Sensory neurons naturally adapt to ongoing stimulation, but harnessing this inherent plasticity for therapeutic purposes has not been explored. The recent clinical observation that dorsal root ganglion field stimulation (GFS) blocks pain, provides a clue that an unrecognized process regulates conduction of impulses through the DRG since exactly the opposite, i.e. production of pain, would be expected. The paradoxical phenomenon of GFS analgesia indicates that our current understanding of peripheral neuron signal transmission is fundamentally insufficient, and that a novel, clinically applicable modality of use-dependent neuronal manipulation awaits discovery. That is the goal of this proposal. Sensory neurons also convey retrograde impulses from the dorsal horn to peripheral tissues, where they trigger inflammation and tissue damage, for instance in rheumatoid arthritis. We will therefore explore bidirectional GFS modulation of both afferent and efferent signal transmission through the DRG. In three Aims, we will test the overall hypothesis that GFS, by triggering action potentials (APs) in the somata of sensory neurons, reduces the intrinsic excitability of their T-junction, which reduces bidirectional propagation of APs through the DRG, and can thereby produce analgesia and block neurogenic inflammation.
In Aim 1, we will first develop a rat model in order to lay the groundwork for mechanistic exploration. GFS analgesia will be tested in the setting of neuropathy, and osteoarthritis. To test GFS blockade of retrograde impulses, we will identify GFS effects on joint changes in a model of rheumatoid arthritis. For these experiments, examination will be by behavioral tests and functional magnetic resonance imaging (fMRI) of the brain, examining both male and female rats.
In Aim 2, to identify the exact neuronal targets of GFS, we will test GFS activation of sensory neuron somata, and determine which DRG neuronal subtypes are modulated by GFS and at which component (axon vs. soma) this takes place.
Aim 3 will employ electrophysiological approaches to directly measure the effects of GFS on functional properties of DRG neurons, in order to identify the mechanism of GFS impulse regulation. Additionally, we will explore the role of CaMKII, and we will compare GFS effects between the various sensory neuron subpopulations. Together, our proposed experiments will establish a mechanistic foundation for a novel regulatory process that governs impulse train transmission in the peripheral nervous system. As molecular and electrical neuromodulatory therapies move forward in the clinical setting, understanding this new regulatory node will have direct translational utility for harnessing an inherent impulse regulating system and applying it to control sensory and peripheral inflammatory disorders.
A previously undiscovered process regulating the passage of impulses along the peripheral nerves has been revealed by the paradoxical ability to relieve pain by electrically stimulating the dorsal root ganglion in the peripheral nervous system. The proposed experiments will explore the underlying mechanisms of this impulse control system in models in which such impulse trains produce chronic pain and peripheral inflammation. Completing this project will reveal a novel regulatory process that may be harnessed for clinical use to control sensory and peripheral inflammatory disorders.