Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior
Open accessAbstract
A major site of extrahypothalamic expression of corticotropin-releasing factor (CRF) and its G-protein-coupled CRF1 and CRF2 receptors is the amygdala, a key player in emotions and affective disorders. Pain-related plasticity in the laterocapsular division of the central nucleus of the amygdala (CeLC) generates emotional-affective responses and anxiety-like behavior. CRF1 receptor antagonists have anxiolytic effects. Although both CRF1 and CRF2 receptors couple positively to adenylyl cyclase, they can have opposite effects, but the underlying mechanism is unknown. This study addressed CRF1 and CRF2 receptor functions and mechanisms in the amygdala in a model of arthritic pain. Using whole-cell patch-clamp recordings of CeLC neurons, we found that a selective CRF1 receptor antagonist (NBI27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)]) amino-pyridine inhibited synaptic facilitation in brain slices from arthritic rats through a postsynaptic mechanism. Inhibition of the NMDA receptor-mediated synaptic component was occluded by a protein kinase A (PKA) inhibitor, consistent with our previous demonstration of PKA-dependent increased NMDA receptor function in arthritis pain-related plasticity. NBI27914 also decreased neuronal excitability through inhibition of highly tetraethylammonium (TEA)-sensitive ion channels that contribute to action potential repolarization and firing rate. In contrast, a CRF2 receptor antagonist (astressin-2B [cyclo(31–34) [d-Phe11,His12,CαMeLeu13,39, Nle17, Glu31, Lys34] Ac-Sauvagine(8–40)]) facilitated synaptic transmission through presynaptic inhibition of GABAergic transmission (disinhibition). NBI27914 inhibited arthritis pain-related behaviors (audible and ultrasonic vocalizations and hindlimb withdrawal reflexes). Astressin-2B had no significant behavioral effect. The data suggest that endogenous CRF1 receptor activation in the amygdala contributes to pain-related synaptic facilitation, increased excitability, and pain behavior through a postsynaptic mechanism involving activation of PKA and highly TEA-sensitive K+-currents. Presynaptic CRF2 receptor-mediated inhibition does not reach behavioral significance.
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Blockade of CRF1 receptors in the CeA inhibits both pain- and anxiety-like behaviors in a model of arthritic pain.
“In a model of arthritic pain, the blockade of CRF 1 receptors in the CeA inhibited both pain-and anxiety-like behaviors (Ji et al., 2007;Fu and Neugebauer, 2008).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Fu and Neugebauer, 2008
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- Authors
- Fu, Y., & Neugebauer, V.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-04-09
- Volume
- 28
- Issue
- 15
- Pages
- 3861-3876
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2557030
- OpenAlex
- W2050750919
- Cited by
- 184
- References
- 97
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 7 · 2023: 4 · 2022: 7 · 2021: 9 · 2020: 13 · 2019: 11 · 2018: 12 · 2017: 8 · 2016: 11 · 2015: 17 · 2014: 16 · 2013: 9 · 2012: 7
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Northwestern University
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS-38261, NS11255, P01NS011255, R01NS038261)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- corticotropin-releasing factor, CRF1 receptor, CRF2 receptor, amygdala, central amygdala, arthritic pain, protein kinase A, NMDA receptor, neuronal excitability, presynaptic inhibition, GABAergic neurotransmission, anxiety-like behavior, ultrasonic vocalizations
- MeSH terms
- CRF Receptor, Type 1, Amygdala, Aniline Compounds, Animals, Arthritis, Behavior, Animal, Electrophysiology, Enzyme Activation, Hindlimb, Neurons, Pain, Peptide Fragments, Peptides, Cyclic, Pyrimidines, Reflex, Spinal Cord, Synapses, Vocalization, Animal, Potassium Channels, Rats, Sprague-Dawley, Cyclic AMP-Dependent Protein Kinases, Receptors, Corticotropin-Releasing Hormone, Patch-Clamp Techniques, Tetraethylammonium, Rats, In Vitro Techniques
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