The mechanisms of GABAergic signalling in the peripheral pain pathway

Peripheral pain pathway plays a crucial role in how pain is perceived and felt. The dorsal root ganglia (DRG) which house the primary sensory neurons have become the focus of many emerging pain studies due to its potential as a functional structure in controlling pain transmission, and not only for producing proteins and providing nutrients essential for neuron survival. The major inhibitory neurotransmitter in the nervous system, GABA has been shown to play a significant role in this regard.
Within the present study, the mechanism of GABA release within DRG neurons was investigated by studying the expression of vesicular GABA transporter (VGAT) in the DRG neurons. VGAT was highly expressed in the DRG neuron somata. The VGAT-positive neurons also expressed markers of subpopulations of DRG neurons, including those involved in nociception. The availability of VGAT luminal (VGAT-C) and cytoplasmic (VGAT-N) domains were utilised to investigate the mechanism of GABA release in a live DRG neuron culture. This mechanism involves the recycling process of vesicles following their exocytosis. Imaging of the internalization of VGAT-C domain during vesicle recycling indicates GABA is released via exocytosis and has both, tonic and activity-dependent components. Using the in vivo electrophysiological recordings, neuronal firing in the spinal nerve and dorsal branches of the peripheral nerve (before and after the DRG, respectively), was investigated. These data revealed existence of a ‘filter’ in the DRG that decreased the frequency of the neuronal firing passing through the DRG. This filtering effect was overcome by bicuculline, a GABAA receptor antagonist indicating the role of GABAA receptor in peripheral pain pathway. This role of GABAA receptor was also supported by the decrease in GABAA receptor activation in the presence of bicuculline in DRG neurons co-cultured with HEK293 cells.
In sum, in the DRG, GABA is liberated into the interneuronal space via Ca2+-dependent vesicular exocytosis, which in turn acts on GABAA receptors. This GABAergic signalling is responsible for filtering the action potentials from the periphery to the central terminals in the spinal cord. These findings identify and further characterize peripheral ‘gate’ within the somatosensory system.