As an alternative to morphine, researchers present a new nano-painkiller they've tested in rodents. In their study, three versions of their natural nanoparticle showed anti-pain effects when administered to inflamed rat paws. The new approach could open the door to treatments for intense pain without the severe side effects associated with morphine or related synthetic opioids, the authors say. Chronic pain is highly prevalent around the world, an important global heath challenge. The most commonly used medications to treat it are morphine and synthetic opioids, which have severe side-effects - most notably, addiction. With more than 115 people dying after overdosing on opioids every day in the U.S., finding a new, less addictive painkiller is vital. Small, naturally occurring peptides in the body like enkephalin, which bind to the body's opioid receptors, are an appealing option to treat pain because they activate δ-opioid receptor ligands, which are thought to have a lower abuse potential than receptors morphine activates. However, enkephalin-based approaches have not been adopted in the clinic because of pharmacokinetic problems, including difficulties for these peptides crossing the blood-brain-barrier. In search of a better solution to control pain, Jiao Feng, Patrick Couvreur and colleagues created a new nano-drug using Leu-enkephalin (LENK) neuropeptides. By connecting LENK to squalene, a natural and biocompatible lipid, the authors created nanoparticles that could be precisely delivered to the area of pain through intravenous injection. In the swollen paws of rats four hours after the drug was administered, they saw signs of reduced thermal sensitivity to pain in all treated rats. Additionally, LENK-SQ NPs' pain-alleviating effect lasted longer than that achieved with morphine, the authors say. Real-time in vivo imaging of the rats after intravenous injection of fluorescent DiD-labeled LENK-SQ-Am NPs showed that a significant portion of the NPs reached the inflamed tissue, with no indication of toxicity. Further analysis revealed the LENK-SQ nanoparticles acted through peripherally located opioid receptors, which have a lower abuse potential than those morphine activates.