USING AN OPTOPHARMACOLOGICAL APPROACH TO STUDY TYPE 4 METABOTROPIC GLUTAMATE RECEPTORS IN CHRONIC PAIN – ExPLORER

The present project focuses on chronic pain. Contrary to acute pain, chronic pain is not serving as a warning signal, as it persists for a long time after the initial affliction, and must be considered as a disease per se. It not only causes physical pain, but also induces severe affective and cognitive disorders, seriously impairing patient’s life quality. This massive disease burden affects about 20% of the European population. Unfortunately, current therapies have limited efficacies: only half of patients suffering from chronic pain receive adequate pain relief using the current treatments, often with adverse central nervous system side effects. There is a clear need for new analgesics against chronic pain. We believe that a better understanding of cellular and molecular pathophysiological mechanisms is essential for identifying new pharmacological targets for the treatment of chronic pain.

Glutamate is the main neurotransmitter involved in the transmission of pain throughout the pain pathway. A loss of the balance between excitatory glutamatergic transmission and inhibitory GABAergic transmission is involved in the development of central sensitization of the pain neuraxis, and leads to the development of the symptoms observed in patients with chronic pain. Therefore, regulating glutamate and GABA signaling could be one way of alleviating chronic pain.

Metabotropic glutamate receptors (mGluRs) constitute an endogenous modulatory system expressed all along the pain neuraxis where they modulate the perception of pain. We have previously shown that systemic activation of mGlu4, known to modulate both glutamatergic and GABAergic transmission, alleviates pain hypersensitivity while leaving acute pain unchanged. This property makes mGlu4 a potentially interesting target for new analgesics active solely in chronic pain states. However, the precise role, location and mode of action of these particular receptors at different levels of the pain pathway are still largely unknown.

Optopharmacology (also known as photopharmacology) is a very promising innovative technology that offers unique opportunities for in vitro and in vivo investigation. During the past years, optogenetics, which allows for the control of neuronal activity with light due to the expression of exogenous light-sensitive proteins, has completely revolutionized the study of brain circuits in neurobiology. Optopharmacology is a more recent development based on photoswitchable ligands that can be switched ON and OFF with light. Contrary to optogenetics which requires the use of transgenes, this novel method allows for the modulation of the activity of endogenous receptors, providing precise spatial and temporal control of the drug/target activity. Therefore, optopharmaoclogy has invaluable outcomes for the understanding of endogenous receptor function. Although very promising, optopharmacology has, to date, never been used to explore new regulatory mechanisms of pain.

In the present project, we propose to take advantage of the first light-regulated positive and negative allosteric modulators of mGlu4 recently developed by our teams in preliminary results to selectively turn on/off receptors. These optopharmacological tools will provide us with a fine spatial and temporal control of the drug/target activity to dissect the role and mode of action of mGlu4 at precise locations along the pain neuraxis. Behavioral, electrophysiological and cellular consequences of optical control of mGlu4 will be monitored in order to better understand the role of mGlu4 in chronic pain, and ideally, to validate this receptor as a novel therapeutic target.