Researchers block morphine's itchy side effect

Itching is one of the most prevalent side effects of powerful, pain-killing drugs like morphine, oxycodone and other opioids. The opiate-associated itch is so common that even women who get epidurals for labor pain often complain of itching. For many years, scientists have scratched their own heads about why drugs that so effectively suppress pain also induce itch.

Now in mice, researchers at Washington University School of Medicine in St. Louis have shown they can control opioid-induced itching without interfering with a drug's ability to relieve pain. The discovery raises tantalizing possibilities for new treatments to eliminate itch in cancer and surgery patients as well as others who rely on opioids to relieve chronic and severe pain.

The investigators report the findings Oct. 14 in the journal Cell.

By identifying and blocking a specific variant of the opioid receptor in the spinal cord, Zhou-Feng Chen, PhD, director of Washington University's Center for the Study of Itch, a newly established multidisciplinary center aimed at translating basic itch research into novel treatments, and his colleagues have demonstrated for the first time that it is possible to inhibit itch without dulling morphine's pain-killing effects.

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One of the most prevalent side effects of pain-killing drugs is itching. Now Washington University itch researchers report that they?ve been able to control the itching related to morphine in mice without interfering with the drug?s ability to relieve pain. The discovery raises new possibilities about treatments that might eliminate itch in patients who have to rely on opioid drugs to relieve pain. Credit: Washington University BioMed Radio

"We've known for decades that there are a number of variants of the opioid receptor, but unfortunately, their physiological importance has been largely overlooked," says Chen, principal investigator on the study. "We identified a particular variant of the receptor called MOR1D that mediates itch. When we blocked MOR1D, mice that got morphine no longer needed to scratch, and they still received the same level of pain relief."

In previous studies, Chen, a professor of anesthesiology, of psychiatry and of developmental biology, had identified an itch-specific receptor in the spinal cord called GRPR (gastrin-releasing peptide receptor). His studies also have shown that neurons containing GRPR specifically transmit itch but do not carry pain information. In the new study, his team found that the opioid receptor MOR1D induced itching in the mice on morphine by activating GRPR.

"It is exciting to know that MORID actually functions as an itch-specific receptor," Chen says. "Depending on different types of itch-producing substances, our study suggests that the body has different ways of activating GRPR to transmit itch. In this case, opioids such as morphine first activate MOR1D, and that receptor subsequently connects to GRPR to relay itch signals."

In a surprising twist, first author Xian-Yu Liu, PhD, a postdoctoral researcher in Chen's lab, found that a major variant of the opioid receptor called MOR1 exclusively mediates morphine's analgesic effects in the spinal cord. When he blocked MOR1D, the mice no longer scratched. When he blocked MOR1, the animals no longer received the drug's pain-killing benefits, but they continued to scratch.

"Scientists have blamed the wrong receptor, but now the culprit has been caught," Chen says. "There are more than a dozen forms of the opioid receptor on nerve cells, but MOR1D is the first one that has nothing to do with killing pain. It only transmits itch."

Other side effects of opioids also have been extremely difficult to separate from the drugs' analgesic effects. But the current study makes Chen suspect that other variants of the receptor may be related to nausea, respiratory depression, constipation or other common side effects associated with the use of pain-killing drugs.

Chen hopes his research will motivate other investigators to look more closely at whether other opioid receptor variants may be responsible for these additional side effects.

"They may do all sorts of different things under the same 'disguise,'" Chen says. "If so, the implications could be clinically significant."

Chen says at first glance, MOR1 and MOR1D appear almost identical, the "bad guy" dressed in the "good guy's" clothing. The only difference is that MOR1 does not have seven amino acids found in MOR1D. But he says those seven amino acids turn out to be critical for the interaction between MOR1D and GRPR in the spinal cord.

"They operate like a key that can be used to open a door," he says. "Without the key, MOR1 can't activate GRPR even though the receptor is activated by morphine."

He says the finding opens up new possibilities for designing novel therapeutic strategies to relieve opioid-induced itching without blocking the analgesic effects of the drugs.

"If you can somewhow alter the key, you may eliminate itching without actually destroying MOR1D and GRPR," Chen says. "We wouldn't want to knock out those receptors in people because it's possible that they may have other important functions not related to itching."

Chen's team plans to look more closely at other opioid receptors to learn what they do, but he also hopes to quickly determine whether blocking MOR1D might alleviate itch people taking morphine or other opioids.

"There is a similar MOR1D receptor in humans, so we hope to find out whether blocking the same receptor in patients could alleviate itching without interfering with the analgesic effects of pain-killing drugs," he says.

