Understanding the biological basis of pain-related behaviors is essential for the development of improved therapeutic options for chronic pain. The main goal of our research program is to identify brain mechanisms underlying maladaptive changes in somatosensation and affective behaviors in chronic pathological pain states. We have focused on the central amygdala (CeA), a structure in the limbic brain system that modulates pathological pain and affective behaviors. Previous studies have demonstrated that CeA neurons are morphologically, electrophysiologically and molecularly diverse. More importantly, modulation of emotional behaviors in the CeA has been shown to be both cell-type and circuit-specific. The contribution of different CeA cell types and circuits to the modulation of pain-related behaviors, however, has not been established. Our overarching hypothesis is that modulation of pain-related behaviors in chronic pathological states is encoded by plastic changes in distinct CeA cell types and by alterations in the functional connectivity between the CeA and other brain regions. This is the fourth year of this project. Over the last four years, we have successfully built a multidisciplinary research program that uses state-of-the-art molecular genetics, electrophysiological and in-vivo mouse behavioral approaches to begin to address these ambitious but also fundamentally important questions in the field. Our experiments identified at least three functionally distinct populations of nociceptive neurons in the CeA: 1) a population of pain ON cells that becomes hyperexcitable in the context of persistent pain; 2) a second population of pain ON cells that undergoes pain-induced changes in ERK activation; and 3) a population of pain OFF cells that becomes hypoexcitable in the context of pain. In vivo selective chemogenetic inhibition of either of the pain ON cell populations decreased tactile hypersensitivity in models of persistent pain, demonstrating that activation of these cells is necessary for pathological tactile hypersensitivity. In contrast, in vivo selective inactivation of the OFF cells in nave animals induced tactile hypersensitivity in the absence of injury, demonstrating that inactivation of these cells is sufficient to induce pain-like behaviors. Altogether, these innovative findings reveal previously underappreciated complexities of pain modulation in the CeA and provide the first causal evidence for endogenous bidirectional, cell-type-specific modulation of pain-related behaviors in the CeA in models of persistent pain. These results further set a solid foundation for our current efforts, future studies and long-term goals that aim at elucidating the cellular and synaptic mechanisms underlying the physiological contributions of distinct CeA cell types and anatomical circuits to the modulation of maladaptive changes in pain-related behaviors.
