Molecular and cellular mechanisms for bidirectional control of pain in the brain

National Center For Complementary & Integrative Health

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Abstract

In previous years, we showed that the central amygdala (CeA) functions as a pain rheostat system that can amplify or suppress pain. We further showed that the directionality of pain modulation is dependent on the activity of two subsets of genetically distinct CeA neurons, with activity of one population increasing pain responses and activity of the second population decreasing pain-related responses. At the cellular level, we have also shown that these genetically distinct CeA neurons are electrophysiologically and morphologically distinct and contributed to building an agent-based computational model that allows dynamic simulation of nociceptive signal propagation through the CeA network. We have also increased the understanding of sex as a biological variable in pain processing by demonstrating important sex differences in a behavioral visceral responses, disease progression and bowel pathology in a model of colitis. The main focus of our research program during FY23 was to investigate CeA circuits contributing to pain processing. We published a study that characterized 17 anatomical efferent projections of CeA neurons expressing PKC-delta throughout the basal forebrain, striatum, thalamus, hypothalamus, midbrain, pons and medulla. We further showed that an inhibitory projection from CeA-PKCd neurons to a subthalamic structure called the zona incerta contributes to neuropathic pain-like responses. In a second publication, we showed that excitatory afferent inputs to the CeA from the parabrachial nucleus (PBN) is critical for injury-induced hypersensitivity but not acute somatosensation. Lastly, in collaboration with the Kolber lab at UT Dallas, we published an additional study that shows that calcitonin gene-related peptide (CGRP) signaling in the parabrachial-to-amygdala pathway determines hemispheric lateralization of visceral pain.