Opioids are the gold standard of chronic pain treatment, but they come with a host of negative side effects including constipation, addiction potential and respiratory depression that can lead to death. This study, published in Scientific Reports, offers a potential new way to treat acute and chronic pain by reducing the amount of opioid needed for pain relief while also lowering its addiction potential.

“We have been investigating the role of Heat shock protein 90 in regulating opioid signaling in the spinal cord for some time,” said John Streicher, PhD, member of the Comprehensive Center for Pain & Addiction at UArizona Health Sciences and a professor in the College of Medicine — Tucson’s Department of Pharmacology. “This study provides proof of principle that Hsp90 isoform inhibitors are effective at improving opioid pain relief and reducing side effects. This is the critical link that makes our work translationally relevant, giving us a clear path forward to develop a new drug that could benefit millions of people who live with chronic pain.”

Heat shock protein 90 is a chaperone protein that helps other proteins function, including those that promote tumor growth. It has been studied primarily in the context of cancer. Streicher is leading in a long-term effort to investigate its role in opioid receptor activation and pain relief.

Streicher’s prior research showed that Heat shock protein 90 acted upon opioid receptors in the brain differently than in the spinal cord. Inhibiting Hsp90 in the brain blocked the analgesic properties of morphine, meaning the opioid lost its ability to reduce the sensation of pain. But inhibiting Hsp90 in the spinal cord amplified the pain-relieving effects of morphine.

Building on that research, the team tested nonselective Hsp90 inhibitors in mouse models and saw a twofold-to-fourfold increase in the potency of pain relief provided by morphine. At the same time, tolerance was reduced and established tolerance was reversed. Tolerance is a condition where the body gets used to a medication so that more medication or a different medication is needed to achieve the same response.

Early cancer-focused studies, however, found that nonselective Hsp90 inhibitors can cause serious side effects, including macular degeneration. Streicher’s solution was to target individual isoforms of Hsp90, of which there are four.

“Isoforms are different versions of the same thing, like trim packages on a car,” Streicher said. “They are all slightly different and have similar roles, but not identical roles. So these four Hsp90 isoforms are four proteins that we can target individually.”

By using selective inhibitors to target each isoform, they were able to identify and isolate the isoforms that are active in the spinal cord from Hsp90-alpha, the one that is active in the brain. Recent reports have linked Hsp90-alpha with the serious side effect of retinal degeneration.

“We took isoform-selected inhibitors that we got from our collaborator, Brian Blagg, PhD, at the University of Notre Dame, and gave them to mice systemically via IV injection,” Streicher said. “We found that you can give these isoform-selective inhibitors by a translatable route and get the benefits. Pain relief goes up and side effects go down, and presumably we’re going to avoid some of those nasty side effects of the nonselective Hsp90 inhibitors.”

The findings suggest that selective Hsp90 inhibitors could be used as part of a dose-reduction plan in conjunction with opioid therapy prescribed by a physician for chronic pain. The goal is for doctors to be able to prescribe lower amounts of opioids that provide patients with the same pain-relieving benefits and fewer negative side effects.

“What I’m envisioning is you’d be given a pill that is a combination therapy of an opioid with one of these isoform inhibitors,” Streicher said. “The addition of that Hsp90 inhibitor would make the opioid better — it would increase the effectiveness of the pain relief and decrease the side effects.”

Streicher and his team are working to optimize the selective Hsp90 inhibitors to produce a stable drug that can be taken orally.

“Dr. Streicher’s research is an excellent example of the innovative, translational science that is needed to transform health care for pain and addiction,” said Todd Vanderah, PhD, director of the Comprehensive Center for Pain & Addiction, Regents Professor and head of the Department of Pharmacology. “This study is an important step toward developing a novel evidence-based therapy that will provide better treatment options with fewer disruptive side effects, empowering people with chronic pain to thrive.”

The research team included four co-first authors: David Duron, PhD, JD, former doctoral candidate in the Streicher Lab; Parthasaradhireddy Tanguturi, PhD, researcher/scientist in the Department of Pharmacology; former doctoral candidate Christopher Campbell, PhD; and Kerry Chou, former undergraduate student at the UArizona College of Nursing. Other co-authors included Paul Bejarano, and former doctoral candidates Katherin Gabriel, PhD, and Jessica Bowden, DVM, PhD, all of the Department of Pharmacology; Sanket Mishra, PhD, Christopher Brackett, PhD, and Brian Blagg, PhD, of the Department of Chemistry and Biochemistry at the University of Notre Dame’s College of Science; and Deborah Barlow and Karen Houseknecht, PhD, of the Department of Biomedical Sciences at the University of New England’s College of Osteopathic Medicine.

