Pathological Factors Combine to Cause Hyperexcitability in Primary Afferent Neurons: Implications for Nociceptive Sensory Processing
Year: 2018
Type: dissertation
Abstract: Hyperexcitability in primary afferent neurons is necessary and sufficient to cause many forms of chronic pain. Several molecular changes have been linked to primary afferent neuron hyperexcitability, but developing better pain therapies remains challenging because most molecular changes have been studied in isolation. I investigated how hyperexcitability relies on combinations of molecular changes. First, I addressed an important feature of primary afferent neuron hyperexcitability wherein spiking pattern switches from transient spiking to repetitive spiking during sustained somatic depolarization. I measured the susceptibility of neurons to switch their spiking pattern by applying a virtual sodium conductance (g_Na ) using dynamic clamp. Second, I investigated how the switch from transient to repetitive spiking (i.e. a change in intrinsic excitability) interacted with changes affecting inhibitory synaptic input onto primary afferent neurons. GABA-mediated paradoxical excitation requires a combined shift in the GABA reversal potential (E_GABA) and a change in intrinsic excitability. Third, I addressed whether the required combination of changes, initially demonstrated with dynamic clamp recordings in the soma, is necessary for GABA-evoked spiking at the central axon terminals of primary afferent neurons. From this work, several conclusions can be drawn: Pathological changes (e.g. inflammation or elevated extracellular potassium) do not individually convert the spiking pattern. The summation of the individual effects is necessary for the net pathological change to cause hyperexcitability. Small neurons (corresponding to unmyelinated fibers) are more susceptible than large neurons (corresponding to myelinated fibers) to becoming hyperexcitable. However, because inflammation had a larger effect in the latter, both cell types become equally susceptible to switch to repetitive spiking under inflammatory conditions. The co-occurrence of a depolarizing shift in E_GABA and an increase in intrinsic excitability is necessary to enable GABAergic transmission, which normally has inhibitory effects, to paradoxically evoke spiking in primary afferent neurons. Neither factor on its own can enable paradoxical spiking. GABA-evoked spikes can be initiated at the central axon terminals and propagate antidromically towards the periphery. Spikes evoked by GABA at the central axon terminals, like in the soma, require a combined change in intrinsic excitability and E_GABA.
Source: TSpace (University of Toronto)
Author: Petri Takkala
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2937317551