More information: Liu XY, Liu ZC, Sun YG, Ross M, Kim S, Tsai FF, Li QF, Jeffry J, Kim JY, Loh HH, Chen ZF, Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell, vol. 147. Oct. 14, 2011. DOI: 10.1016/j.cell.2011.08.043

Provided by Washington University School of Medicine (news : web)

Krypton Hall effect thruster for spacecraft propulsion

 Electric propulsion (EP) is the future of astronautics. It can already compete successfully with chemical thrusters, especially for attitude control, orbit transfer and/or orbital station-keeping as well as for the main propulsion system for deep space missions. However, xenon, the propellant of choice in most EP devices, has a substantial drawback: its cost is very high. On the basis of the experience with plasma jet accelerators, a team of scientists and engineers from the Institute of Plasma Physics and Laser Microfusion in Warsaw has designed the Hall effect thruster optimised to work with krypton, a much more affordable noble gas.

Chemical propulsion is invaluable for the launch of payloads into space. The thrust, generated exclusively from the energy released by combustion of the propellants, is very large, but limited to durations of the order of seconds or minutes. In space, however, where atmospheric drag is negligible, technologies delivering much lower thrust over significantly longer durations (months or even years) have proven much more efficient. The leading low-thrust technology is plasma propulsion, where xenon is the preferred working gas. In the Institute of Plasma Physics and Laser Microfusion (IPPLM) in Warsaw, a Hall effect thruster has been designed to work with krypton, a noble gas ten times cheaper than xenon.

The Hall effect thruster is one of several existing electric propulsion technologies. In use since the 1970s in unmanned space flights, it has made it possible to manoeuvre precisely and correct satellite orbits. Lately, devices of this type have increasingly been used as the main propulsion system for deep space missions.

Hall effect thrusters convert the propellant into a plasma and produce thrust using an external electrical power source, most typically solar panels. Plasma particles (ions and electrons) are electrically charged and can thus be accelerated by an electric field to high velocities, of the order of 15-30 km/s as is the case with Hall thrusters (in contrast, expelled gases do not reach more than 4 km/s with chemical propulsion). Plasma propulsion produces a low thrust (from a few to 1000 mN depending on available power) but can operate over long durations and ultimately increase the velocity of the spacecraft by several kilometres per second.

"Plasma jet accelerators have been studied for many years in IPPLM. Building on this experience, our team has started, in May 2008, the development of a plasma Hall effect thruster using krypton as a propellant," said Dr Jacek Kurzyna, the person responsible for the project.

The propellant used in the vast majority of Hall effect thrusters is xenon, a very rare and therefore expensive noble gas. Krypton, another noble gas, is up to ten times less expensive. Although a slightly higher energy is necessary to produce krypton ions, they are lighter than xenon ions and accordingly require lower acceleration voltages to achieve the same velocity. "From the very beginning, our thruster has been developed and optimised to operate with krypton. We had to design properly the magnetic field configuration and the appropriate magnetic circuit. Some elements had to be constructed in such a way that they can withstand increased heat loads," explains Dariusz Daniłko, a PhD student from IPPLM.

The new thruster is medium-power, continuous-thrust propulsion device. Weighing less than 5 kg, it operates at a power of about half a kilowatt. "The SMART-1 lunar space probe sent by the European Space Agency (ESA) had a xenon thruster with power below 2 kW. It accelerated the vehicle by 3,6 km/s. Our thruster could therefore prove suitable as a main propulsion system in small spacecrafts," says Dr Serge Barral from IPPLM.

The newly built Hall effect thruster is a prototype device ready to be tested in vacuum conditions. "If the outcome of the tests is positive, optimization of the device and a round of assessment tests will follow. The project, submitted to the second PECS call (Plan for European Cooperating State, an agreement concluded between Poland and ESA), has been recommended for funding. If funding is confirmed, this project will mark the beginning of the qualification process," explains Dr Kurzyna.

The research on krypton Hall effect thrusters is expected to find applications beyond the field of astronautics. Plasma accelerators are routinely used in many technological processes, inter alia, for surface cleaning by plasma sputtering or etching, surface modification and thin film (e.g. diamond-like carbon) deposition. The team of scientists from IPPLM has suggested, in particular, a deposition process of thin oxide layers for photovoltaic solar panels based on the Hall thruster technology.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Institute of Plasma Physics and Laser Microfusion, via AlphaGalileo.

Future of inks, paints and coatings takes shape: Researchers determine that particle shape affects the 'coffee ring effect'

 If you've ever spilled a drop of coffee on a surface, you might have noticed the curious way the color concentrates at the edges when the coffee dries. This is known as the "coffee ring effect," and recently, researchers have determined that the shape of the particles in the liquid is an important factor in creating this pattern. The research results could eventually translate into new techniques or formulations for product coatings, or better inks and paints.

This work, published in the August 18 issue of the journal Nature was performed by Arjun Yodh and colleagues at the University of Pennsylvania.

"We found that if you change the shape of the particles in the solution, the coffee ring effect goes away, and you end up with a uniform coating," said Peter Yunker, a graduate student in Yodh's lab.

