Protein kinase A-dependent enhanced NMDA receptor function in pain-related synaptic plasticity in rat amygdala neurones

• Published in: The Journal of physiology Vol. 564; no. 3; pp. 907 - 921
• Main Authors: Bird, Gary C., Lash, L. Leanne, Han, Jeong S., Zou, Xiaoju, Willis, William D., Neugebauer, Volker
• Format: Journal Article
• Language: English
• Published: 9600 Garsington Road , Oxford , OX4 2DQ , UK The Physiological Society 01-05-2005; Blackwell Science Ltd; Blackwell Science Inc
• Subjects: Amygdala - physiopathology; Animals; Arthralgia - etiology; Arthralgia - physiopathology; Arthritis, Experimental - chemically induced; Arthritis, Experimental - complications; Arthritis, Experimental - physiopathology; Cyclic AMP-Dependent Protein Kinases - metabolism; Disease Models, Animal; Integrative Physiology; Kaolin; Neuronal Plasticity; Neurons - metabolism; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - metabolism; Synaptic Transmission
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2005.084780

Mechanisms of pain-related plasticity in the amygdala, a key player in emotionality, were studied at the cellular and molecular
levels in a model of arthritic pain. The influence of the arthritis pain state induced in vivo on synaptic transmission and N -methyl- d -aspartate (NMDA) receptor function was examined in vitro using whole-cell voltage-clamp recordings of neurones in the latero-capsular part of the central nucleus of the amygdala
(CeA), which is now defined as the ‘nociceptive amygdala’. Synaptic transmission was evoked by electrical stimulation of afferents
from the pontine parabrachial area (part of the spino-parabrachio-amygdaloid pain pathway) in brain slices from control rats
and from arthritic rats. This study shows that pain-related synaptic plasticity is accompanied by protein kinase A (PKA)-mediated
enhanced NMDA-receptor function and increased phosphorylation of NMDA-receptor 1 (NR1) subunits. Synaptic plasticity in the
arthritis pain model, but not normal synaptic transmission in control neurones, was inhibited by a selective NMDA receptor
antagonist. Accordingly, an NMDA receptor-mediated synaptic component was recorded in neurones from arthritic animals, but
not in control neurones, and was blocked by inhibition of PKA but not protein kinase C (PKC). Exogenous NMDA evoked a larger
inward current in neurones from arthritic animals than in control neurones, indicating a postsynaptic effect. Paired-pulse
facilitation, a measure of presynaptic mechanisms, was not affected by an NMDA-receptor antagonist. Increased levels of phosphorylated
NR1 protein, but not of total NR1, were measured in the CeA of arthritic rats compared to controls. Our results suggest that
pain-related synaptic plasticity in the amygdala involves a critical switch of postsynaptic NMDA receptor function through
PKA-dependent NR1 phosphorylation.