of developing a range of neurodevelopmental disorders.

The key finding that Neurexin1 deletion impacts on insulin signaling and glucose metabolism in the prefrontal cortex suggests that using drugs to increase insulin signaling may be an effective therapeutic strategy.

Lead researcher Dr Neil Dawson from Lancaster University said: “There is an urgent need to further understand the underlying neurobiology of neurodevelopmental disorders in order to develop new treatments. Drugs to help people with their cognitive and social problems are particularly urgently needed, as these symptoms dramatically impact on their quality of life.”

In addition, the researchers also showed that Neurexin1 deletion causes deficits in cognitive functions that depend on the prefrontal cortex, including a deficit in the ability to be flexible.

The research also found that the reduced glucose metabolism in the prefrontal cortex that results from Neurexin1 deletion was linked with being hyperactive when experiencing novel situations.

A second brain region identified as being impacted by Neurexin1 deletion was the dorsal raphé, which showed increased activity. This region is the origin of serotonin neurons that project throughout the brain, suggesting that Neurexin1 deletion also makes the serotonin neurotransmitter system dysfunctional.

Dr Neil Dawson said: “In addition, the observation that the serotonin system may be dysfunctional requires further research, and suggests that drugs targeting this neurotransmitter system may also be useful. We can now test the ability of drugs that target these mechanisms to restore these translational changes seen as part of ongoing research to develop better treatments for people with 2p16.3 deletion, autism, schizophrenia and Tourette’s syndrome”.