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.