Amygdala pain mechanisms

Abstract

A limbic brain area, the amygdala plays a key role in emotional responses and affective states and disorders such as learned fear, anxiety, and depression. The amygdala has also emerged as an important brain center for the emotional-affective dimension of pain and for pain modulation. Hyperactivity in the laterocapsular division of the central nucleus of the amygdala (CeLC, also termed the "nociceptive amygdala") accounts for pain-related emotional responses and anxiety-like behavior. Abnormally enhanced output from the CeLC is the consequence of an imbalance between excitatory and inhibitory mechanisms. Impaired inhibitory control mediated by a cluster of GABAergic interneurons in the intercalated cell masses (ITC) allows the development of glutamate- and neuropeptide-driven synaptic plasticity of excitatory inputs from the brainstem (parabrachial area) and from the lateral-basolateral amygdala network (LA-BLA, site of integration of polymodal sensory information). BLA hyperactivity also generates abnormally enhanced feedforward inhibition of principal cells in the medial prefrontal cortex (mPFC), a limbic cortical area that is strongly interconnected with the amygdala. Pain-related mPFC deactivation results in cognitive deficits and failure to engage cortically driven ITC-mediated inhibitory control of amygdala processing. Impaired cortical control allows the uncontrolled persistence of amygdala pain mechanisms.

Figure 1

Dimensions of pain.

Figure 2. Amygdala circuitry and interactions with cortical systems and brainstem

Input regions (lateral and basolateral amygdala, LA, BLA) process and transmit polymodal sensory and nociceptive information from thalamocortical systems to the amygdala output region (central nucleus, CeA) through direct excitatory projections or indirect feedforward inhibition involving interneurons in the intercalated cell mass (ITC). BLA forms close connections with mPFC that involve inhibitory interneurons in the cortex resulting in feedforward inhibition of mPFC principal cells. mPFC output neurons can engage ITC cells to control amygdala output. Dashed line indices area of the amygdala.

Figure 3. Role of the amygdala in pain

Pain producing events generate hyperactivity in the amygdala network of lateral, basolateral and central nuclei (LA, BLA, CeA), which accounts for emotional-affective aspects of pain. Output from BLA deactivates medial prefrontal cortex through feedforward inhibition, resulting in cognitive deficits such as impaired decision making. Decreased medial prefrontal cortical output to the amygdala allows the uncontrolled persistence of amygdala hyperactivity hence persistence of pain.

Figure 4. Pharmacology of pain-related amygdala changes

Glutamatergic/GABAergic and peptidergic mechanisms are depicted in separate diagrams for the sake of clarity. BLA, basolateral amygdala; CeA, central nucleus of the amygdala; ITC, intercalated cells; mGluR, metabotropic glutamate receptor; NR1/2B, NMDA receptor subunits NR1 and NR2B; NPSR, neuropeptide S receptor. Dashed blue line indicates intra-amygdalar CRF release from CeA neurons.