Cortico-limbic pain mechanisms

Abstract

Pain has a strong emotional component and is defined by its unpleasantness. Chronic pain represents a complex disorder with anxio-depressive symptoms and cognitive deficits. Underlying mechanisms are still not well understood but an important role for interactions between prefrontal cortical areas and subcortical limbic structures has emerged. Evidence from preclinical studies in the rodent brain suggests that neuroplastic changes in prefrontal (anterior cingulate, prelimbic and infralimbic) cortical and subcortical (amygdala and nucleus accumbens) brain areas and their interactions (corticolimbic circuitry) contribute to the complexity and persistence of pain and may be predetermining factors as has been proposed in recent human neuroimaging studies.

Keywords: Affective; Amygdala; Cognitive; Hippocampus; Neuroplasticity; Nucleus accumbens; Pain modulation; Prefrontal cortex; Vulnerability.

Figure 1.. Pain-related changes in cortico-amygdala interactions.

Projection neurons in the BLA synapse on PV-GABAergic interneurons as well as on mPFC projection neurons in the infra- and pre-limbic cortices through a mechanism involving mGluR1, mGluR5, and CB1. PV-GABAergic interneurons in turn project to mPFC projection neurons, resulting in BLA-driven feedforward inhibition of mPFC projection neuron activity. BLA activity is increased in arthritis pain, resulting in pain-related cortical dysfunction. Projection neurons from the infralimbic cortex synapse on BLA projection neurons, as well as GABAergic ITC neurons. GABAergic ITC neurons and BLA projection neurons synapse on CeL projection neurons. Reduced cortical drive onto BLA and ITC neurons in the arthritis pain state results in reduced feedforward inhibition onto CeL projection neurons. This, coupled with increased drive from the BLA, results in pain-related amygdala hyperactivity. mPFC, medial prefrontal cortex; CB1, cannabinoid receptor 1; mGluR, metabotropic glutamate receptor; CeL, lateral division of the central nucleus of the amygdala; ITC, intercalated cell mass of the amygdala.

Figure 2.. Pain-related cortico-limbic interactions.

Connections between cortical (prefrontal cortex including infralimbic, prelimbic, and anterior cingulate cortices) and limbic (amygdala, hippocampus, and nucleus accumbens) regions. Within the amygdala, the CeA (brown) with its medial (left) and lateral (right) divisions, ITC (green), and LA/BLA are shown. Within the nucleus accumbens, the core (green) and shell (blue) divisions are shown. mPFC, medial prefrontal cortex; IL, infralimbic mPFC; PL, prelimbic mPFC; ACC, anterior cingulate cortex; NAc, nucleus accumbens.