Dysfunction of Glutamate Delta-1 Receptor-Cerebellin 1 Trans-Synaptic Signaling in the Central Amygdala in Chronic Pain.

Autor: Gandhi PJ; Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, NE 68178, USA., Gawande DY; Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, NE 68178, USA., Shelkar GP; Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, NE 68178, USA., Gakare SG; Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, NE 68178, USA., Kiritoshi T; Department of Pharmacology and Neuroscience, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA., Ji G; Department of Pharmacology and Neuroscience, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.; Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA., Misra B; Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, NE 68178, USA., Pavuluri R; Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, NE 68178, USA., Liu J; Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, NE 68178, USA., Neugebauer V; Department of Pharmacology and Neuroscience, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.; Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.; Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA., Dravid SM; Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, NE 68178, USA.
Jazyk: angličtina
Zdroj: Cells [Cells] 2021 Oct 03; Vol. 10 (10). Date of Electronic Publication: 2021 Oct 03.
DOI: 10.3390/cells10102644
Abstrakt: Chronic pain is a debilitating condition involving neuronal dysfunction, but the synaptic mechanisms underlying the persistence of pain are still poorly understood. We found that the synaptic organizer glutamate delta 1 receptor (GluD1) is expressed postsynaptically at parabrachio-central laterocapsular amygdala (PB-CeLC) glutamatergic synapses at axo-somatic and punctate locations on protein kinase C δ -positive (PKCδ + ) neurons. Deletion of GluD1 impairs excitatory neurotransmission at the PB-CeLC synapses. In inflammatory and neuropathic pain models, GluD1 and its partner cerebellin 1 (Cbln1) are downregulated while AMPA receptor is upregulated. A single infusion of recombinant Cbln1 into the central amygdala led to sustained mitigation of behavioral pain parameters and normalized hyperexcitability of central amygdala neurons. Cbln2 was ineffective under these conditions and the effect of Cbln1 was antagonized by GluD1 ligand D-serine. The behavioral effect of Cbln1 was GluD1-dependent and showed lateralization to the right central amygdala. Selective ablation of GluD1 from the central amygdala or injection of Cbln1 into the central amygdala in normal animals led to changes in averse and fear-learning behaviors. Thus, GluD1-Cbln1 signaling in the central amygdala is a teaching signal for aversive behavior but its sustained dysregulation underlies persistence of pain. Significance statement: Chronic pain is a debilitating condition which involves synaptic dysfunction, but the underlying mechanisms are not fully understood. Our studies identify a novel mechanism involving structural synaptic changes in the amygdala caused by impaired GluD1-Cbln1 signaling in inflammatory and neuropathic pain behaviors. We also identify a novel means to mitigate pain in these conditions using protein therapeutics.
Databáze: MEDLINE
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