Bacteria have developed special defense mechanisms to protect themselves against viruses, which by no means infect only humans. As part of these so-called CRISPR-Cas systems, a CRISPR ribonucleic acid (crRNA), which serves as a “guide RNA,” recognizes regions of a foreign genome, such as viral DNA. The CRISPR-associated (Cas) nuclease, directed by a crRNA, then renders it harmless by cutting it like a pair of scissors. Humans have exploited this strategy: “CRISPR, often referred to as ‘gene scissors’, is the basis of many molecular technologies,” says Chase Beisel, head of the RNA Synthetic Biology department at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg. The institute is a site of the Braunschweig Helmholtz Centre for Infection Research (HZI) in cooperation with the Julius-Maximilians-Universität (JMU) of Würzburg, where Beisel holds a professorship.

The diagnostic platform LEOPARD, developed by Beisel’s lab in cooperation with JMU in 2021, also leverages CRISPR as a technology. LEOPARD has the potential to detect a variety of disease-related biomarkers in just one test. The approach is based on reprogramming RNA factors, so-called tracrRNAs. Those RNAs are naturally involved in helping produce guide RNAs used by Cas9 and different Cas12 nucleases. “LEOPARD focused on Cas9. However, CRISPR-Cas systems also include another diverse set of nucleases, called Cas12,” explains Beisel. While both Cas9 and Cas12 cut DNA targets, Cas12 can increase the output signal by performing cuts on “collateral” DNA. This can make detection technologies more sensitive and, therefore, more efficient.

The team led by Chase Beisel has now extended the unique features of LEOPARD to Cas12. The researchers have named the resulting method PUMA (Programmable tracrRNAs Unlock protospacer-adjacent Motif-independent detection of ribonucleic Acids by Cas12 nucleases). The details of their findings are the subject of a paper in the journal Nature Communications.

Overcoming hurdles

Although Cas12 nucleases are widely used in molecular diagnostics, two major limitations have persisted: Cas12-based technologies have been restricted to DNA targets, and a specific recognition sequence called a PAM, short for protospacer-adjacent motif, is required to identify the target molecule.

PUMA elegantly addresses these challenges. Like LEOPARD, this new method also relies on tracrRNAs. “Using PUMA, we can reprogram the tracrRNAs. This allows us to decide which RNA biomarker becomes a guide RNA. This guide RNA, in turn, directs Cas12 to a DNA molecule that we provide and activates the gene scissors,” explains the study’s first author, Chunlei Jiao. Chunlei Jiao, a former graduate student and postdoctoral researcher in the Beisel lab, was also involved in the development of LEOPARD. He recently started a professorship at the National University of Singapore. “DNA cutting then tells us which biomarker was present in the sample, such as biomarkers specific to different pathogens,” adds Beisel.

The novel method therefore enables the detection of RNA biomarkers using CRISPR nucleases that can normally only recognize DNA. “This is particularly important for molecular biomarkers that can only be found at the RNA level. This includes RNA viruses, for example,” says Beisel. And yet, PUMA does not require a specific recognition sequence: The PAM is contained in the DNA target molecule provided. Since the researchers provide the target molecule, they can also introduce truncated DNA. As a result, they were able to significantly increase the speed of the method.

Several birds, one stone

“PUMA has the potential to become a flexible and precise tool for RNA detection,” concludes Beisel. Finally, the team demonstrated the potential of the method by identifying five bacterial pathogens associated with acute sepsis. Their detection relied on a single universal, reprogrammed tracrRNA, which provides a simplified means of differentiating between various types of bacteria. This opens up a wide range of potential applications in medicine: “The new technology represents a novel form of CRISPR diagnostics that enables reliable molecular testing at the point of care — whether for the identification of viral or bacterial pathogens or the detection of cancer biomarkers,” says Jiao.

The research team is already planning its next steps: “Our goal is to achieve a multiplexed readout similar to that of LEOPARD and to expand the range of applications for the technology,” says Beisel, who also anticipates broad use in the research community: “We hope that our study will spur further exploration of tracrRNA reprogramming.”

