Novel GABAergic mechanisms modulating nociception and pain

Pathological pain is a vast and unmet clinical problem which brings about poor quality of life for sufferers and puts a colossal burden on healthcare systems worldwide. Yet, despite of decades of research and investment, there is no ultimate clinical solution to pathological pain and opioids are still a gold standard, despite severe side effects. While there is steady progress in understanding the molecular and cellular mechanisms of pain, the rational design of new therapies is painstakingly slow. Part of the problem is that most targets for current analgesics are within the CNS and, thus, often cause cognitive and behavioural side-effects and are subject to tolerance and addiction issues. Therefore, new ideas for peripherally-targeted therapies are urgently needed.

Recent work from the principal supervisor’s laboratory revealed that cell bodies of peripheral sensory neurons (the dorsal root ganglia or DRG neurons) contain a fully functional GABAergic system that can modulate nociceptive signals even before these enter the CNS. Using electrophysiology, optogenetics, chemogenetic (DREADD) approach, behavioural tests and computer modelling we demonstrated that DRG neurons can produce and release GABA within the ganglion in response to painful stimulation and that this GABA release, in turn, produces strong analgesic effect in vivo. Our findings therefore indicate that peripheral somatosensory ganglia may represent a new type of a ‘gate’ within the somatosensory system, a finding that calls for a substantial revision to the current understanding of how somatosensory information is generated and processed.

These recently published findings were included in Discover magazine’s 100 top stories of 2017 and recognised in recent Wellcome Trust Investigator award to the principal supervisor. Yet, there are currently more questions than answers as there is no known interneurons or synapses between the sensory neurons within the spinal ganglia and it is at present unknown how exactly sensory neuron cell bodies communicate within a ganglion. This PhD project is a part of a larger endeavour of the Gamper’s laboratory to develop a comprehensive mechanistic concept for peripheral somatosensory processing. A successful candidate will use electrophysiology, various imaging and microscopy approaches, transgenics and, potentially, optogenetics in order to establish mechanisms of neuronal communication within spinal ganglia.