The multidimensional character of pain presents a therapeutic challenge that would benefit greatly from a better understanding of higher brain functions that regulate its complex emotional-affective aspects. Neuropathic pain is generally believed to result from maladaptive neuroplasticity but underlying mechanisms, particularly those in higher brain centers, are not well understood. This project will focus on abnormal function of the amygdala, a brain area that is recognized as a key player in the emotional-affective dimension of pain. Our goal is to mitigate maladaptive amygdala plasticity and block the development of chronic neuropathic pain. A critical determinant, we believe, is pain-related plasticity of serotonin 5-HT2C receptor (5-HT2CR) control of corticotropin-releasing factor (CRF) signaling in the amygdala because CRF is associated with 5-HT2CR- mediated negative affective states and CRF1 receptors mediate amygdala plasticity in inflammatory pain. Here we advance the novel concept that abnormal function of 5-HT2CR in the amygdala is a critical mechanism of chronic neuropathic pain and its emotional-affective component, and is also the likely cause of the limited efficacy of selective serotonin reuptake inhibitors (SSRIs) to treat neuropathic pain. Specifically, we propose the novel hypothesis that 5-HT2CR in the basolateral amygdala (BLA, amygdala input region), drives a vicious cycle involving CRF1 receptors that results in abnormal activity in the central nucleus (CeA, output region). 5- HT2CR-driven maladaptive plasticity in the BLA-CeA circuitry plays a critical role in chronic neuropathic pain.
Three Specific Aims (SAs) will determine synaptic and cellular mechanisms and behavioral consequences of manipulation of 5-HT2CR function in the amygdala in the spinal nerve ligation (SNL) rat model of neuropathic pain. Complementary pharmacological and novel viral vector knockdown strategies will be utilized in all aims for local inactivation or elimination of 5-HT2CR in the amygdala. Behavioral experiments (SA1) will determine the role of 5-HT2CR and CRF1 in the BLA in the emotional-affective component of neuropathic pain. Electrophysiology in vivo (SA2) will examine the hypothesis that 5-HT2CR in the BLA drives CRF1 activation and central sensitization of CeA output neurons. Patch-clamp studies in brain slices (SA3) will determine excitatory and (dis-)inhibitory synaptic and cellular mechanisms of plasticity in the BLA-CeA network that results from abnormal 5-HT2CR function driving persistent CRF1 signaling. Systemic application of a 5-HT2CR antagonist and SSRI in SA1 and SA2 will validate their clinical utility and viability. These conceptually novel studies will characterize the 5-HT2CR/CRF1 interaction in the amygdala as an important mechanism of chronic neuropathic pain. We will also identify strategies to eliminate or disrupt this signaling mechanism to block maladaptive amygdala plasticity and thus neuropathic pain. The mechanistic analysis of higher brain functions and drug targets in pain will boost basic science knowledge required for evidence-based medicine and provide translational strategies for pharmacotherapeutics and/or gene therapy.

Public Health Relevance

Neuropathic pain is notoriously difficult to treat. A better understanding of its complex nature is required for novel and improved therapeutic strategies and necessitates the comprehensive analysis of higher brain functions, which is thus an important but understudied area of pain research. The proposed multidisciplinary studies will identify a novel neuropathic pain mechanism in an emotional center of the brain (amygdala) and explore strategies to eliminate this target (serotonin 5-HT2C receptor) to block the persistence of neuropathic pain, thus improving strategies for pain management.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS081121-05
Application #
9039670
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Oshinsky, Michael L
Project Start
2013-05-01
Project End
2018-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Texas Tech University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Lubbock
State
TX
Country
United States
Zip Code
79430
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Ji, Guangchen; Yakhnitsa, Vadim; Kiritoshi, Takaki et al. (2018) Fear extinction learning ability predicts neuropathic pain behaviors and amygdala activity in male rats. Mol Pain 14:1744806918804441
Kiritoshi, Takaki; Neugebauer, Volker (2018) Pathway-Specific Alterations of Cortico-Amygdala Transmission in an Arthritis Pain Model. ACS Chem Neurosci 9:2252-2261
Thompson, Jeremy M; Neugebauer, Volker (2017) Amygdala Plasticity and Pain. Pain Res Manag 2017:8296501
Ji, Guangchen; Zhang, Wei; Mahimainathan, Lenin et al. (2017) 5-HT2C Receptor Knockdown in the Amygdala Inhibits Neuropathic-Pain-Related Plasticity and Behaviors. J Neurosci 37:1378-1393
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Kim, Hyunyoung; Thompson, Jeremy; Ji, Guangchen et al. (2017) Monomethyl fumarate inhibits pain behaviors and amygdala activity in a rat arthritis model. Pain 158:2376-2385
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
Zhang, Yafang; Crofton, Elizabeth J; Fan, Xiuzhen et al. (2016) Convergent transcriptomics and proteomics of environmental enrichment and cocaine identifies novel therapeutic strategies for addiction. Neuroscience 339:254-266
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:

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