Cellular and molecular mechanisms undelying amygdala-dependent pain modulation

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DESCRIPTION (provided by applicant): Chronic pain presents a serious burden to human patients afflicting over 30% of the population. Although much research has focused on the peripheral and spinal cord control of pain, I am Interested In evaluating brain-localized pain modulation. The amygdala, an important site for emotional processing of anxiety, fear and learning behaviors, is well situated to be a higher order locus for the control of pain. The central nucleus of the amygdala (CeA) receives nociceptive Inputs via the spino-ponto- amygdaloid pain pathway and polymodal sensory Information via other amygdalar nuclei. Recently, our group has identified a critical role for extracellular-signal regulated kinase (ERK) signaling in the CeA of mice. ERK activation in the CeA is both necessary for behavioral sensitization in a model of inflammatory pain and sufficient to produce hypersensitivity to mechanical stimuli in the absence of peripheral inflammation. However, the upstream activators and downstream effectors of ERK in the CeA remain unknown. Interestingly, signaling through group I metabotropic glutamate receptors (mGluRs) in the CeA serves as an important component in the behavioral and cellular response to arthritic pain. In the spinal cord, group I mGluRs couple to ERK to affect behavioral sensitization and neuronal excitability. Therefore, we hypothesize that CeA group I mGluRs mediate increases In ERK signaling to alter behavioral sensitization during inflammation and to modulate neuronal excitability in the amygdala. In our first specific aim, we will use pharmacological techniques to evaluate the role of group I mGluR signaling in modulating ERK activation and behavioral sensitization. In aim two, we will use electrophysiological techniques to evaluate the effect of mGluR and ERK on neuronal excitability. PUBLIC HEALTH RELEVANCE: Our poor understanding of pain modulation In the brain is partially responsible for the relatively poor efficacy of treatments for chronic pain. This research plan Is designed to study the role of the amygdala, a brain region Involved In emotional responses to pain, in chronic pain by focusing on the signaling mechanisms in the amygdala that regulate pain. Identification of the mechanisms of pain modulation in this area will aid in the identification of therapeutic targets for novel treatment development.