How the Naked Mole Rat Escapes Inflammatory Pain

Summary: Findings from a study of naked mole rats could be important for helping develop pain therapies for humans.

Source: MDC.

In injuries and inflammation, naked mole-rats do not develop normal hypersensitivity to temperature stimuli. This is due to a tiny change in a receptor molecule on cells called TrkA, as a research team from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) has now discovered. The work, which appears in the journal Cell Reports, may be important for pain therapy in humans.

When an animal suffers an injury or inflammation, nearby tissue usually becomes highly sensitive to pain. Skin becomes red and puffy, for example, and is hypersensitive to heat. This condition, called “thermal hyperalgesia,” acts as a warning that helps animals avoid further injuries.

The only known animals unable to feel thermal hyperalgesia are naked mole-rats, rodents which live in extremely harsh conditions in underground tunnels. MDC researchers Dr. Damir Omerbasic and Dr. Ewan St. J. Smith from Prof. Gary Lewin’s lab now found out the reasons and presented their work in the latest issue of the journal Cell Reports.

Hyperalgesia is mediated by the signaling molecule Nerve Growth Factor (NGF), which is also responsible for the growth of new nerves, especially during embryonic development. Hyperalgesia occurs when inflamed or injured tissue releases NGF molecules which subsequently bind to protein molecules on the surfaces of specialized, pain-sensing nerve cells. These surface proteins are called TrkA receptors, and when they are stimulated by NGF they relay a signal into the nerve cell. This causes other proteins to interact with the receptor, starting a cascade of biochemical signals which ultimately makes the cell oversensitive to thermal stimuli.

A naked mole mole-rat in a laboratory. NeuroscienceNews.com image is credited to Laura-Nadine Schuhmacher, Cambridge University.

TrkA receptors evolved in an ancient animal and have been passed down to all its descendants. TrkA is so important that it has been protected from most evolutionary change.

When the researchers compared the receptor of naked mole-rats to TrkA receptors in other mammals, they found minute differences in a region of the molecule that projects into the cell interior. This region triggers the biochemical signaling cascade and is virtually identical in all mammals.

In naked mole-rats, the differences in this portion of the receptor alter a few of the protein’s building blocks and severely diminishes the signal-relaying action of the TrkA receptor. The researchers found that it took ten times the amount of NGF compared to TrkA receptors from other animals to trigger the signaling cascade, explaining why naked mole-rats are almost completely insensitive to thermal hyperalgesia.

NGF has another important function: it stimulates the growth and maintenance of nerves as the nervous system develops in the embryo. That’s why defects of the TrkA receptor in other mammals often lead to a degeneration of the nervous system during embryonic development. “The nervous system of the naked mole-rat can develop normally because while the function of its TrkA receptors is lowered, it is not completely abolished,” principal investigator Gary Lewin explains. “Evolution has selected a version of the molecule that can send just enough signal to build a proper nervous system, but not enough to make cells hypersensitive to pain.”

The difference surely makes life more bearable for the rodents, which live underground in densely packed colonies. Injuries and inflammations are common, and under the same conditions other mammals would suffer intense, continual pain.

That’s a daily experience for many people who suffer from chronic pain. In many cases the problem also involves NGF and TrkA; treatments that block the binding of these two molecules have had very positive effects in clinical trials. It’s another example, Gary says, of how basic research – even when it starts in a very unusual animal – could pave the way toward new human therapies.

ABOUT THIS PAIN RESEARCH ARTICLE

Damir Omerbasic and Ewan St. J. Smith contributed equally to this work. This study was funded by the European Research Council (ERC) and the Alexander von Humboldt foundation.

Source: Vera Glaßer – MDC
Image Source: NeuroscienceNews.com image is credited to Laura-Nadine Schuhmacher, Cambridge University..
Original Research: Full open access research for “Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat” by Damir Omerbašić, Ewan St. J. Smith, Mirko Moroni, Johanna Homfeld, Ole Eigenbrod, Nigel C. Bennett, Jane Reznick, Chris G. Faulkes, Matthias Selbach, and Gary R. Lewin in Cell Reports. Published online October 11 2016 doi:10.1080/23297018.2016.1207202

CITE THIS NEUROSCIENCENEWS.COM ARTICLE
MDC “How the Naked Mole Rat Escapes Inflammatory Pain.” NeuroscienceNews. NeuroscienceNews, 11 October 2016.
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Abstract

Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat

Highlights
•TRPV1 ion channels in naked mole-rat nociceptors are not sensitized by NGF
•Naked mole-rat TRPV1 channels are sensitized by NGF in mouse nociceptors
•NGF activation of naked mole-rat TrkA receptors does not sensitize TRPV1
•One to three amino acids in the naked mole-rat TrkA receptors may render it hypofunctional

