Translational studies in chronicity of pain: Neuroplasticity in corticolimbic dopamine and glutamate pathways

Our project utilizes a pioneering approach to study chronic pain by conceptualizing it from a motivational affective perspective. This new conceptualization of chronic pain is based on emerging evidence showing overlapping molecular mechanisms and network alterations (or neurobiological mechanisms) in the transition to addictive behavior and to chronic pain disorders.

Dorsal root ganglia section showing putative C-LTMRs in green and myelinated neurons in red
Fig. 1. Mangetic Resonance Spectroscopy Results show enhanced Glutamate and Glutamine concentrations in the Prefrontal Cortex in a mouse model of acute pain. Peak resonances are N-acetylaspartarte (NAA), creatine and phosphocreatine (Cr), choline-containing compounds (Cho), myo-Inositol (mI), glutamate (Glu), glutamine (Gln), Glu+Gln (Glx), taurine (Tau), and γ-aminobutyric acid (GABA).

We investigate the acute responses and chronic adaptations in reward reinforcement processing during pain chronicity across the whole lifespan: from the general “life quality” like exploration, anxiety, or motivated behavior, to the specific pain-associated affective memories, their persistence and reactivation by environmental factors. We apply commonly used methods by addiction research neuroscientists: intracranial self-stimulation (ICSS) to measure reward system sensitivity and conditioned place-aversion (CPA) to evaluate the formation, persistence and reactivation of pain-conditioned memories. These behavioral measurements are correlated with alterations in the glutamate and dopamine neurotransmission within the mesolimbic system by the use of highly sophisticated genetically modified mouse models.

 In addition to these measurements, a unique reverse translation approach of human neuroimaging data are provided by the use multimodal neuroimaging in the mice. In this respect, within a longitudinal approach we will assess structural, functional and biochemical changes in the brain of mice that develop chronic pain with voxel based morphometry (VBM), resting-state functional magnetic resonance imaging (rsfMRI) measurements and Magnetic resonance  spectroscopy (MRS)

While VBM is a procedure to detect even subtle structural changes through non-linear normalization of 3D-images, MRS is a unique method to assess the local concentrations of several important brain metabolites in the living animal. Resting-state fMRI on the other hand can detect functional brain networks and their changes due to pathology. These three methods have the added benefit, that they are applied in almost the same fashion in human imaging and the results yield comparable results.

Dorsal root ganglia section showing putative C-LTMRs in green and myelinated neurons in red
Fig:2: Graph-analytical analyses of resting state functional Magnetic resonance imaging in a mouse model of acute Pain showing significan network changes in Pain-related regions of the brain.

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