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

National Center For Complementary & Integrative Health

Investigators

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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. In addition, we identified and functionally characterized a new efferent pain circuit from CeA-PKCδ neurons to a subthalamic structure called the zona incerta (ZI), specifically showing that injury-induced activation of CeA-PKCδ neurons monosynaptically inhibits ZI-GABAergic cells, subsequently leading to pain-related hypersensitivity. At the afferent level, we showed that excitatory afferent inputs to the CeA from the parabrachial nucleus (PBN) is critical for injury-induced hypersensitivity but not acute somatosensation and that PBN neurons undergo divergent changes in excitability following nerve injury. The main focus of our research program during FY25 was to investigate CeA cells and circuits contributing to the transition from acute to chronic pain. In collaboration with the Neugebauer lab (Texas Tech), we demonstrated that the PB→CeA pathway and cell-type-specific hyperexcitability of CeA neurons are critical for the initiation but not the maintenance of chronic neuropathic pain, underscoring that the mechanisms for acute and chronic pain are distinct. In separate studies, we identified an intra-amygdala circuit that contributes to pain chronicity, demonstrating that CeA modulates both acute and chronic pain states, but different circuits are engaged in the transition to pain chronicity. A second focus of FY25 was to dissect out neurochemical mechanisms underlying CeA modulation of pain sensitization. We completed a study that demonstrated sexually dimorphic functions of central amygdala neurons expressing CGRP receptor and PKCδ in pain modulation. In a separate study, in collaboration with the Eiden lab (NIMH), we characterized the functional contributions of specific neurochemicals in PBN neurons to pain sensitization and stress response in rodents, revealing that while PBN neurons modulate both pain sensitization and stress responses, modulation of specific behaviors involves distinct neurochemical mechanisms. Lastly, during FY25 we continued making progress on experiments that aim at identifying mechanisms at the intersection of pain and affective states, including stress-induced analgesia, pain-related aversion, and pain-related affective comorbidities.