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Blocking opioid tolerance Targeting sensory neurons could prevent side effects that make patients seek higher and higher drug doses When people take opioids for long periods of time, they often need higher and higher doses to get relief from pain. This so-called dose escalation increases a patient’s risk of addiction or even overdosing. A research team from Stanford University now reports that the activity of a certain type of sensory neuron drives this phenomenon in mice. The findings suggest that blocking the action of opioids at these neurons could prevent dose escalation (Nat. Med. 2017, DOI: 10.1038/nm.4262). The study proposes a new mechanism for two opioid side effects that are responsible for dose escalation: tolerance, in which a patient becomes less sensitive to a given dose of a drug, and hyperalgesia, in which opioid use paradoxically makes a person more sensitive to pain. The mechanism outlined by Grégory Scherrer and his Stanford team centers on cells called nociceptors, which relay pain
signals from the skin and internal organs to the spinal cord. They hypothesized that when drugs activate µ-opioid receptors (MORs) on the cells, they trigger signaling pathways that lead to tolerance and hyperalgesia. To test this hypothesis, the Stanford scientists engineered mice so that the animals no longer expressed MORs on their nociceptors. They then observed how effectively a daily dose of the opioid morphine relieved different forms of pain in the mice over 10 days. While nonengineered mice barely responded to the dose by the tenth day, the engineered animals continued to experience pain relief. “This demonstrates that MORs in these pain-sensing neurons are absolutely necessary for tolerance to develop,” Scherrer says. The scientists could prevent tolerance in nonengineered mice with the help of methylnaltrexone, an FDA-approved drug
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Methylnaltrexone that blocks MORs. Methylnaltrexone cannot cross the blood-brain barrier because of its positively charged quaternary ammonium group. This means it blocks MORs only on cells outside of the brain and spinal cord, such as nociceptors, and not on those within the brain, where opioids trigger most of their pain-relieving effects. Mice given morphine with methylnaltrexone experienced pain relief without developing tolerance. The data are interesting, says Christopher J. Evans, the director of the Brain Research Institute at UCLA, “but how it translates to people may be another story.” He thinks the team needs to test the drug combination under more clinical conditions, such as more regular morphine doses instead of daily ones. Still, says Theodore J. Price of the University of Texas, Dallas, the study represents “an interesting and potentially important advance.” He hopes the team investigates the nociceptor signaling pathways triggered by opioids to find other possible drug tolerance targets. Scherrer says his team is pursuing such studies.—MICHAEL
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ADHESIVES
Gecko-inspired adhesion controlled by light CREDIT: SCI. ROBOTICS (AZOBENZENE); SHUTTERSTOCK (GECKOS)
Adhesive grips and releases objects thanks to UV-triggered azobenzene chemistry A team of German researchers have created an adhesive pad inspired by the sticky feet of geckos that unsticks from objects when triggered by ultraviolet light. The pad could lead
to robotic fingers controlled by light that can pick up and release delicate objects. Geckos can scurry up and down walls thanks to about half a million fibers called seta on each of their feet. R Each setae is divided into hundreds of spatula-like R R nanostructures that individN N ually grip a surface through N N weak van der Waals interactions. Collectively, these R millions of interactions lead to strong adhesion. In the new work, Emre Kizilkan of Kiel University and his colleagues used preUnder UV light, azobenzene (R = various groups) viously developed surfaces changes conformation from trans to cis, allowing the with mushroom-shaped adhesive to lift up. polydimethylsiloxane micro-
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C&EN | CEN.ACS.ORG | JANUARY 23, 2017
structures to produce geckolike adhesion. But for easy manipulation, they desired a system that could attach and detach its adhesive hold at will. “We wanted to control the adhesion by light,” Kizilkan says. To do so, the team incorporated a stretchy liquid crystalline elastomer layer containing azobenzene molecules underneath the adhesive pad. Azobenzene undergoes a trans to cis isomerization in the presence of UV light, which causes the adhesive layers to bend (Sci. Robotics 2017, DOI: 10.1126/scirobotics.aak9454). The layers revert to normal when the researchers turn off the UV light. When the adhesive surface lies flat against an object, it sticks. Under UV illumination, the adhesive bends, releasing the bulk of its contact with the object, relinquishing its grip. Kizilkan showed that the device could move objects such as glass beads and glass slides.—RYAN CROSS
