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.

The Emotional Brain as a Predictor and Amplifier of Chronic Pain

“…In rodent models of persistent pain, amygdala excitability rapidly increases, which increases spinal cord excitability. Moreover, amygdala inputs to the mPFC change the inhibitory drive to the region (Neugebauer et al 2004;Ji and Neugebauer 2011;Neugebauer 2015). In humans, Following an injury that gives rise to a large and persistent increase in nociceptive barrage, the properties of the corticolimbic circuitry dictate long-term outcome.…”

Subliminal (latent) processing of pain and its evolution to conscious awareness

“…Specifically, recurrent pain episodes disrupt the regulatory inhibitory GABA-ergic output in subcortical limbic structures such as basolateral amygdala (BLA) leading to hyperactivity (including diminished after hyperpolarization; (Faber et al, 2008)) of the principal glutamatergic excitatory outputs (Neugebauer, 2015), underlying anxiety, associative learning, pain conditioning and outpouring of the stress hormones. Such impairments in the BLA microcircuitry and in its projections to the respective structures involved in cognition and in motivational drives, namely the medial prefrontal cortex and ventral and dorsal striatum, also results in poor inhibitory control and impulsivity in conjunction with limited behavioral repertoire in the form of habit-based, rather than value-based, decision making processes and behavioral choices fixated on pain-related content including irresistible urges to seek and consume analgesic drugs and catastrophizing (Elman et al, 2011).…”

Monomethyl fumarate inhibits pain behaviors and amygdala activity in a rat arthritis model

“…The amygdala plays a key role in emotional-affective aspects of pain [43]. Neuroplastic changes have been shown to increase amygdala output and behavioral responses in different pain models.…”

“…Neuroplastic changes have been shown to increase amygdala output and behavioral responses in different pain models. The central nucleus (CeA) serves major amygdala output functions and receives nociceptive information through the spino-parabrachio-amygdaloid pathway and highly processed affect-related information from the lateral-basolateral (LA-BLA) network [43]. CeA activity correlates positively with emotional-affective behaviors and can also modulate pain sensitivity.…”