期刊
MOLECULAR PSYCHIATRY
卷 23, 期 3, 页码 509-520出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2016.223
关键词
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资金
- Agence Nationale de la Recherche [ANR-12-NEUR-0003, ANR-13-BSV1-006]
- ERANET Neuron LIGHTPAIN project
- Fundacio La Marato de TV3 [110230, 110231, 110232]
- Fondation Recherche Medicale (FRM team) [DEQ20130326522]
- Centre National de la Recherche Scientifique
- Catalan government [2012 BEI_00597, 2014SGR-0109]
- Federation of European Biochemical Societies [CTQ2014-57020-R, SAF2014-58396-R]
- Spanish Government [CTQ2014-57020-R, SAF2014-58396-R]
- Beatriu de Pinos program of Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR)
- Charitable Hertie Foundation
- Austrian Science Fund (Fonds zur Forderung der Wissenschaftlichen Forschung, Sonderforschungsbereich) [F44-17-B23, W012060-10]
- Werner Reichardt Centre for Integrative Neuroscience at the University of Tuebingen, an Excellence Cluster
- Deutsche Forschungsgemeinschaft (DFG) [EXC 307]
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 (mGlu(4)) 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 mGlu(4) 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 mGlu(4). This ligand allows the control of endogenous mGlu(4) 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 mGlu(4) 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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