In a world first study, published in BMJ Open Sport & Exercise Medicine and funded by the Health Research Council, participants completed two four-hour evening intervention sessions of prolonged sitting, and sitting interrupted with three-minute activity breaks every half hour.

The researchers found that after the participants completed the activity breaks intervention they slept for 30 minutes longer.

Lead author Jennifer Gale, PhD candidate in the Department of Human Nutrition, says sitting for long periods is associated with an increased risk of diabetes, cardiovascular disease and death.

“We know that for many of us, our longest period of uninterrupted sitting happens at home in the evening. In our previous studies we have found that getting up and doing 2-3 minutes of exercise every 30 minutes reduces the amount of sugar and fat in your blood stream after a meal.

“However, many sleep guidelines tell us we shouldn’t do longer bouts or higher intensity exercise in the hours before sleep, so we wanted to know what would happen if you did very short bouts of light intensity activity repeatedly throughout the evening,” she says.

Primary investigator Dr Meredith Peddie, Senior Lecturer in the Department of Human Nutrition, says the exercise intervention involved three exercises — chair squats, calf raises, and standing knee raises with straight leg hip extensions.

“These simple, bodyweight exercises were chosen because they don’t require equipment, or a lot of space and you can do them without interrupting the TV show you are watching.

“From what we know from other studies, you could probably get a similar effect if you walked around your house, marched on the spot, or even danced in your living room — the most important thing is that you get out of your chair regularly and move your body,” she says.

The fact this exercise resulted in longer sleep is important because insufficient sleep can negatively affect diet and has been associated with heart disease and type 2 diabetes.

“We know higher levels of physical activity during the day promotes better sleep, but current sleep recommendations discourage high-intensity exercise before bed because it can increase body temperature and heart rate resulting in poor sleep quality.

“It might be time to review these guidelines as our study has shown regularly interrupting long periods of sitting is a promising health intervention,” Dr Peddie says.

The study, appearing today in the Journal of Clinical Investigation, focused on two proteins called melanocortin 3 and melanocortin 4 found primarily on the surface of neurons in the brain that play a central role in regulating feeding behavior and maintaining the body’s energy balance.

Melanocortin 3 and melanocortin 4 impact everything from sensing long-term energy stores to processing signals from the gut regarding short-term fullness, or satiety, said U-M physiologist Roger Cone, who led the study.

The class of drugs known as GLP-1 agonists, which includes semaglutides (e.g., Ozempic) and tirzepatides (e.g., Mounjaro), have received substantial attention recently for their effectiveness in treating not only type 2 diabetes, but also obesity, heart disease and potentially addiction. They work by mimicking a natural hormone that the gut produces when it is full, triggering the brain to reduce feeding behavior.

“So the obvious question for us was: How do these GLP-1 drugs, which work by manipulating satiety signals, function when we prime the melanocortin system?” said Cone, professor of molecular and integrative physiology at the U-M Medical School and director of the U-M Life Sciences Institute where his lab is located.

Working in mouse models, Cone and his colleagues tested the effects of several hormones that reduce food intake. They compared the results in normal mice with mice that genetically lacked the MC3R protein, in mice that were given chemicals to block the activity of MC3R, and in mice that were given a drug to increase the activity of MC4R. (Because MC3R is a natural negative regulator of MC4R, meaning it decreases the activity of MC4R, blocking MC3R and increasing MC4R activity has similar effects.)

In all cases, Naima Dahir, first author of the study and a postdoctoral research fellow in Cone’s lab, and colleagues found that adjusting the melanocortin system — either by inhibiting MC3R or increasing MC4R activity — made the mice more sensitive to GLP-1 drugs and other hormones that affect feeding behavior. The mice that were given a GLP-1 drug in combination with an MC4R agonist or MC3R antagonist showed up to five times more weight loss and reduced feeding than mice receiving only the GLP-1 drugs.

“We found that activating the central melanocortin system hypersensitizes animals to the effects of not just GLP-1s, but to every anti-feeding hormone we tested,” Cone said.

The researchers also measured activity in parts of the brain thought to trigger nausea in response to GLP-1 drugs and observed no increased activation when GLP-1 drugs were combined with alterations to the melanocortin system. In contrast, priming of the melanocortin neurons significantly increased GLP-1 drug activation of neurons in hypothalamic feeding centers in the brain.

