Cognitive impairment such as the inability to make advantageous decisions is one of the consequences of persistent pain but the underlying neural mechanisms are not known (NIH PA-06-544). The role of the prefrontal cortex in cognitive function, including decision-making and avoidance of emotion-based risky choices, is well established. Impaired prefrontal cortical function was recently shown in pain patients with cognitive deficits. A major source of input to the mPFC is the basolateral amygdala (BLA), a key element in the emotional-affective amygdala circuitry. Our previous studies showed enhanced synaptic transmission from the BLA to the central nucleus of the amygdala (CeA) in an arthritis pain model. We hypothesize that the BLA is an important structure underlying pain-related emotional-affective behavior (through projections to the CeA) and cognitive deficits (through connections with the mPFC). To determine the role of the BLA-mPFC interaction in cognitive effects of pain, we will use a multidisciplinary approach that combines behavior, systems and cellular electrophysiology and pharmacology. We will continue to use our well-established pain model, the kaolin/carrageenan-induced knee joint arthritis. The following specific hypotheses will be tested: 1. Restoring normal function in the BLA and mPFC improves pain-related decision-making deficits. 2. Pain-related sensitization of BLA projection neurons inhibits mPFC neurons. 3. Pain leads to synaptic plasticity in the BLA and increases inhibitory transmission from the BLA to mPFC neurons.
The Specific Aims are: 1. Determine if restoring normal function in the BLA (deactivation with APS, an NMDA receptor antagonist) and in the mPFC (removing inhibition with bicuculline, a GABAA receptor antagonist) improves pain-related cognitive impairment in a novel behavioral test modeled after a decision-making gambling task in humans. Arthritic and control animals decide between disadvantageous high-risk and advantageous low-risk strategies based on food reward. 2. Analyze the effect of arthritis on BLA and mPFC neurons and determine if inhibiting BLA sensitization (with APS) or disinhibiting the mPFC (with bicuculline) reverse pain-related inhibition of mPFC neurons in anesthetized rats in vivo. 3. Determine the effect of arthritis on excitatory and inhibitory synaptic transmission in the BLA and at the BLA-mPFC synapse in vitro, using whole-cell patch-clamp recordings in brain slices from arthritic and control animals. This translational research project will determine the neurobiological mechanism by which pain produces clinically documented cognitive deficits. If our hypotheses are correct, the proposed studies will be the first to demonstrate that the amygdala impairs mPFC function resulting in pain-related decision-making deficits. The long-term goal of this project is the better understanding of higher brain functions involved in the different pain components to improve pain management strategies and decision making.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038261-12
Application #
8016557
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
1999-07-01
Project End
2012-06-30
Budget Start
2011-02-01
Budget End
2012-06-30
Support Year
12
Fiscal Year
2011
Total Cost
$291,336
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Ji, Guangchen; Zhang, Wei; Mahimainathan, Lenin et al. (2016) 5-HT2C receptor knockdown in the amygdala inhibits neuropathic pain related plasticity and behaviors. J Neurosci :
Buzhdygan, Tetyana; Lisinicchia, Joshua; Patel, Vipulkumar et al. (2016) Neuropsychological, Neurovirological and Neuroimmune Aspects of Abnormal GABAergic Transmission in HIV Infection. J Neuroimmune Pharmacol 11:279-93
Lu, Yun-Fei; Neugebauer, Volker; Chen, Jun et al. (2016) Distinct contributions of reactive oxygen species in amygdala to bee venom-induced spontaneous pain-related behaviors. Neurosci Lett 619:68-72
Kiritoshi, Takaki; Ji, Guangchen; Neugebauer, Volker (2016) Rescue of Impaired mGluR5-Driven Endocannabinoid Signaling Restores Prefrontal Cortical Output to Inhibit Pain in Arthritic Rats. J Neurosci 36:837-50
Cragg, Bryce; Ji, Guangchen; Neugebauer, Volker (2016) Differential contributions of vasopressin V1A and oxytocin receptors in the amygdala to pain-related behaviors in rats. Mol Pain 12:
Ji, Guangchen; Li, Zhen; Neugebauer, Volker (2015) Reactive oxygen species mediate visceral pain-related amygdala plasticity and behaviors. Pain 156:825-36
Kiritoshi, Takaki; Neugebauer, Volker (2015) Group II mGluRs modulate baseline and arthritis pain-related synaptic transmission in the rat medial prefrontal cortex. Neuropharmacology 95:388-94
Neugebauer, Volker (2015) Amygdala pain mechanisms. Handb Exp Pharmacol 227:261-84
Yuan, Su-Bo; Ji, Guangchen; Li, Bei et al. (2015) A Wnt5a signaling pathway in the pathogenesis of HIV-1 gp120-induced pain. Pain 156:1311-9
Thompson, Jeremy M; Ji, Guangchen; Neugebauer, Volker (2015) Small-conductance calcium-activated potassium (SK) channels in the amygdala mediate pain-inhibiting effects of clinically available riluzole in a rat model of arthritis pain. Mol Pain 11:51

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