Chronic pain is the most common complaint of patients, affecting over 100 million Americans, and costing the nation more than $650 billion/year in medical treatment and lost productivity. Most chronic pain patients are resistant to pharmaceutical or surgical therapies, in large part because the underlying pathophysiology of their chronic pain condition is unknown. The ultimate goal of this research program is to rectify this deficiency. Most spinal cord pain-related afferents target the parabrachial nuclear complex (PB), which then projects to multiple pain-related cortical and subcortical targets. New preliminary data indicate that inhibitory inputs from the central nucleus of the amygdala (CeA) to PB are reduced in a rodent neuropathic pain model: chronic constriction of the infraorbital nerve (CCI). This reduced inhibition dramatically `amplifies' both spontaneous and evoked PB neural activity. As a consequence, there is increased PB excitation of several pain-related nuclei, including the rostral ventral medulla (RVM), a key node of the descending pain modulation system. Based on this exciting new evidence we hypothesize that chronic pain results from the development of a pathologic positive feedback network: Reduced inhibition from CeA to PB ?> amplified PB activity ?> increased activation of RVM neurons ?> increased activation of nociceptive neurons in the spinal cord. With the use of electrophysiological recordings from intact rodents and from brain slices, and taking advantage of behavioral approaches, optogenetics and pharmacogenetics, we will directly test this overarching hypothesis. Specifically, we will (1) Test the hypothesis CCI causes a progressive and significant reduction of inhibitory inputs to nociceptive PB neurons that project to RVM, and dramatically increases their firing; (2) Test the hypothesis that amplified PB activity is due to reduced inhibition from CeA.; (3) Test the hypothesis that reduced CeAI inhibition to PB is causally related to the development of CCI-Pain. The anticipated findings are expected to reveal novel mechanisms for the development of chronic pain, and may lead to development of novel therapies to ameliorate, and perhaps even prevent, this devastating condition.

Public Health Relevance

One of the most debilitating consequences of nerve injury is the development of chronic, intractable pain. Most patients complain of spontaneous, ongoing pain, as well as an increased sensation to both painful and normally non-painful stimuli. Available treatments produce either incomplete and temporary pain relief, or adverse side effects. Understanding the mechanisms that contribute to neuropathic pain is important for the development of new and effective therapeutic strategies. This is the focus of this proposal. The project described in this proposal is based on exciting new findings, showing that the parabrachial nucleus, a relatively unknown center of pain processing, plays a critical role in the development of chronic pain. We will test the hypothesis that chronic, neuropathic pain results from abnormally amplified activity of the parabrachial nucleus, due to reduce inhibition from the amygdala, a key nucleus for processing emotions. Findings from this research project will provide insights on how nerve injury results in neuropathic pain. This will allow for the development of novel treatments to prevent and manage the debilitating consequences of nerve injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS099245-04
Application #
9934292
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Oshinsky, Michael L
Project Start
2017-08-15
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Uddin, Olivia; Studlack, Paige; Akintola, Titilola et al. (2018) Amplified parabrachial nucleus activity in a rat model of trigeminal neuropathic pain. Neurobiol Pain 3:22-30
Keller, Asaf; Akintola, Titilola; Colloca, Luana (2018) Placebo Analgesia in Rodents: Current and Future Research. Int Rev Neurobiol 138:1-15