A new nano-drug based on natural leu-enkephalin (LENK) neuropeptides has longer lasting effects and is less addictive than morphine, according to new work by researchers at the Université Paris-Saclay and Université Paris Descartes. The treatment, which has been tested on rodents, is easy to make, which means that it could readily be scaled up to industry – if human clinical trials also prove positive.

LENK-SQ-Am nanoparticles

Biodistribution of fluorescent LENK-SQ-Am nanoparticles in mice with inflamed right hind paw. The particles (in red) reach their inflamed tissue target. Credit: Institut Galien Paris-Sud, Faculté de Pharmacie

Chronic pain is an important global health challenge. The most common treatments today are morphine and synthetic opioids but these can lead to severe side effects, including addiction. Indeed, more than 115 people die in the US each day from overdosing on opioids. Finding new, less addictive painkillers is thus crucial.

Endogenous neuropeptides such as enkephalin are promising in this context since they activate both μ- and δ-opioid receptor ligands in the body, with a ten-times higher affinity for the latter. Compared with the former, these are thought to have lower abuse potential than receptors that morphine activate. They also have fewer respiratory, gastrointestinal and cognitive impairment side effects.

One of the main problem with enkephalin-based approaches, however, is that these small, naturally occurring peptides readily degrade once in the blood stream.

LENK neuropeptides

A team of researchers led by Patrick Couvreur of the Institut Galien Paris-Sud (Université Paris-Sud/CNRS) in Chatenay Malabry has now succeeded in creating a new nano-analgesic using the currently unusable leu-enkephalin (LENK) neuropeptides. By connecting LENK to squalene (SQ), a natural and biocompatible lipid, using chemical linkers the researchers created nanoparticles that they could precisely inject into the area of pain in rodents.

They tested out their treatment on rats with painfully swollen paws and found that that the animals were less sensitive to applied heat four hours after the drug had been administered. Less sensitivity implies less pain. What is more, the LENK-SQ pain-alleviating effect of the nanoparticles lasted longer (up to 24 hours after being injected) than that obtained with morphine, they say.

Opioid receptors located on the periphery

Thanks to real-time in vivo imaging of the rats after intravenous injection of fluorescent DiD-labelled nanoparticles, Couvreur and colleagues observed that a significant amount of the particles reached their inflamed tissue target, with no sign of toxicity. Further analyses revealed that the LENK-SQ nanoparticles do not cross the important blood-brain barrier and act through opioid receptors located on the periphery – and not those in the central nervous system responsible for addiction.

“Although further studies are needed to more precisely determine how dosage, administration frequency, and timing of treatment with LENK-SQ may affect the clinical outcome, this study opens a new exciting perspective for an efficient treatment of intense pain, which evades the severe side effects associated with morphine or related synthetic opioids,” write the researchers in their paper, published in Science Advances.

The other French labarotories involved in this study are: the Institut de Psychiatrie et Neurosciences de Paris (Inserm/Université Paris Descartes); and the Laboratoire de Neuropharmacologie (Université Paris-Sud/Inserm).

For more information: A new painkiller nanomedicine to bypass the blood-brain barrier and the use of morphine, Jiao Feng et al., Science Advances 10.1126/sciadv.aau5148