Light Treatment Reduces Pain Sensitivity In Mice

Today's post from news.stanford.edu (see link below) is a strange sounding one that looks at the effect of using gene therapy to alter the responses of mice to light being shone on their paws. The result is that pain responses can be toned up or down. Stanford scientists believe this can have far-reaching consequences for controlling human pain responses. It's called optogenetics and seems to me to require external genetic manipulation in order to be effective. Whether humans will respond positively to that idea remains to be seen but for those living with stubborn chronic pain, it may well be a price worth paying. This fascinating article is definitely worth a read.

Technique developed by Stanford scientists could lead to new treatments for pain
By Amy Adams, Shrivats Iyer, Kate Montgomery Stanford Report, February 19, 2014 

 A team of Bio-X researchers at Stanford has developed mice whose sensitivity to pain can be dialed up or down by shining light on their paws. The research could help scientists understand and eventually treat chronic pain in humans.

Light-sensitive proteins, or opsins, are used in a Stanford study on pain control through optogenetics.

The mice in Scott Delp's lab, unlike their human counterparts, can get pain relief from the glow of a yellow light.

Right now these mice are helping scientists to study pain – how and why it occurs and why some people feel it so intensely without any obvious injury. But Delp, a professor of bioengineering and mechanical engineering, hopes one day the work he does with these mice could also help people who are in chronic, debilitating pain.

"This is an entirely new approach to study a huge public health issue," Delp said. "It's a completely new tool that is now available to neuroscientists everywhere." He is the senior author of a research paper published Feb. 16 in Nature Biotechnology.
 
A switch for pain

The mice are modified with gene therapy to have pain-sensing nerves that can be controlled by light. One color of light makes the mice more sensitive to pain. Another reduces pain. The scientists shone a light on the paws of mice through the Plexiglas bottom of the cage.

Graduate students Shrivats Iyer and Kate Montgomery, who led the study, say it opens the door to future experiments to understand the nature of pain and also touch and other sensations that are part of our daily lives but little understood.

"The fact that we can give a mouse an injection and two weeks later shine a light on its paw to change the way it senses pain is very powerful," Iyer said.

For example, increasing or decreasing the sensation of pain in these mice could help scientists understand why pain seems to continue in people after an injury has healed. Does persistent pain change those nerves in some way? And if so, how can they be changed back to a state where, in the absence of an injury, they stop sending searing messages of pain to the brain?

Leaders at the National Institutes of Health agree the work could have important implications for treating pain. "This powerful approach shows great potential for helping the millions who suffer pain from nerve damage," said Linda Porter, the pain policy adviser at the National Institute of Neurological Disorders and Stroke and a leader of the NIH's Pain Consortium.

"Now, with a flick of a switch, scientists may be able to rapidly test new pain relieving medications and, one day, doctors may be able to use light to relieve pain," she said. 

Accidental discovery

The researchers took advantage of a technique called optogenetics, which involves light-sensitive proteins called opsins that are inserted into the nerves. Optogenetics was developed by a colleague of Delp, Karl Deisseroth, a co-author of the journal article. He has used the technique as a way of activating precise regions of the brain to better understand how the brain functions. Deisseroth is a professor of bioengineering, psychiatry and behavioral sciences.

Delp, who has an interest in muscles and movement, saw the potential for using optogenetics not just for studying the brain – interesting though those studies may be – but also for studying the many nerves outside the brain. These are the nerves that control movement, pain, touch and other sensations throughout our body and that are involved in diseases like amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease.

A few years ago Stanford Bio-X, which encourages interdisciplinary projects like this one, supported Delp and Deisseroth in their efforts to use optogenetics to control the nerves that excite muscles. In the process of doing that work, Delp said, his student at the time, Michael Llewellyn, would occasionally find that he'd placed the opsins into nerves that signal pain rather than the ones that control muscle.

That accident sparked a new line of research. Delp said, "We thought 'wow, we're getting pain neurons, that could be really important.'" He suggested that Montgomery and Iyer focus on those pain nerves that had been a byproduct of the muscle work. 

A faster approach

A key component of the work was a new approach to quickly incorporate opsins into the nerves of mice. The team started with a virus that had been engineered to contain the DNA that produces the opsin. Then they injected those modified viruses directly into mouse nerves. Weeks later, only the nerves that control pain had incorporated the opsin proteins and would fire, or be less likely to fire, in response to different colors of light.

The speed of the viral approach makes it very flexible, both for this pain work and for future studies. Researchers are developing newer forms of opsins with different properties, such as responding to different colors of light. "Because we used a viral approach we could, in the future, quickly turn around and use newer opsins," said Montgomery, who is a Stanford Bio-X fellow.