Summary
The naked mole-rat is a subterranean rodent lacking several pain behaviors found in humans, rats, and mice. For example, nerve growth factor (NGF), an important mediator of pain sensitization, fails to produce thermal hyperalgesia in naked mole-rats. The sensitization of capsaicin-sensitive TRPV1 ion channels is necessary for NGF-induced hyperalgesia, but naked mole-rats have fully functional TRPV1 channels. We show that exposing isolated naked mole-rat nociceptors to NGF does not sensitize TRPV1. However, the naked mole-rat NGF receptor TrkA displays a reduced ability to engage signal transduction pathways that sensitize TRPV1. Between one- and three-amino-acid substitutions in the kinase domain of the naked mole-rat TrkA are sufficient to render the receptor hypofunctional, and this is associated with the absence of heat hyperalgesia. Our data suggest that evolution has selected for a TrkA variant that abolishes a robust nociceptive behavior in this species but is still compatible with species fitness.

“Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat” by Damir Omerbašić, Ewan St. J. Smith, Mirko Moroni, Johanna Homfeld, Ole Eigenbrod, Nigel C. Bennett, Jane Reznick, Chris G. Faulkes, Matthias Selbach, and Gary R. Lewin in Cell Reports. Published online October 11 2016 doi:10.1080/23297018.2016.1207202

Panel Advises Routine Brain Health Screening for People Over 70

A panel of world experts in aging convened at Saint Louis University recommended that everyone 70 and older should have their memory and reasoning ability evaluated annually by a doctor or health care provider.

This is the first time routine brain health screenings have been recommended for patients, starting at age 70. Patients found to have cognitive problems also should be screened for physical frailty, and vice versa, suggested the panel.

Published in the September issue of JAMDA, the recommendation for brain health comes in light of numerous studies, including those in The Lancet and New England Journal of Medicine, that suggest 30 percent of those older than 70 have memory problems. Approximately 16 percent of this group has mild cognitive impairment, while 14 percent has dementia, which includes Alzheimer’s disease.

“This is an important step in toward enhancing brain health for aging populations throughout the world,” said John Morley, M.D., director of geriatric medicine at Saint Louis University and lead author of the consensus paper. “The ability to learn, solve problems and remember is a key to successful health and aging.”

Some causes of early cognitive disorder, can be reversed and treated when caught early. These include depression, hypothyroidism, sleep apnea, problems with sight and hearing, and treatments of multiple health conditions with medications. “You can actually fix some of these issues, which is one reason why it’s critical to identify a problem and try to find a root cause,” said Morley, who also is a SLUCare Physician Group geriatrician.

The progression of cognitive impairment sometimes can be slowed through a series of lifestyle changes, the panel said.

They endorsed changes suggested in FINGER, a Finnish geriatric study published in The Lancet, which found those who ate a healthy diet, exercised, trained their memories and managed cardio-vascular risks were less likely to develop cognitive decline and memory problems than older adults who did not.

“There are things you can do to slow down the progression of not thinking well,” Morley said.

The panel endorsed a Mediterranean-type diet — packed with fruits and vegetables, fish twice a week, olive oil, nuts, legumes and whole grains — for patients who have early cognitive problems. Further, because population-based studies show brain health as well as physical well-being is connected to exercise, they encouraged physical exercise that can include resistance training and Tai Chi. The panelists also noted that population-based studies show those who dance, engage in intellectual activity and play a musical instrument have less mental decline than those who not pursue these hobbies. And video games can improve reasoning, memory, reaction time and attention in older adults.

Physicians need to know if their patients are not remembering or thinking clearly because they might not be able to follow doctors’ orders for medical problems, such as diabetes or heart disease.

“If you have diabetes and are not thinking as well as the general population, you might forget how to do the required daily finger prick to determine your blood sugar levels, which would compromise your health,” Morley said.

“However, if your doctor knows you have difficulty remembering, someone in his or her office can make sure you understand exactly how to check your glucose levels and give you written instructions as a ready reference. It’s a simple common sense thing that can make a huge difference in your health.”

Drawing of an elderly lady.

Finally, for those patients whose reasoning and memory problems likely will worsen, knowing in advance can help them plan for the future. They can begin considering tough questions, such as when to stop driving or remove dangerous tools from their homes, and set up advanced directives for health, financial and legal matters. They can identify sources of support like family members or friends and organizations such as the Alzheimer’s Association.

Information is power, Morley said.

