Management of acute and chronic pain has been proven challenging because the pathophysiological mechanisms responsible for certain pain entities and their symptoms are poorly understood. Numerous different subsets of peripheral sensory fibres contribute to acute nociceptive and pathological pain. Not less complex are spinal and supraspinal pain processes; here, pain entities play a major role for specificity, which are driving the chronification processes relevant for pain and pain-related symptoms (non-evoked pain, pain evoked by all different types of stimuli) including those with affective components.
The overall aim of this project is to investigate sex differences and to characterize peripheral and spinal signalling pathways and concomitant changes in the brain circuitry during the initiation and maintenance of clinically relevant pain-related behaviours in models for incisional and neuropathic pain in mice. We use a unique approach by combining a versatile set of behavioural outcomes, precise spatiotemporal optogenetic probing, and supraspinal fMRI-based connectome analysis after both injuries. Central to this collaboration is the use of the same stimulation modalities for behavioural as well as fMRI studies. For this, we use optogenetic probing to investigate supraspinal correlates of relevant pain-related behaviours and pathways of Tropomyosin Receptor Kinase C (TrkC+) Aβ-fibers and spinal inhibitory GABAergic neurons positive for glutamate decarboxylase 2 (GAD2+). Further, we previously developed an MRI-compatible device that allows mechanical stimulation of rat hind paws3,10. We have now redesigned this stimulator to fit a mouse cryogenic probe and it allows sequential stimulation of up to four different mechanical modalities (e.g. von Frey filaments, pin prick, cotton swab) thereby closely mimicking in vivo behavioural experiments. Finally, we perform functional network analysis to identify central hubs and connectomes related to distinct pain-related behaviours in both pathological pain states and to extract network signatures that are sex, modality, or pain entity-specific.
Funding Period: 10.2020 – 09.2023