Dr. Amit Agarwal

Institute of Anatomy, Medical Faculty Heidelberg, Heidelberg University

Prof. Dr. Frank Kirchhoff

Centre for Integrative Physiology and Molecular Medicine, University of Saarland

Dr. Manuela Simonetti

Institute of Pharmacology, Medical Faculty Heidelberg, Heidelberg University

Calcium signalling in glial cells and their role in antidepressant-mediated analgesia in neuropathic pain.

Some forms of neuropathic pain don’t respond to the conventional analgesic treatments and can be treated with tricyclic antidepressants (TCA) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Noradrenalin signaling seems to be essential for the antidepressants mediated pain relief, and the activation of adrenergic receptors lead to inhibition of neuropathic pain, but the mechanism is still unknown. In the brain and spinal cord, adrenergic receptors are highly expressed by astrocytes and in microglia, suggesting that the glia cells might drive the antidepressants mediated analgesia.

Using chronic in vivo2P-LSM, we will study astrocytic and microglial dynamics (Ca²⁺signaling and morphological changes) in response to nerve injury in the areas important for pain perception such as the primary somatosensory cortex (S1) and the dorsal anterior cingulate cortex (dACC), the dorsal horn of the spinal cord (dSpC) and the dorsal root ganglion. We want to address how these changes lead to pathophysiological changes in vivo. We will study the expression of functional adrenergic receptor subtypes on astrocytes and microglia through gene expression analyses and pharmacological manipulations. To understand the unique role of glial cells GPCR signaling in pain, we will conditionally delete various adrenergic receptor subtypes and modulate G-protein coupled receptor signaling using chemogenetic approaches in a cell-specific manner. To gain further mechanistic insights, using primary astrocyte and microglia culture systems, we want to identify factors released by these cells in response to adrenergic receptor activation.

The central aim of this study is to identify molecular mechanism by which activation of adrenergic signaling can modulate neuropathic pain condition. Our long long-term goal is to identify downstream molecular targets on glial cells, which can treat neuropathic pain without affecting other cognitive functions