“Our recommendations are going to shape clinical practice in a big way,” Morley said. “Physicians are hungry for this information to help their patients, and as the message gets out, patients will request screenings.”

Members of the consensus panel were geriatricians, neurologists, psychiatrists, social workers and psychologists who specialized in caring for older adults. They represented institutions around the world including Saint Louis University; Washington University in St. Louis; University Hospital of Toulouse in France; Alzheimer’s Association; Mayo Clinic; University of California Los Angeles; Alzheimer Center in Amsterdam; Albert Einstein College of Medicine in New York; Oxford Institute of Population Ageing in the United Kingdom; Center for Alzheimer Research in Sweden; Chinese University of Hong Kong; University of Washington in Seattle; Indiana University; University of Pittsburgh; and Salpetriere Hospital in Paris.

ABOUT THIS NEUROLOGY RESEARCH

Funding: Study supported by Health Resources and Services Administration and Nutricia Advanced Medical Nutrition.

Source: Nancy Solomon – St Louis University
Image Source: The image is in the public domain
Original Research: Abstract for “Brain Health: The Importance of Recognizing Cognitive Impairment: An IAGG Consensus Conference” by John E. Morley, MB, BCh, John C. Morris, MD, Marla Berg-Weger, PhD, LCSW, Soo Borson, MD, Brian D. Carpenter, PhD, Natalia del Campo, PhD, Bruno Dubois, MD, Keith Fargo, PhD, L. Jaime Fitten, MD, Joseph H. Flaherty, MD, Mary Ganguli, MD, MPH, George T. Grossberg, MD, Theodore K. Malmstrom, PhD, Ronald D. Petersen, PhD, MD, Carroll Rodriguez, BSW, Andrew J. Saykin, PsyD, Philip Scheltens, MD, Eric G. Tangalos, MD, Joe Verghese, MBBS, Gordon Wilcock, MD, Bengt Winblad, MD, Jean Woo, MD, and Bruno Vellas, MD in Journal of the American Medical Directors Association. Published online September 1 2015 doi:10.1016/j.jamda.2015.06.017


Abstract

Brain Health: The Importance of Recognizing Cognitive Impairment: An IAGG Consensus Conference

Cognitive impairment creates significant challenges for patients, their families and friends, and clinicians who provide their health care. Early recognition allows for diagnosis and appropriate treatment, education, psychosocial support, and engagement in shared decision-making regarding life planning, health care, involvement in research, and financial matters. An IAGG-GARN consensus panel examined the importance of early recognition of impaired cognitive health. Their major conclusion was that case-finding by physicians and health professionals is an important step toward enhancing brain health for aging populations throughout the world. This conclusion is in keeping with the position of the United States’ Centers for Medicare and Medicaid Services that reimburses for detection of cognitive impairment as part the of Medicare Annual Wellness Visit and with the international call for early detection of cognitive impairment as a patient’s right. The panel agreed on the following specific findings: (1) validated screening tests are available that take 3 to 7 minutes to administer; (2) a combination of patient- and informant-based screens is the most appropriate approach for identifying early cognitive impairment; (3) early cognitive impairment may have treatable components; and (4) emerging data support a combination of medical and lifestyle interventions as a potential way to delay or reduce cognitive decline.

“Brain Health: The Importance of Recognizing Cognitive Impairment: An IAGG Consensus Conference” by John E. Morley, MB, BCh, John C. Morris, MD, Marla Berg-Weger, PhD, LCSW, Soo Borson, MD, Brian D. Carpenter, PhD, Natalia del Campo, PhD, Bruno Dubois, MD, Keith Fargo, PhD, L. Jaime Fitten, MD, Joseph H. Flaherty, MD, Mary Ganguli, MD, MPH, George T. Grossberg, MD, Theodore K. Malmstrom, PhD, Ronald D. Petersen, PhD, MD, Carroll Rodriguez, BSW, Andrew J. Saykin, PsyD, Philip Scheltens, MD, Eric G. Tangalos, MD, Joe Verghese, MBBS, Gordon Wilcock, MD, Bengt Winblad, MD, Jean Woo, MD, and Bruno Vellas, MD in Journal of the American Medical Directors Association. Published online September 1 2015 doi:10.1016/j.jamda.2015.06.017

Nature is the great inventor

biomimicry

Biologist Janine Benyus likes to tell stories about using nature to solve our problems. For instance, a company called Arnold Glas was concerned about all the birds killed when they fly into windows. The company’s scientists asked, How has nature solved this kind of problem? The answer, Benyus says, is spiders. “Spiders build webs for bugs,” she explains. “But birds obviously would destroy the webs, so spiders weave in strands of silk that reflect UV light. Birds can see it, but bugs and humans can’t.” So the company includes UV-reflective material in its Ornilux glass. “Now it sells bird-safe windows,” says Benyus.

