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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Medical Br Galveston
Schools of Medicine
United States
Zip Code
Medina, Georgina; Ji, Guangchen; Gr├ęgoire, St├ęphanie et al. (2014) Nasal application of neuropeptide S inhibits arthritis pain-related behaviors through an action in the amygdala. Mol Pain 10:32
Anastasio, Noelle C; Stutz, Sonja J; Fox, Robert G et al. (2014) Functional status of the serotonin 5-HT2C receptor (5-HT2CR) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence. Neuropsychopharmacology 39:370-82
Ji, Guangchen; Neugebauer, Volker (2014) CB1 augments mGluR5 function in medial prefrontal cortical neurons to inhibit amygdala hyperactivity in an arthritis pain model. Eur J Neurosci 39:455-66
Lichti, Cheryl F; Fan, Xiuzhen; English, Robert D et al. (2014) Environmental enrichment alters protein expression as well as the proteomic response to cocaine in rat nucleus accumbens. Front Behav Neurosci 8:246
Apkarian, A Vania; Neugebauer, Volker; Koob, George et al. (2013) Neural mechanisms of pain and alcohol dependence. Pharmacol Biochem Behav 112:34-41
Ren, Wenjie; Kiritoshi, Takaki; Gregoire, Stephanie et al. (2013) Neuropeptide S: a novel regulator of pain-related amygdala plasticity and behaviors. J Neurophysiol 110:1765-81
Gregoire, Stephanie; Neugebauer, Volker (2013) 5-HT2CR blockade in the amygdala conveys analgesic efficacy to SSRIs in a rat model of arthritis pain. Mol Pain 9:41