In an article published in Nature Communications, researchers from the Valrose Biology Institute (Université Côte d’Azur/CNRS/Inserm) have presented a tool that was developed to allow for instant and reversible remote control of pain-related animal behavior, using light. By reversibly controlling the pain signal, this protocol will pave the way for the discovery and validation of new analgesic drugs.

Pain, especially when it becomes chronic, is the most frequent reason for seeing a doctor and is a major public health issue. The painkillers currently available on the market are often ineffective and all have side effects that diminish patients’ quality of life. Development of new painkillers is one of the areas researched by Guillaume Sandoz and his team at the Valrose Institute of Biology (Université Côte d’Azur/CNRS/Inserm).

When studying pain, one of the main challenges is to determine how to induce it. Because of the low spatiotemporal resolution and highly variable effects of the stimuli used to induce pain, in vivo dissection of pain pathways has been limited. Furthermore, the stimuli used are invasive, they cause pain to the animals, which is unethical but unavoidable when studying nociception, and their effects are variable from one animal to the other.

Control by a simple pulse of light

Researchers have now developed an optopharmacological method of controlling, with high spatiotemporal precision, the neurons involved in pain in freely moving animals using a brief pulse of light in the ultraviolet range (UV). By controlling these neurons, they can reversibly control painful behavior in nematodes and mice.

LAKI, the chemical compound developed by the team is inactive in ambient light but can be activated by UV illumination and this activation is instantaneous, reversible and highly reproducible. After a simple injection of LAKI and its activation in UV light, the pain signal is sent. This new tool has multiple applications. It can be used to study pain pathways in mice, for example. Since pain is evolutionarily conserved, the system was tested in another laboratory model using the nematode worm C. elegans. When it was incubated in a bath containing LAKI, light induced an escape behavior (the worm started moving in circles instead of swimming). This behavior was inhibited when a painkiller such as ibuprofen, paracetamol or Nefopam was added. Thus, by combining the worm model with the LAKI compound, it is now possible to screen new analgesic molecules on a large scale without the need for genetic manipulation or surgery.

The search for new pain killers is open

This study lifts a conceptual lock and will allow research on new analgesics using high-throughput screening in worms. This opens the possibility of characterizing the drugs validated via a first screening in the nematode without inflicting permanent pain on a mammal. Finally, by dissecting the mode of action of the molecule, the team demonstrated that the UV-activated form acts on the membrane proteins TREK1, TREK2 and TRESK, which are responsible for potassium ion flows into the cells. The use of LAKI will also open new avenues for the study of signals controlled by TREK1, TREK2 and TRESK, whose activity can now be finely controlled by LAKI.

Côte d’Azur University (French: Université Côte d’Azur, Azure coast, France) is a public research university located in Nice, France and neighboring areas. In 2019, it replaced the University of Nice Sophia Antipolis and the community (ComUE) that was created in 2013.

The University of Nice Sophia Antipolis was founded in 1965 and organised in eight faculties, two autonomous institutes and one engineering school. It was merged in 2019 into the University of Côte d’Azur.

It has nearly 30,000 students in initial and continuing education, including 20% foreign students, and eight University and Research Schools (EUR). Its university campuses are located in several cities of the Alpes-Maritimes department (Nice, Cannes, Menton) as well as Sophia Antipolis technology park. It is part of the academic region Provence-Alpes-Côte d’Azur which includes the academies of Aix-en-ProvenceMarseille and Nice.

Under the chairmanship of Frédérique Vidal, the university was awarded IDEX for its project called “UCA Jedi” supported by numerous companies. The “University Côte d’Azur Foundation” was created in 2017 to collect donations to finance research projects.

It also hosts the first WWW Interactive Multipurpose Server (WIMS).

It is a member of the Coordination of French Research-Intensive Universities (CURIF), the equivalent of the Russell Group in the UK.

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