This entire project, which spans bioengineering, neuroscience and psychiatry, is one Delp says could never have happened without the environment at Stanford that supports collaboration across departments. The pain portion of the research came out of support from NeuroVentures, which was a project incubated within Bio-X to support the intersection of neuroscience and engineering or other disciplines. That project was so successful it has spun off into the Stanford Neurosciences Institute, of which Delp is now a deputy director.

Delp said there are many challenges to meet before results of these experiments – either new drugs based on what they learn, or optogenetics directly – could become available to people, but that he always has that as a goal.

"Developing a new therapy from the ground up would be incredibly rewarding," he said. "Most people don't get to do that in their careers."

Delp and Deisseroth have started a company called Circuit Therapeutics to develop therapies based on optogenetics.
Media Contact

Amy Adams, Stanford News Service: (650) 796-3695, amyadams@stanford.edu

http://news.stanford.edu/news/2014/february/biox-numb-pain-021914.html

HONEYBEE HIVE SEALANT PROMOTES HAIR GROWTH IN MICE

Hair loss can be devastating for the millions of men and women who experience it. Now scientists are reporting that a substance from honeybee hives might contain clues for developing a potential new therapy. They found that the material, called propolis, encouraged hair growth in mice. The study appears in ACS' Journal of Agricultural and Food Chemistry.

Ken Kobayashi and colleagues note that propolis is a resin-like material that honeybees use to seal small gaps in their hives. Not only does it work as a physical barrier, but it also contains active compounds that fight fungal and bacterial invasions. People from ancient times had noticed propolis' special properties and used it to treat tumors, inflammation and wounds. More recently, research has shown that the substance promotes the growth of certain cells involved in hair growth though no one had yet tested whether that in turn would result in new locks. Kobayashi's team wanted to find out.

When the researchers tested propolis on mice that had been shaved or waxed, the mice that received the treatment regrew their fur faster than those that didn't. The scientists also noticed that after the topical application, the number of special cells involved in the process of growing hair increased. Although they tried the material on mice that could grow fur rather than balding mice, the researchers note that hair loss conditions often result from abnormal inflammation. Propolis contains anti-inflammatory compounds, so they expect it could help treat balding conditions.

They add that further testing is needed to see if the beehive material affects human hair follicles.

GRAPEFRUIT JUICE STEMS WEIGHT GAIN IN MICE FED A HIGH FAT DIET

Fad diets come and go, but might there be something to the ones that involve consuming grapefruit and grapefruit juice? New research at the University of California, Berkeley, suggests that a closer look at grapefruit juice is warranted.

A new study, to be published in the peer-reviewed journal PLOS ONE, found that mice fed a high-fat diet gained 18 percent less weight when they drank clarified, no-pulp grapefruit juice compared with a control group of mice that drank water. Juice-drinking mice also showed improved levels of glucose, insulin and a type of fat called triacylglycerol compared with their water-drinking counterparts.

If these findings sound somewhat familiar, it may be because the link between grapefruit juice and weight loss -- or just decreased weight gain -- has been touted in Hollywood diets before. However, the earlier studies behind those claims were often small, not well-controlled and contradictory, according to Andreas Stahl and Joseph Napoli, the two UC Berkeley faculty members who led the new research.

This latest work was funded by the California Grapefruit Growers Cooperative, but the UC Berkeley researchers emphasized that the funders had no control or influence over the study design or research findings. Both Stahl and Napoli said they went into this research with some skepticism.

"I was surprised by the findings," said Stahl, associate professor of nutritional sciences and toxicology. "We even re-checked the calibration of our glucose sensors, and we got the same results over and over again."

Napolli added that "we see all sorts of scams about nutrition. But these results, based on controlled experiments, warrant further study of the potential health-promoting properties of grapefruit juice."

Pitting juice against water

The study authors randomly divided mice into six groups, including a control group that drank only water. Those drinking grapefruit juice got a mixture diluted with water at different concentrations, and sweetened slightly with saccharin to counteract grapefruit's bitterness. The researchers also added glucose and artificial sweeteners to the control group's water so that it would match the calorie and saccharin content of the grapefruit juice.

At the end of the study period, the mice that ate the high-fat diet and drank diluted grapefruit juice not only gained less weight than their control counterparts, they also had a 13 to 17 percent decrease in blood glucose levels and a threefold decrease in insulin levels, which reveals greater sensitivity to insulin. (In Type 2 diabetes, the pancreas makes extra insulin to compensate for increased resistance to the hormone.)

