boosting chlorine transporters improves the effectiveness of antidepressants

France –A French study reveals a mechanism explaining the limited effectiveness of antidepressants in the treatment of chronic neuropathic pain. It also shows that the combination of an antidepressant with a chlorine transporter enhancer can reduce pain, in an animal model. The explanations of Professor Pascal Fossat, professor at the University of Bordeaux and researcher at the Institute of Neurodegenerative Diseases (IMN).

Chronic neuropathic pain is linked to lesions of the central or peripheral nervous system and affects around 8% of the adult population in France. “What is very difficult with these pains is that they are resistant to opioid-based treatments,” explains Professor Fossat.

In the first line of treatment, it is mainly antiepileptics and so-called tricyclic antidepressants (TCA) or serotonin and norepinephrine reuptake inhibitors (SNRIs) that are used, but they have a very partial effectiveness: “With these treatments , the level of pain is improved by 50% in about one in three patients. Unfortunately, we have many patients in therapeutic wandering, ”points out Professor Fossat.

We have many patients in therapeutic wandering.
Professor Pascal Fossat

Optogenetic techniques

In his research, he is interested in monoamines, in particular serotonin, which has long been known for its role in pain.

“Our team used optogenetic techniques to stimulate populations of neurons in the brainstem,” he says. Optogenetics is a technique which dates from 2005 and which consists of introducing into a cell a gene which codes for a photosensitive protein, the opsin, which will be activated when it is illuminated with a specific light. “We made express the opsin in the serotonin neurons only, which allows us to activate them in a certain way at a certain wavelength, thanks to an optical fiber”, describes the researcher. By specifically stimulating serotonin neurons in the brainstem in an animal model, the researchers observed that serotonin was able to modulate nociceptive information. “The stimulation threshold at which the animals generated a pain response increased. They had less pain in a way, ”summarizes Professor Fossat.

But when the team performs this same stimulation on animal models suffering from peripheral neuropathy, amazement: “the stimulation had the opposite effect. Instead of having less pain, the animals had even more pain! We were a little puzzled, because we couldn’t really explain why,” says the scientist.

Alterations in chlorine transport

Thanks to a collaboration with Laval University in Quebec, a hypothesis puts researchers on the track. “Quebec researchers had highlighted alterations in the transport of chlorine in the spinal cord, in connection with neuropathic pain. We have ourselves demonstrated intermediaries, activated by serotonin, called inhibitory interneurons. However, they could only act as inhibitors if there was a good balance of chlorine. We therefore hypothesized that the hyperalgesia in neuropathic mice was due to a chlorine imbalance,” he explains.

We therefore hypothesized that hyperalgesia in neuropathic mice was due to a chlorine imbalance.
Professor Pascal Fossat

To verify their hypothesis, the researchers played on the modulation of KCC2 type transporters controlling chlorine homeostasis. “In our neuropathic animal model, their expression was decreased. We used molecules to re-express them. And when we did that, the serotonin became analgesic again! “, he underlines. These results explain why specific serotonin reuptake inhibitors (known as SSRIs) such as Prozac are ineffective in patients suffering from chronic neuropathic pain, but also the low efficacy of other families of antidepressants.

Based on these findings, the team then looked at a possible therapeutic treatment. “We said to ourselves that if our mechanism was true, perhaps using a chlorine booster would make these molecules effective”.

Boost chlorine carriers

This is what the researchers did and what they show in the study: “By boosting the chlorine transporters, the analgesic effect of serotonin is restored in neuropathic mice. And by combining this with SSRIs, we obtain an effect of at least 24 hours, even 48 hours”. This discovery has been the subject of a patent application and opens up prospects for patients suffering from chronic neuropathic pain. “The association between an antidepressant and a chlorine amplifier could make it possible to treat these pains”, concludes Professor Fossat.

The association between an antidepressant and a chlorine amplifier could help treat these pains.
Professor Pascal Fossat

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