The findings indicate that pairing the existing GLP-1 drugs with an MC4R agonist could increase sensitivity to the desired effects of the drugs by up to fivefold, without increasing unwanted side effects.Ultimately, this approach could enable patients who are sensitive to the side effects to take a lower dose, or could improve the results in patients who have not responded to the existing drug dosages. Further drug development and clinical testing are needed before this can occur.

While this research has been conducted only in mouse models, Cone is optimistic that the results will translate well to humans.

“The melanocortin system is highly conserved in humans,” he said. “Everything we’ve observed in the mouse over the past decades studying these proteins has also been found in humans, so I suspect that these results would also be translatable to patients.”

This research was funded by the National Institutes of Health and Courage Therapeutics.

The study — published in PLOS ONE — found that as states responded to the pandemic with school closures and other lockdown measures, citizens’ diet quality improved by up to 8.5% and food diversity improved by up to 2.6%.

Co-author Edward Jaenicke, professor of agricultural economics in the College of Agricultural Sciences, said the findings provide a snapshot of what Americans’ diet and eating habits might look like in the nearly complete absence of restaurant and cafeteria eating.

“When dine-in restaurants closed, our diets got a little more diverse and a little healthier,” Jaenicke said. “One post-pandemic lesson is that we now have some evidence that any future shifts away from restaurant expenditures, even those not caused by the pandemic, could improve Americans’ food diversity and healthfulness.”

Prior to the pandemic, the researchers said, the average U.S. diet was considered generally unhealthy. According to the Dietary Guidelines for Americans, eating patterns in the U.S. have remained far below the guidelines’ recommendations, with only slight improvements in the population’s average Healthy Eating Index score between 2005 and 2016.

Also, before the pandemic, the research team was in the midst of a grant-funded project that asked how people would feed themselves after a giant global catastrophe, such as an asteroid strike or nuclear war. In particular, Jaenicke’s team was tasked with investigating how consumers and food retailers might behave during such a disaster.

“At first, the most impactful events we could study using actual, real-world data were hurricanes and other natural disasters,” Jaenicke said. “But then, along came the COVID-19 pandemic, and we realized that this event was an opportunity to study the closest thing we had to a true global catastrophe.”

For the study, the researchers analyzed data from the NielsenIQ Homescan Consumer Panel on grocery purchases, which includes 41,570 nationally representative U.S. households. Data consisted of the quantity and price paid for every universal product code each family purchased during the study period.

Data was gathered from both before the pandemic hit and after the pandemic led to schools, restaurants and other establishments temporarily closing. Because states did not respond to the pandemic simultaneously, the researchers designated each household’s post-pandemic period as the weeks following the date that their county of residence closed schools in 2020.

Jaenicke noted that this allowed the team to show a true causal effect of the pandemic school closures, which generally occurred around the same time that restaurants and other eateries also closed.

“To establish causality, an individual household’s pre- and post-pandemic food purchases were first compared to the same household’s food purchases from one year earlier,” Jaenicke said. “This way, we controlled for the food-purchasing habits, preferences and idiosyncrasies of individual households.”

The researchers found that in the two to three months following pandemic-based school closures — spanning March to June 2020, depending on the specific U.S. state — there were modest increases in Americans’ food diversity, defined as how many different categories of food a person eats over a period of time.

They also found larger, temporary increases in diet quality, meaning the foods purchased were healthier. This was measured by how closely a household’s purchases adhered to the U.S. Department of Agriculture’s (USDA) Thrifty Food Plan, which was designed to meet the requirements of the recommended healthy diet according to the Dietary Guidelines for Americans.

These patterns were found across households with many different demographics; however, those households with young children, lower incomes and without a car exhibited smaller increases in these measures.

“During the COVID-19 pandemic, dine-in restaurants closed, schools and school cafeterias closed, and many supermarket shelves were empty,” Jaenicke said. “Since about 50% of Americans’ food dollars are spent on ‘away from home’ food from restaurants and cafeterias, the pandemic was a major shock to the food system.”

The researchers said there are several possible explanations for these findings. First, because other studies have found that food from restaurants is often less healthy than food made at home, the dramatic decrease of meals eaten at and purchased from restaurants during the pandemic could have contributed to an increase of food diversity and healthfulness at home.

Second, they said it was possible that a global pandemic triggered some consumers to become more health conscious and contributed to them buying healthier, more diverse groceries. Third, because the pandemic caused widespread disruptions to the supply chain, it’s possible that when familiar products were sold out, consumers shifted to newer ones that led to increased diversity and healthfulness.

