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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS067761-02
Application #
8032461
Study Section
Special Emphasis Panel (ZRG1-F02B-Y (20))
Program Officer
Porter, Linda L
Project Start
2010-02-01
Project End
2011-12-01
Budget Start
2011-02-01
Budget End
2011-12-01
Support Year
2
Fiscal Year
2011
Total Cost
$43,535
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Lax, Neil C; George, David C; Ignatz, Christopher et al. (2014) The mGluR5 antagonist fenobam induces analgesic conditioned place preference in mice with spared nerve injury. PLoS One 9:e103524
Crock, Lara W; Kolber, Benedict J; Morgan, Clinton D et al. (2012) Central amygdala metabotropic glutamate receptor 5 in the modulation of visceral pain. J Neurosci 32:14217-26
Montana, Michael C; Conrardy, Beth A; Cavallone, Laura F et al. (2011) Metabotropic glutamate receptor 5 antagonism with fenobam: examination of analgesic tolerance and side effect profile in mice. Anesthesiology 115:1239-50
Kolber, Benedict J; Montana, Michael C; Carrasquillo, Yarimar et al. (2010) Activation of metabotropic glutamate receptor 5 in the amygdala modulates pain-like behavior. J Neurosci 30:8203-13