title: Dynamic modulation of inflammatory pain-related affective and sensory symptoms by optical control of amygdala metabotropic glutamate receptor 4.
abstract: Contrary to acute pain, chronic pain does not serve as a warning signal and must be considered as a disease per se. This pathology presents a sensory and psychological dimension at the origin of affective and cognitive disorders. Being largely refractory to current pharmacotherapies, identification of endogenous systems involved in persistent and chronic pain is crucial. The amygdala is a key brain region linking pain sensation with negative emotions. Here, we show that activation of a specific intrinsic neuromodulatory system within the amygdala associated with type 4 metabotropic glutamate receptors (mGlu4) abolishes sensory and affective symptoms of persistent pain such as hypersensitivity to pain, anxiety- and depression-related behaviors, and fear extinction impairment. Interestingly, neuroanatomical and synaptic analysis of the amygdala circuitry suggests that the effects of mGlu4activation occur outside the central nucleus via modulation of multisensory thalamic inputs to lateral amygdala principal neurons and dorso-medial intercalated cells. Furthermore, we developed optogluram, a small diffusible photoswitchable positive allosteric modulator of mGlu4. This ligand allows the control of endogenous mGlu4activity with light. Using this photopharmacological approach, we rapidly and reversibly inhibited behavioral symptoms associated with persistent pain through optical control of optogluram in the amygdala of freely behaving animals. Altogether, our data identify amygdala mGlu4signaling as a mechanism that bypasses central sensitization processes to dynamically modulate persistent pain symptoms. Our findings help to define novel and more precise therapeutic interventions for chronic pain, and exemplify the potential of optopharmacology to study the dynamic activity of endogenous neuromodulatory mechanisms in vivo.
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS, UMR-5203, Université de Montpellier, Montpellier, France.|INSERM, U1191, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Zussy
authors.affiliation: MCS, Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.|Laboratory of Molecular Neuropharmacology and Bioinformatics, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: X
authors.initials: X
authors.lastname: Gómez-Santacana
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS, UMR-5203, Université de Montpellier, Montpellier, France.|INSERM, U1191, Montpellier, France.
authors.forename: X
authors.initials: X
authors.lastname: Rovira
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS, UMR-5203, Université de Montpellier, Montpellier, France.|INSERM, U1191, Montpellier, France.
authors.forename: D
authors.initials: D
authors.lastname: De Bundel
authors.affiliation: Department of Pharmacology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Ferrazzo
authors.affiliation: Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|Werner Reichardt Centre for Integrative Neuroscience, University of Tübingen, Tübingen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Bosch
authors.affiliation: Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|Werner Reichardt Centre for Integrative Neuroscience, University of Tübingen, Tübingen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Asede
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS, UMR-5203, Université de Montpellier, Montpellier, France.|INSERM, U1191, Montpellier, France.
authors.forename: F
authors.initials: F
authors.lastname: Malhaire
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR8601, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Acher
authors.affiliation: Laboratory of Molecular Neuropharmacology and Bioinformatics, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Network Biomedical Research Center on Mental Health (CIBERSAM), Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Giraldo
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS, UMR-5203, Université de Montpellier, Montpellier, France.|INSERM, U1191, Montpellier, France.
authors.forename: E
authors.initials: E
authors.lastname: Valjent
authors.affiliation: Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.|Werner Reichardt Centre for Integrative Neuroscience, University of Tübingen, Tübingen, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Ehrlich
authors.affiliation: Department of Pharmacology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Ferraguti
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS, UMR-5203, Université de Montpellier, Montpellier, France.|INSERM, U1191, Montpellier, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Pin
authors.affiliation: MCS, Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Llebaria
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS, UMR-5203, Université de Montpellier, Montpellier, France.|INSERM, U1191, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Goudet
mesh_terms: D000679:Amygdala / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D066272:Basolateral Nuclear Complex / Q000378:metabolism; D059350:Chronic Pain / Q000378:metabolism*; D005239:Fear / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D010146:Pain / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism* / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D013788:Thalamus / Q000378:metabolism
chemical_list: D018377:Neurotransmitter Agents; D018094:Receptors, Metabotropic Glutamate; C108823:metabotropic glutamate receptor 4