GABAergic Signalling in the Peripheral Somatosensory System: Local and Multicellular Mechanisms Underlying Sensory Modulation

Primary sensory neurons of the dorsal root ganglia (DRGs) constitute the first relay in somatosensory signal transmission and play a central role in nociception and pain. These neurons exhibit a unique pseudo-unipolar morphology, with a bifurcating stem axon that imposes distinct biophysical constraints on action potential propagation. In particular, the axonal bifurcation, or T-junction, functions as a frequency-dependent filter regulating the transmission of sensory signals from the periphery to the spinal cord. While nociceptive processing has traditionally been considered neuron-centric, increasing evidence indicates that glial and immune cells critically modulate sensory signalling under both physiological and pathological conditions.
This thesis investigates mechanisms regulating nociceptive signal transmission within the peripheral nervous system (PNS), with a focus on GABAergic signalling and neuro-glial-immune interactions. The organization and functional properties of primary sensory neurons are examined, highlighting how axonal geometry, ion channel distribution, and excitability shape filtering at the DRG T-junction. Using compartmentalized in vitro models, the spatially distinct effects of GABA receptor activation across neuronal compartments are characterized.
Furthermore, Schwann cells are identified as active contributors to peripheral GABAergic signalling. They are shown to express a complete GABAergic molecular machinery and to release a bioactive ligand capable of activating GABAA receptors. Peripheral nerve injury induces a downregulation of Schwann cell GABAergic components, suggesting that loss of this inhibitory glial tone contributes to pathological sensory signalling. Finally, GABAergic signalling is shown to attenuate pro-inflammatory macrophage activation and reduce immune cell accumulation in models of neuropathic pain.
Together, these findings support a model in which nociceptive transmission is regulated by integrated interactions between neurons, glia, and immune cells in the PNS, identifying peripheral GABAergic signalling as a potential therapeutic target for chronic pain.