The multidimensional character of pain presents a therapeutic challenge that calls for better understanding of higher brain functions that regulate its complex emotional-affective and cognitive aspects (NIH PA-10-006). This project will continue to provide valuable insight into these higher brain mechanisms. Neuroplasticity in the amygdala, an emotional brain center, is now recognized as a key factor in the emotional-affective dimension of pain. Amygdala dysfunction in pain also causes cognitive deficits by impairing medial prefrontal cortex (mPFC) function. For that reason, control of amygdala activity is a desirable therapeutic goal in pain management. Here we advance the novel concept that cognitive deficits and impaired cortical output result in the persistence of pain and its emotional affective component. Based on our previous studies and preliminary data we propose the novel hypothesis that the cognitive control system for negative emotions consists of mPFC-driven inhibition of excessive amygdala activity, which is impaired in pain but can be restored for pain relief.
Three Specific Aims (SAs) will determine synaptic and cellular mechanisms and behavioral consequences of a vicious cycle in which abnormal deactivation of the mPFC in a rat model of arthritis pain causes failure of mPFC-driven inhibition of amygdala output. Cortical control of output neurons in the central nucleus of the amygdala (CeA) requires activation of inhibitory neurons in the intercalated cell mass (ITC) of the amygdala. The goal is to identify pharmacological targets that can restore cortical control of amygdala dysfunction in pain. These include metabotropic glutamate receptor mGluR5 to activate mPFC neurons, cannabinoid receptor CB1 to release excessive synaptic inhibition of mPFC neurons, and novel neuropeptide S (NPS) to activate selectively ITC cells that inhibit CeA neurons (feedforward inhibition). Behavioral experiments (SA1) will test the hypothesis that restoring mPFC-amygdala control pharmacologically will decrease pain and shorten its duration. Nocifensive, emotional-affective and cognitive behaviors will be measured. Electrophysiology in vivo (SA2) will examine dysfunction of the mPFC-ITC-CeA pathway in pain, measured as mPFC and ITC deactivation and CeA hyperactivity. Pharmacological rescue strategies will be tested. SA1 and SA2 will use stereotaxic and systemic drug applications. Patch-clamp studies in brain slices (SA3) will determine pain-related changes of synaptic and cellular modulation of mPFC output by mGluR5 and CB1 and of feedforward inhibition of CeA neurons by NPS. Patch-clamp analysis will clarify the usefulness of pharmacological targets to restore normal transmission at individual synapses of the mPFC-ITC-CeA circuitry. These conceptually novel studies will identify cortico-amygdala control deficits as an important mechanism of persistent pain. They will provide novel targets to restore cognitive control functions for pain relief. The mechanistic analysis of higher brain functions and drug targets in pain will boost basic science knowledge required for evidence-based medicine and provide new and improved strategies for pain management.
The complex nature of pain with its emotional and cognitive aspects necessitates a comprehensive analysis of higher brain functions, which is thus an important but understudied area of pain research. The proposed studies will identify a novel pain mechanism that involves failure of cognitive brain systems to control an emotional brain center, resulting in the persistence of pain and its emotional-affective component. This project will not only advance our knowledge of brain pain mechanisms but also provide novel targets to rescue impaired cognitive pain control, thus improving strategies for pain management.
|Medina, Georgina; Ji, Guangchen; Grégoire, Stéphanie et al. (2014) Nasal application of neuropeptide S inhibits arthritis pain-related behaviors through an action in the amygdala. Mol Pain 10:32|
|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|
|Ji, Guangchen; Fu, Yu; Adwanikar, Hita et al. (2013) Non-pain-related CRF1 activation in the amygdala facilitates synaptic transmission and pain responses. Mol Pain 9:2|
|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|
|Kiritoshi, Takaki; Sun, Hao; Ren, Wenjie et al. (2013) Modulation of pyramidal cell output in the medial prefrontal cortex by mGluR5 interacting with CB1. Neuropharmacology 66:170-8|
|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|
|Tappe-Theodor, Anke; Fu, Yu; Kuner, Rohini et al. (2011) Homer1a signaling in the amygdala counteracts pain-related synaptic plasticity, mGluR1 function and pain behaviors. Mol Pain 7:38|
|Ji, Guangchen; Neugebauer, Volker (2011) Pain-related deactivation of medial prefrontal cortical neurons involves mGluR1 and GABA(A) receptors. J Neurophysiol 106:2642-52|
|Sun, Hao; Neugebauer, Volker (2011) mGluR1, but not mGluR5, activates feed-forward inhibition in the medial prefrontal cortex to impair decision making. J Neurophysiol 106:960-73|
|Ren, Wenjie; Palazzo, Enza; Maione, Sabatino et al. (2011) Differential effects of mGluR7 and mGluR8 activation on pain-related synaptic activity in the amygdala. Neuropharmacology 61:1334-44|
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