With that, she illustrates the big idea behind “biomimicry” (the term she coined in 1997): that humans can borrow the best ideas from the natural world. Her consulting firm, Biomimicry 3.8, works with major corporations, like Nike, GE, and Boeing, as they look to the earth to create smarter products and services.

You’ve said, “If something can’t be found in nature, there’s probably a good reason for its absence.” Can you explain this?

Ninety-nine percent of all species that existed on earth are extinct. The 1 percent here are the ones that work best. Think of our planet as a research-and-development lab in which the best ideas have moved forward, and the ones that used too much energy or materials or were toxic were dropped. What you wind up with are organisms that are efficient.

Do those organisms include humans?

No. Humans have been around for only 200,000 years, as opposed to the 3.8 billion years that life has existed on earth. I see us as toddlers with matches. We’re experimental; we try a lot of things because we can. But at this point, we have to ask ourselves as a species: Do we want to be here 1,000 generations from now? If so, we need to choose things that are good for life. I think we can invent things that don’t have negative consequences. Other people are more pessimistic than I am; I’m optimistic by choice because I believe that pessimism doesn’t do a whole heck of a lot of good. I work with large companies, and they’re all trying to figure out how to do what they do and make profits without penalties and harmful consequences.

What’s an example of how businesses are using biomimicry?

Continental Tires uses a tread that enables drivers to stop on a dime. It comes from cat paws.

The company uses actual cat paws to make them?!

No, but good question. In biomimicry, we borrow the blueprints and ideas rather than use nature itself. One cool example is a new paint that helps a building clean itself with rainwater. The product is called Lotusan, as in lotus leaves. Even though lotuses grow in the mud, they stay pristine. Scientists found that microscopic bumps on the leaves cause rain to form balls like beads of mercury. As these balls of water roll off the leaves, they pick up the dirt. GE is making bottles based on the leaves so that if you have ketchup or mustard in them, you can pour out every single drop.

fungi plant

What one plant or animal do you consider the star, the one that we can learn from the most?

Mycorrhizal fungus. It’s everywhere, and without it, we couldn’t exist. If you look at the roots of plants and trees, you’ll often see this white cobwebby stuff. This fungus works in partnership with plants and trees. It can’t get sunlight, since it’s underground, but trees can, and they use the sun to produce sugars, which they send down to the fungi. Trees can’t get phosphorous, but the fungi can, so they give it to the trees. In forests, this fungus creates an interconnected network—the Wood Wide Web, it’s been called—and trees and plants can share nutrients, sugars, and water with others a half acre away.

How would an ordinary person use biomimicry?

I’ll give you an example. I wanted to plant willow trees around my pond in Montana, and I wondered, How far back from the water’s edge should they go? I went online for the answer, and then I realized, I’m surrounded by ponds. Why don’t I look at where the willows are doing well and see where I should plant mine?

I would’ve Googled it too.

But isn’t that crazy? The thing with biomimicry is to think functionally. When I built my house, I looked at how the ground squirrels on my property ventilated their dens. They build these long underground chambers. There’s a mound with an entrance on one end and a taller mound with an entrance at the other end. The wind zips through the taller mound, creating a vacuum that pulls air through the chambers, ventilating them. I told our architect I wanted to do this, and he put a cupola with windows at the top of the house. When I open the doors, the breezes go through the cupola and suck the air through the house, ventilating it.

What’s your holy grail?

I’d like us to become a species that not only fits in but contributes. Forests clean the water for cities, but whom do cities clean the water for? Nobody. No species gets to live here for long without figuring out how to create conditions conducive to the life of the whole ecosystem. And it’s doable. The Bank of America building in New York has a filtration system that leaves the air cleaner than when it enters. Cities could build permeable sidewalks so rainwater would seep into the pavement and into the soil, cleaning it. It’s about mimicking the wild land next door. The cool thing about nature’s technologies is that they don’t come from outer space. They’re here because they work well on earth.

Is there one ability you’d personally like to borrow from the natural world?

I’d love to run off the mountains, spread my wings, and fly. And you know what else I wish I could do? Swim deep underwater without a tank and just take air out of the water like a fish. I’d love that: to fly in the air and to fly in the water!

What would you say to a skeptic who asks, “What’s so great about nature anyway?”

We are nature, but we’re really young. Our biological elders are wise. I tip my hat to anything that has lived on earth for the long haul and succeeded.
what is worth saving