Depressed mood is a common feature of both acute and chronic postoperative pain. The nucleus accumbens (NAc), the reward center of the brain, may be a key region to regulate pain-induced depression. At the synapses of NAc neurons, increased levels of GluA1 subunits of AMPA receptors lead to the formation of calcium permeable AMPA receptors (CPARs) that modulate calcium-dependent synaptic plasticity to regulate depressive symptoms. To study the role of GluA1 in the postoperative pain state we have established rat paw incision (PI) and spared nerve injury (SNI) models to mimic acute incisional pain and chronic neuropathic pain after surgery. Both models have been shown to cause depression-like behaviors in rats. Using these models, we have established that pain increases GluA1 levels at the synapses of NAc neurons, and antagonizing CPARs in SNI-treated rats worsens the depressive symptoms of pain. Based on these data, we will test the hypothesis that postoperative pain increases GluA1 at the synapses of the NAc neurons, leading to the formation of CPARs, which in turn attenuate depression-like behaviors.
In aim 1, we will use biochemical assays to show increased synaptic levels of GluA1 with no changes in GluA2 levels. We will use synaptosome and postsynaptic density preparations to isolate the synaptic fraction and use a protein crosslinker to isolate the surface fraction of the NAc neurons. We will perform these biochemical assays at defined time points after SNI or PI to study the time course of GluA1 upregulation. We will investigate the mechanism of GluA1 trafficking by examining the role of Ser845 phophorylation, a known step in surface GluA1 trafficking. Next, we will confirm biochemical evidence of increased synaptic GluA1 expression with electrophysiology to show that postoperative pain induces characteristic CPAR currents. After establishing that pain increases GluA1 expression leading to the formation of CAPRs, in aim 2, we will show that these CPARs reduce depression-like behaviors. We will perform standard depression assays after direct antagonism of CPARs via cannuli placed in the NAc. Finally, we will potentiate CPAR currents using an ampakine in the NAc to treat depression-like behaviors in SNI or PI treated rats. Our project will have a high clinical impact, as the identification of CPARs as a positive regulator of pain-induced depression will provide a novel target to improve mood and function in postoperative patients. This project provides a great opportunity for learning advanced techniques in biochemistry and behavior and knowledge of receptor trafficking in the reward system. I will benefit from the mentorship of Dr. Edward Ziff, renowned neurobiologist, Dr. Blanck, Chair of my department, Dr. Charles Inturrisi, experienced pain researcher, and Dr. Eric Stone, an experienced depression researcher. This K08 proposal is an exciting opportunity for me to launch a successful translational research program.
Depressed mood associated with postoperative pain is a major public health issue, leading to poor postoperative function. The current project seeks to find a key molecular mechanism- GluA1 upregulation in the nucleus accumbens- for depression induced by postoperative pain. We will show that postoperative pain increases GluA1 at the synapses of NAc neurons, leading to the formation of CPARs, which in turn attenuate depression-like behaviors. The identification of GluA1-containing CPARs as a positive regulator of pain-induced depression provides a novel pharmaceutical target to improve mood and function in postoperative patients.
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|Lee, Michelle; Manders, Toby R; Eberle, Sarah E et al. (2015) Activation of corticostriatal circuitry relieves chronic neuropathic pain. J Neurosci 35:5247-59|
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|Le, Alexander M; Lee, Michelle; Su, Chen et al. (2014) AMPAkines have novel analgesic properties in rat models of persistent neuropathic and inflammatory pain. Anesthesiology 121:1080-90|
|Tukey, David S; Lee, Michelle; Xu, Duo et al. (2013) Differential effects of natural rewards and pain on vesicular glutamate transporter expression in the nucleus accumbens. Mol Brain 6:32|
|Goffer, Yossef; Xu, Duo; Eberle, Sarah E et al. (2013) Calcium-permeable AMPA receptors in the nucleus accumbens regulate depression-like behaviors in the chronic neuropathic pain state. J Neurosci 33:19034-44|