The researchers gave one group of mice naringin, a bioactive compound in grapefruit juice that has been identified as a key agent in weight loss, and another group metformin, a glucose-lowering drug often prescribed for those with Type 2 diabetes.

The mice were fed a diet that was either 60 percent fat or 10 percent fat for 100 days, and their metabolic health was monitored throughout the study.

"The grapefruit juice lowered blood glucose to the same degree as metformin," said Napoli, professor and chair of nutritional sciences and toxicology. "That means a natural fruit drink lowered glucose levels as effectively as a prescription drug."

Weight effects only seen in high-fat diet

The group of high-fat-diet mice that received naringin had lower blood glucose levels than the control group, but there was no effect on weight, suggesting that some other ingredient in grapefruit juice is also beneficial.

"There are many active compounds in grapefruit juice, and we don't always understand how all those compounds work," said Stahl.

The study did not find as big an impact on mice that ate a low-fat diet. Those that drank the grapefruit juice saw a two-fold decrease in insulin levels, but there was no significant change in weight or other metabolic variables.

"The effects were more subtle for the low-fat diet group," explained Stahl. "Mice are incredibly healthy animals with naturally low levels of bad cholesterol. So if they are eating a healthy, low-fat diet, it will take more to see a significant effect on their health."

The researchers said they ruled out the typical explanations for weight loss in their study. It wasn't the amount of food consumed, since the ingested calories among the different groups were about the same. The level of activity and body temperatures were comparable, and the authors even checked the calories eliminated in the feces of the mice to check for problems with the body's absorption of nutrients.

"Basically, we couldn't see a smoking gun that could explain why or how grapefruit juice affects weight gain," said Stahl.

The researchers said they hope to continue the investigation into grapefruit juice. "Obesity and insulin resistance are such huge problems in our society, " said Stahl. "These data provide impetus to carry out more studies."

HIGH FAT DIET POSTPONES BRAIN AGING IN MICE

New Danish-led research suggests that signs of brain aging can be postponed in mice if placed on a high-fat diet. In the long term, this opens the possibility of treatment of children suffering from premature aging and patients with Alzheimer's and Parkinson's disease. The research project is headed by the Center for Healthy Aging, University of Copenhagen and the National Institute of Health.

When we get older, defects begin to develop in our nervous system, our brain loses some of its intellectual capacity, and the risk of developing diseases such as Parkinson's and Alzheimer's increases. Alzheimer's disease is currently the fastest-growing age-related disease.

Throughout our lives, it is important that our cells -- to the extent possible -- keep our DNA undamaged, and, therefore, the cells have a system that repairs the damage that occurs all the time. Humans age when the repair system ceases to function. In diseases such as Alzheimer's, the researchers also see damage to the DNA

A new research project headed by the Center for Healthy Aging, University of Copenhagen and the National Institute of Health has studied mice having a defect in their DNA repair system. In humans, this defect causes the disorder Cockayne syndrome, where patients prematurely age as children and die at an age of 10-12 years. The study shows that placing a mouse model of Cockayne syndrome on a high-fat diet will postpone aging processes such as impaired hearing and weight loss.

Fat putting a stop to premature aging

"The study is good news for children with Cockayne syndrome, because we do not currently have an effective treatment. Our study suggests that a high-fat diet can postpone aging processes. A diet high in fat also seems to postpone the aging of the brain. The findings therefore potentially imply that patients with Alzheimer's and Parkinson's disease in the long term may benefit from the new knowledge," says Professor Vilhelm Bohr from the Center for Healthy Aging, University of Copenhagen and the National Institute of Health, who has headed the study.

Our brain has a constant need for fuel in the form of either sugar or so-called ketones. Ketones are the brain's fuel reserve, and, in particular, play an important role in periods of low blood sugar levels, e.g. if you are fasting. This is because the body breaks down fat if it needs sugar, and during this process it produces ketones. The researchers see a particular positive effect when the mice are given the so-called medium chain fatty acids -- e.g. from coconut oil.

Brain cells need extra fuel

"In cells from children with Cockayne syndrome, we have previously demonstrated that aging is a result of the cell repair mechanism being constantly active. It eats into the resources and causes the cell to age very quickly. We therefore hope that a diet with a high content of coconut oil or similar fats will have a beneficial effect, because the brain cells are given extra fuel and thus the strength to repair the damage," says postdoc Morten Scheibye-Knudsen from the National Institute of Health.

The study has just been published in the scientific journal Cell Metabolism.