Neurons in the central amygdala (CeA) contribute to pain modulation. However, their contribution to the sensory- discriminative and/or emotional-affective dimensions of chronic pain, nor their neurochemical modulation, are understood. Our preliminary data using slice recordings and behavior provide a compelling premise for the idea that drugs targeting the receptors for the bioactive lysophospholipid, sphingosine-1-phosphate (S1P) act within the CeA to inhibit inflammatory and neuropathic pain. This sets the stage for our long-term goal to understand how lipid signaling controls the supraspinal control of acute and chronic pain. The objectives of this proposal are to: determine neurophysiological changes to molecular specific CeA neurons in multiple models of pain (Aim 1), elucidate the effects of S1P signaling on the intrinsic and synaptic excitability of defined subpopulations of CeA neurons (Aim 2), and determine if S1PR agonism in the CeA is analgesic in models of inflammatory and neuropathic pain (Aim 3).
In Aim 1, we use transgenic mouse lines, electrophysiology, and optogenetics to test the hypotheses that tissue or nerve injury reduces excitability of specific subclasses of CeA neurons based on their molecular profile.
In Aim 2, we test the hypotheses that activation of S1P signaling increases the excitability and synaptic connectivity within a population of molecularly distinct CeA neurons.
In Aim 3, we use intracranial drug infusions and chemogenetics to test the hypothesis that activation of S1P receptors in the CeA attenuates inflammatory and neuropathic pain via a specific subtype of CeA neuron. Experimental support of these concepts will facilitate the development of existing (e.g. FDA-approved fingolimod) and novel S1PR compounds for the treatment of chronic pain.

Public Health Relevance

Delineating the functionality and pharmacology of specific supraspinal pathways involved in pain modulation is of critical importance if we are to understand neural dysfunction that contributes to chronic pain. The goal of this project is to define neural mechanisms through which a common lipid signaling pathway drives antinociception by altering the excitability of specific supraspinal pathways sensitized by chronic pain. Findings of this project have promising potential for uncovering preclinical and clinical drug targets within sensory-discriminative and affective supraspinal circuits that could lead to novel approaches exploiting lipid signaling pathways for treating chronic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS112632-01A1
Application #
9972163
Study Section
Somatosensory and Pain Systems Study Section (SPS)
Program Officer
Mohapatra, Durga Prasanna
Project Start
2020-04-01
Project End
2025-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pharmacology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202