Abstract
The amygdala is a limbic brain region that plays a key role in emotional processing, neuropsychiatric disorders, and the emotional-affective dimension of pain. Preclinical and clinical studies have identified amygdala hyperactivity as well as impairment of cortical control mechanisms in pain states. Hyperactivity of basolateral amygdala (BLA) neurons generates enhanced feedforward inhibition and deactivation of the medial prefrontal cortex (mPFC), resulting in pain-related cognitive deficits. The mPFC sends excitatory projections to GABAergic neurons in the intercalated cell mass (ITC) in the amygdala, which project to the laterocapsular division of the central nucleus of the amygdala (CeLC; output nucleus) and serve gating functions for amygdala output. Impairment of these cortical control mechanisms allows the development of amygdala pain plasticity. Mechanisms of abnormal amygdala activity in pain with particular focus on loss of cortical control mechanisms as well as new strategies to correct pain-related amygdala dysfunction will be discussed in the present review.
Highlights
A pain-related function was rst suggested by the discovery of a dedicated nociceptive pathway from the spinal cord through the external lateral parabrachial (PB) nucleus to the central nucleus of the amygdala [13, 14]
Patients with irritable bowel syndrome (IBS) had higher positive resting-state functional connectivity between the amygdala and the insula, pre- and postcentral gyri, and supplementary motor area compared to healthy controls, and this increased connectivity positively correlated to pain intensity [47]
A separate study demonstrated that IBS patients that did not have visceral hypersensitivity had decreased positive resting-state functional connectivity of the amygdala within the default mode network compared to healthy controls as well as IBS patients with visceral hypersensitivity [48]
Summary
Changes in the amygdala neurocircuitry have been detected in di erent preclinical models of pain and linked mechanistically to pain behaviors, indicating that these maladaptive neuroplastic changes are a brain mechanism of pain. E clinical relevance of these neuroplastic changes in preclinical pain models is supported by neuroimaging studies, indicating that amygdala activity is increased in subjects with previously diagnosed pain conditions, including osteoarthritis, IBS, and bromyalgia compared to matched controls [10]. This amygdala pain-related plasticity exhibits hemispheric lateralization. In in ammatory [36] and neuropathic [42] pain conditions, neurons in the right but not left amygdala exhibit a sustained increase in background and evoked activity irrespective of the side of injury, and the receptive eld size of neurons in the right but not left amygdala is increased in an arthritis pain model [36]. Mechanisms and signi cance of pain-related amygdala lateralization remain to be determined
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