First, a little fluid dynamics: As the liquid in a droplet evaporates the edges remain fixed, so as the volume decreases fluid flows outward from the middle of the droplet to its edges. This flow carries particles to the edges, and round particles at the edge will pack closely. By the time all of the liquid in the droplet evaporates, most of the particles will be at the edge, producing the coffee ring effect.

Both the shape that liquid droplets take, and the way the shape changes as the droplets evaporate, is greatly influenced by surface tension at the air-liquid interface. This tension is a property of the interface, based on how the molecules in the liquid interact with one another versus the air. For example, liquids with a high surface tension, like water, may form a raised droplet, because the molecules are very attracted to one another and not so attracted to the air. In contrast, liquids with lower surface tension, like alcohols, are more likely to form flat spots instead of curved droplets.

The Yodh group found that elongated particles in a liquid behave differently than round ones because of the way they are affected by the surface tension of the air-liquid interface. The forces at work are even observable in a common breakfast cereal.

"If you make the particles elongated or ellipsoidal, they deform the air-water interface, which causes the particles to strongly attract one another. You can observe this effect in a bowl of cheerios-if there are only a few left they clump together in the middle of the bowl, due to the surface tension of the milk," explained Yunker.

This clumping changes the way the particles distribute themselves within the droplet. Even if the clumped ellipsoidal particles reach the edge of the droplet, they do not pack as closely as round particles. The loosely packed clumps eventually spread to cover the entire surface, filling it so an even coating of particles is deposited when evaporation is complete.

"This work gives us a new idea about how to make a uniform coating, relatively simply. If you change the particle shape, you can change the way a particle is deposited. You can also make mixtures. In some cases, even just a small amount of ellipsoids can change the way the particles deposit when they dry," said Yodh.

In future studies, the research team will explore drying and deposition of different types of fluids. They will also investigate different particle sizes and shapes, and the interplay of particle mixtures.

"This is an exciting scientific result with potential commercial applications, which was in part enabled by support of the Materials Research Science and Engineering Center at the University of Pennsylvania," said Mary Galvin, program director for the division of materials research at the National Science Foundation, which partially funded the research. The centers program, recently renamed Materials Research Centers and Teams, provides support for interdisciplinary materials research and education while addressing fundamental problems in science and engineering.

Story Source:

The above story is reprinted (with editorial adaptations ) from materials provided by National Science Foundation.

Journal Reference:

Peter J. Yunker, Tim Still, Matthew A. Lohr, A. G. Yodh. Suppression of the coffee-ring effect by shape-dependent capillary interactions. Nature, 2011; 476 (7360): 308 DOI: 10.1038/nature10344

New model predicts environmental effect of pharmaceutical products

 Most synthetic chemical products used in consumer goods end up unchanged in the environment. Given the risks this could pose for the environment and human health, researchers from the Autonomous University of Barcelona (UAB) have developed a new tool to effectively predict what will happen to current and future pharmaceutical products.

Thousands of pharmaceutical products, which are increasingly diverse and increasingly used, are "partially" metabolised by the human body. Those that remain unchanged pass into the waste water treated at sewage plants, which are not always designed to eliminate synthetic organic compounds.

"Sometimes, some substrates can even revert to the original drug within the water treatment plant itself, increasing the concentration of the drug in the effluent discharged, as is the case with carbamazepine (a psychotropic anti-epilepsy drug)," says Xavier Domenech, co-author of the study and a researcher at the Department of Chemistry of the UAB.

The result is that a great variety of drugs that could be harmful to wildlife end up in the environment. "This is of greater concern in the case of water treated for human consumption, in which we are increasingly detecting a cocktail of drugs at low concentrations (nanograms per litre), the long-term effect of which is unknown," explains Domenech.

Pinpointing the effect of a drug

The study, which has been published in Water Air and Soil Pollution, has made it possible to develop a new tool to determine the likelihood of drugs ending up in the environment, and at what concentrations, thereby fulfilling the European Medicines Agency (EMEA) requirement to evaluate the environmental risk of new drugs that are being proposed for marketing.

The new tool, developed by Marc Ribera, lead author of the study, uses some physical-chemical properties of pharmaceuticals and the rate of growth in their use in Spain between 1999 and 2006 to determine how they will behave in the environment. The drugs analysed are those that are most commonly consumed in Spain (more than 1 mg of active substance per person and year), including, among many others, ibuprofen, diazepam, naproxen, omeprazole and paracetamol.

In order to validate the model, the research team compared the model's prediction results on water with values measured by authors in rivers and lakes. "The model used is good at predicting the experimental data, and can be seen as a good predictive model for evaluating the environmental risks of current drugs and those that may be marketed in future," concludes Domenech.

Story Source:

The above story is reprinted (with editorial adaptations) from materials provided by Plataforma SINC, via AlphaGalileo.

Journal Reference:

Xavier Domenech, Marc Ribera, José Peral. Assessment of Pharmaceuticals Fate in a Model Environment. Water, Air, & Soil Pollution, 2010; 218 (1-4): 413 DOI: 10.1007/s11270-010-0655-y