Finally, school and business closures may have led to many households having more time to cook and prepare foods than they had before, while others — like those with small children — may have had less free time than pre-pandemic.

Jaenicke said that in the future, additional studies could continue to explore how different disasters affect purchasing and eating habits.

Douglas Wrenn, associate professor of environmental and resource economics at Penn State, and Daniel Simandjuntak, research associate at Newcastle University, were also co-authors on the study.

Open Philanthropy helped support this research.

Using Webb’s NIRSpec (Near-Infrared Spectrograph), astronomers confirmed a temperature difference between the eternal morning and eternal evening on WASP-39 b, with the evening appearing hotter by roughly 300 Fahrenheit degrees (about 200 Celsius degrees). They also found evidence for different cloud cover, with the forever morning portion of the planet being likely cloudier than the evening.

Astronomers analyzed the 2- to 5-micron transmission spectrum of WASP-39 b, a technique that studies the exoplanet’s terminator, the boundary that separates the planet’s dayside and nightside. A transmission spectrum is made by comparing starlight filtered through a planet’s atmosphere as it moves in front of the star, to the unfiltered starlight detected when the planet is beside the star. When making that comparison, researchers can get information about the temperature, composition, and other properties of the planet’s atmosphere.

“WASP-39 b has become a sort of benchmark planet in studying the atmosphere of exoplanets with Webb,” said Néstor Espinoza, an exoplanet researcher at the Space Telescope Science Institute and lead author on the study. “It has an inflated, puffy atmosphere, so the signal coming from starlight filtered through the planet’s atmosphere is quite strong.”

Previously published Webb spectra of WASP-39b’s atmosphere, which revealed the presence of carbon dioxide, sulfur dioxide, water vapor, and sodium, represent the entire day/night boundary — there was no detailed attempt to differentiate between one side and the other.

Now, the new analysis builds two different spectra from the terminator region, essentially splitting the day/night boundary into two semicircles, one from the evening, and the other from the morning. Data reveals the evening as significantly hotter, a searing 1,450 degrees Fahrenheit (800 degrees Celsius), and the morning a relatively cooler 1,150 degrees Fahrenheit (600 degrees Celsius).

“It’s really stunning that we are able to parse this small difference out, and it’s only possible due Webb’s sensitivity across near-infrared wavelengths and its extremely stable photometric sensors,” said Espinoza. “Any tiny movement in the instrument or with the observatory while collecting data would have severely limited our ability to make this detection. It must be extraordinarily precise, and Webb is just that.”

Extensive modeling of the data obtained also allows researchers to investigate the structure of WASP-39 b’s atmosphere, the cloud cover, and why the evening is hotter. While future work by the team will study how the cloud cover may affect temperature, and vice versa, astronomers confirmed gas circulation around the planet as the main culprit of the temperature difference on WASP-39 b.

On a highly irradiated exoplanet like WASP-39 b that orbits relatively close to its star, researchers generally expect the gas to be moving as the planet rotates around its star: Hotter gas from the dayside should move through the evening to the nightside via a powerful equatorial jet stream. Since the temperature difference is so extreme, the air pressure difference would also be significant, which in turn would cause high wind speeds.

Using General Circulation Models, 3-dimensional models similar to the ones used to predict weather patterns on Earth, researchers found that on WASP-39 b the prevailing winds are likely moving from the night side across the morning terminator, around the dayside, across the evening terminator and then around the nightside. As a result, the morning side of the terminator is cooler than the evening side. In other words, the morning side gets slammed with winds of air that have been cooled on the nightside, while the evening is hit by winds of air heated on the dayside. Research suggests the wind speeds on WASP-39 b can reach thousands of miles an hour!

“This analysis is also particularly interesting because you’re getting 3D information on the planet that you weren’t getting before,” added Espinoza. “Because we can tell that the evening edge is hotter, that means it’s a little puffier. So, theoretically, there is a small swell at the terminator approaching the nightside of the planet.”

The team’s results have been published in Nature.

The researchers will now look to use the same method of analysis to study atmospheric differences of other tidally locked hot Jupiters, as part of Webb Cycle 2 General Observers Program 3969.

WASP-39 b was among the first targets analyzed by Webb as it began regular science operations in 2022. The data in this study was collected under Early Release Science program 1366, designed to help scientists quickly learn how to use the telescope’s instruments and realize its full science potential.