Cognitive deficits such as impaired decision-making can be a consequence of persistent
pain. Normal functions of the intact amygdala and prefrontal cortex are required for emotion-based decision-making that relies on the ability to assess risk, attribute value, and identify advantageous strategies. We tested the hypothesis that
pain-related cognitive deficits result from amygdala-driven impairment of medial prefrontal cortical (mPFC) function. To do this, we used electrophysiological single-unit recordings in vivo, patch clamp in brain slices, and various behavioral assays to show that increased neuronal activity in the amygdala in an animal model of
arthritis pain was accompanied by decreased mPFC activation and impaired decision-making. Furthermore, pharmacologic inhibition (with a
corticotropin-releasing factor 1 receptor antagonist) of
pain-related hyperactivity in the basolateral amygdala (BLA), but not central amygdala (CeA), reversed deactivation of mPFC pyramidal cells and improved decision-making deficits.
Pain-related cortical deactivation resulted from a shift of balance between inhibitory and excitatory synaptic transmission. Direct excitatory transmission to mPFC pyramidal cells did not change in the
pain model, whereas polysynaptic inhibitory transmission increased. GABAergic transmission was reduced by non-
NMDA receptor antagonists, suggesting that synaptic inhibition was
glutamate driven. The results are consistent with a model of BLA-driven feedforward inhibition of mPFC neurons. In contrast to the differential effects of BLA versus CeA hyperactivity on cortical-cognitive functions, both amygdala nuclei modulate emotional-affective
pain behavior. Thus, this study shows that the amygdala contributes not only to emotional-affective but also cognitive effects of
pain. The novel amygdalo-cortical
pain mechanism has important implications for our understanding of amygdala functions and amygdalo-cortical interactions.