[LUM#9] When the pain persists

[LUM Magazine] - Published on March 6, 2019 in Science-Society

Scientists atthe Montpellier Institute of Neuroscience have uncovered the mechanisms responsible for the onset and persistence of chronic neuropathic pain.After nine years of research, a drug candidate is now being tested and could become the first specific therapy for this type of pain.

This is the story of a symbiotic encounter between a molecule called FL and its receptor FLT3. A romance that remained hidden until Jean Valmier, a researcher atthe Montpellier Institute of Neuroscience (INM), brought it to light. Because this story, once again, ends badly and causes what is known as "chronic neuropathic pain." A condition that affects nearly four million people in France.

Chronic pain

"Pain is considered neuropathic when it results from nerve damage," explains the researcher. "It can be caused by surgery, injury, treatment, or infection." This is the case with shingles, for example. Pain becomes chronic "when it lasts for more than three months and can persist even when the triggering cause, such as shingles, has been treated, " says the researcher.

There is no medication that can cure this "pain disease." Morphine, a powerful painkiller, has too many serious side effects to be prescribed long-term. The same is true for other so-called "repositioned" drugs, which were originally designed to treat other conditions such as epilepsy or depression but can also relieve pain. Furthermore, as Jean Valmier points out , "when they work, they only reduce the pain by half, and half the pain is still pain. This is a huge public health issue. There is demand from patients who are suffering, from doctors who are desperate because there is little they can do, and of course from the pharmaceutical industry, because if they had a drug like this, it would be a blockbuster, as they say."

The mechanism goes haywire

This situation can be explained by the ignorance that previously surrounded the mechanism of this pain. We know that when a nerve is damaged, blood cells flock to the site of the injury and secrete molecules capable of activating the sensory neurons that generate pain. This is a normal mechanism. " But sometimes the mechanism goes into overdrive," explains the researcher, "and the molecules they release hyperactivate the sensory neurons. Instead of sending normal information, these neurons create a lot of electrical discharges." These discharges are sent to the central nervous system, which then risks malfunctioning by developing persistent hyper-excitability and, as a result, chronic pain .

And this is where we find our two inseparable companions, who have remained so discreet until now. Nine years after the first experiments began, Jean Valmier succeeded in demonstrating "that the FLT3 receptor located on the neuron is activated by a ligand, the FL molecule secreted by blood cells; and it is their encounter that triggers a chain reaction in the sensory system, causing chronic pain. If I inhibit this receptor, the pain disappears." With the concept proven, the challenge remained to find a way to block this FLT3 receptor without side effects for the patient.

Five million molecules screened

To do this, Jean Valmier called on Didier Rognan, a chemist and director of the Laboratory for Therapeutic Innovation (LIT) in Strasbourg. The chemist used computer technology to screen or sort more than five million molecules according to their physicochemical properties before selecting around sixty of them and sending them to Jean Valmier. "I looked to see if the molecules prevented the ligand (FL) from binding to the receptor and, if so, I checked to see if they prevented the receptor from activating."

The two researchers then focused on the one they named BDT001. Acting as a true chaperone, this molecule prevents FL from binding to FLT3, thereby blocking its activation and thus the pain. Tested on mice, BDT001 not only eliminates chronic neuropathic pain without causing side effects, but also prevents potential pain in cases such as surgery. "It takes effect within three hours and lasts for 48 hours."

Bear with it

Another advantage of this molecule is that "it has no effect on normal pain. It is analgesic but not anesthetic." In other words, there is no risk of accidentally leaving your hand on a 100°C hotplate with BDT001, if its probable application in humans is confirmed .

The discovery has already led to four patents being filed, owned byInserm and the University of Montpellier. The two scientists have founded the company Biodol Therapeutics to continue testing this molecule: "We need to prove that this mechanism is as important in humans as it is in mice. It could take two or three years if all goes well." Next will come tests on patient cohorts, "but it won't be on the market anytime soon." So we'll have to be patient before our old pains are nothing more than a distant memory.

Keywords: LUM#9, LUM Magazine, Research, Health