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 mGlu4 activation 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 mGlu4 activity 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 mGlu4 signaling 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.
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We are grateful to Nicola Romanò, Sophie Laffray, Emmanuel Bourinet, André Calas and Etienne Gontier for research assistance and helpful discussions, and Ebba L. Lagerqvist for critical reading of the manuscript. Cell-based pharmacological assays were performed on the ARPEGE (Pharmacology-Screening-Interactome) platform at the Institute de Génomique Fonctionnelle. We acknowledge financial support from the Agence Nationale de la Recherche (ANR-12-NEUR-0003 and ANR-13-BSV1-006 to CG), the ERANET Neuron LIGHTPAIN project (to AL, JG and J-PP), the Fundació La Marató de TV3 (110230, 110231, 110232, to JG, AL and CG), the Fondation Recherche Médicale (FRM team DEQ20130326522 to J-PP), the Centre National de la Recherche Scientifique (FA, J-PP and CG), the Catalan government (2012 BEI_ 00597 to XG-S and 2014SGR-0109 to AL), the Federation of European Biochemical Societies and the Spanish Government (CTQ2014-57020-R to AL and SAF2014-58396-R to JG), the Beatriu de Pinós program of Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR, to XR), the Charitable Hertie Foundation (to IE), the Werner Reichardt Centre for Integrative Neuroscience at the University of Tuebingen, an Excellence Cluster funded by the Deutsche Forschungsgemeinschaft (DFG, EXC 307, to IE), and the Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung, Sonderforschungsbereich grant F44-17-B23 and W012060-10 to FF).
CZ conceived, performed and analyzed behavioral pharmacology, immunofluorescence microscopy and immediate early gene experiments, and wrote the paper. XGS designed and synthesized optogluram, characterized photoisomerization, and performed and analyzed cell-based pharmacological experiments. XR performed and analyzed cell-based pharmacological experiments. DDB performed and analyzed behavioral pharmacology experiments. SF performed immunofluorescence and electron microscopy experiments. DB and DA performed and analyzed classical and optogenetic-based electrophysiological experiments. FM performed and analyzed cell-based pharmacological experiments. FA designed and synthesized LSP4-2022. JG supervised and analyzed pharmacological experiments. EV supervised and designed behavioral experiments. IE supervised and designed electrophysiology experiments. FF supervised and designed neuroanatomy experiments. J-PP analyzed pharmacological results, designed experiments and analyzed activity data. AL conceived and supervised the project, planned experiments, designed compounds. CG conceived and supervised the project, designed and analyzed results and wrote the paper. All authors made comments and corrections to the manuscript.
AL, JG, XG-S, XR, CG and J-PP have filed a patent application for photochromic allosteric modulators of metabotropic glutamate receptors. FA, CG and J-PP have filed a patent application for the antihyperalgesic activity of hypophosphorous acid derivatives. The remaining authors declare no conflicts of interest.
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Zussy, C., Gómez-Santacana, X., Rovira, X. et al. Dynamic modulation of inflammatory pain-related affective and sensory symptoms by optical control of amygdala metabotropic glutamate receptor 4. Mol Psychiatry 23, 509–520 (2018). https://doi.org/10.1038/mp.2016.223
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