Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior.
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,C alphaMeLeu13,39, 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.
Fu
Yu
Y
Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas 77555-1069, USA.
Neugebauer
Volker
V
D000679:Amygdala / Q000378:metabolism* / Q000503:physiopathology; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001168:Arthritis / Q000150:complications; D001522:Behavior, Animal / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004594:Electrophysiology; D004789:Enzyme Activation; D006614:Hindlimb / Q000503:physiopathology; D066298:In Vitro Techniques; D009474:Neurons / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects; D013116:Spinal Cord / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects; D019789:Tetraethylammonium / Q000494:pharmacology; D014828:Vocalization, Animal / Q000187:drug effects; D000099052:CRF Receptor, Type 1
C471210:2-methyl-4-(N-propyl-N-cycloproanemethylamino)-5-chloro-6-(2,4,6-trichloranilino)pyrimidine; D000814:Aniline Compounds; C101531:CRF receptor type 2; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D015221:Potassium Channels; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; C528574:astressin-2B; D000099052:CRF Receptor, Type 1; D019789:Tetraethylammonium; D017868:Cyclic AMP-Dependent Protein Kinases