Antidepressants and chronic pain, targeting chlorine makes the difference

Antidepressants and chronic pain, targeting chlorine makes the difference

Chronic neuropathic pain is associated with nerve damage that affects 8% of the population in France. With the exception of antiepileptics and so-called tricyclic antidepressants (TCA) or serotonin and norepinephrine reuptake inhibitors (SNRIs) which have very partial efficacy, there is no effective treatment without serious side effects.

Among the targets of antidepressants, serotonin neurons are a privileged target because they project to the spinal cord and control the transmission of nociceptive messages. In a collaboration with Laval University in Quebec, scientists focused on studying these neurons and used modern optogenetic techniques to specifically stimulate these populations of serotonin neurons with light. They show that the activation of these populations of neurons induces an increase in the nociceptive perception threshold in naïve mice but decreases this threshold in neuropathic mice for which the threshold is already very low. These neurons would therefore be capable of producing endogenous analgesia in naïve mice but would induce hyperalgesia in neuropathic mice. This hyperalgesia is directly associated with an imbalance of chlorine in the spinal cord due to a decrease in KCC2 type transporters and which disrupts nociceptive signals before they are perceived as pain. 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. Finally, the scientists show that the combination of an SSRI with a molecule capable of amplifying the extrusion of chlorine from the cells restores, in neuropathic mice, the analgesic effect of serotonin observed in naïve mice. These results (which are the subject of a patent application), make it possible to propose an antidepressant and chlorine amplifier combination as a treatment for painful symptoms in patients with chronic neuropathic pain.

© Zoe Grivet

Image: The descending serotonin pathways control nociceptive transmission at the level of the dorsal horn of the spinal cord. In healthy individuals (top diagram), this control is carried out by activation of local inhibitory interneurons (in green) reducing nociceptive transmission by inhibiting projection neurons (in black and white) which send messages to the brain where the pain will be felt. In a pathological context (bottom diagram), after nerve damage for example, the expression of chlorine transporters of the KCC2 type is reduced, the inhibitory interneurons (in blue) can no longer inhibit the projection neurons and the descending serotonin pathways no longer exert an analgesic action but on the contrary reinforces the hyperalgesia. By rebalancing the spinal chlorine finds the analgesia observed in healthy individuals. By combining an antidepressant that increases spinal serotonin levels and a KCC2 activator, powerful analgesia is obtained in a model of peripheral neuropathy.

To know more :
Switch of serotonergic descending inhibition into facilitation by a spinal chloride imbalance in neuropathic pain.
Aby F, Lorenzo LE, Grivet Z, Bouali-Benazzouz R, Martin H, Valerio S, Whitestone S, Isabel D, Idi W, Bouchatta O, De Deurwaerdere P, Godin AG, Herry C, Fioramonti X, Landry M, De Koninck Y, Fossat P.
Science Advances July 29, 2022. doi: 10.1126/sciadv.abo0689

#Antidepressants #chronic #pain #targeting #chlorine #difference

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