GABA Increases Electrical Excitability in a Subset of Human Unmyelinated Peripheral Axons

Abstract

BackgroundA proportion of small diameter primary sensory neurones innervating human skin are chemosensitive. They respond in a receptor dependent manner to chemical mediators of inflammation as well as naturally occurring algogens, thermogens and pruritogens. The neurotransmitter GABA is interesting in this respect because in animal models of neuropathic pain GABA pre-synaptically regulates nociceptive input to the spinal cord. However, the effect of GABA on human peripheral unmyelinated axons has not been established.Methodology/Principal FindingsElectrical stimulation was used to assess the effect of GABA on the electrical excitability of unmyelinated axons in isolated fascicles of human sural nerve. GABA (0.1–100 µM) increased electrical excitability in a subset (ca. 40%) of C-fibres in human sural nerve fascicles suggesting that axonal GABA sensitivity is selectively restricted to a sub-population of human unmyelinated axons. The effects of GABA were mediated by GABAA receptors, being mimicked by bath application of the GABAA agonist muscimol (0.1–30 µM) while the GABAB agonist baclofen (10–30 µM) was without effect. Increases in excitability produced by GABA (10–30 µM) were blocked by the GABAA antagonists gabazine (10–20 µM), bicuculline (10–20 µM) and picrotoxin (10–20 µM).Conclusions/SignificanceFunctional GABAA receptors are present on a subset of unmyelinated primary afferents in humans and their activation depolarizes these axons, an effect likely due to an elevated intra-axonal chloride concentration. GABAA receptor modulation may therefore regulate segmental and peripheral components of nociception.

Acute inflammation reveals GABAAreceptor-mediated nociception in mouse dorsal root ganglion neurons via PGE2receptor 4 signaling

“…) and humans (Carr et al. ); however, activation of peripheral GABA A receptors elicits neither spontaneous pain behavior nor mechanical sensitivity in naïve animals. One proposal to this apparent paradox is the phenomenon of primary afferent depolarization (Rudomin and Schmidt ; Willis ) whereby sub‐threshold depolarization results in inactivation of voltage‐gated channels.…”

The General Anesthetic Propofol Excites Nociceptors by Activating TRPV1 and TRPA1 Rather than GABAA Receptors

“…Considering the existing literature on the action of GABA on peripheral sensory neurons, these results are in part controversial. In contrast to the inhibitory profile of GABA in the central nervous system, GABA is known to induce a depolarization and an increased excitability in sensory neurons from frogs (45), cats (46), rats (46 -48), and humans (49). Accordingly, GABA A receptors are expressed in primary afferent neurons with a significant coexpression with nociceptive markers such as TRPV1 (50 -53).…”

“…Whereas GABA A receptors appear to be expressed in the majority of DRG neurons, it was suggested that only those neurons expressing the Ca v 3.2/␣1H T-type calcium channel are able to generate GABA-induced action potentials (57). Accordingly, a recent report from Carr et al (49) demonstrated a GABA A receptor-mediated increase in excitability in only ϳ40% of C-fibers in human peripheral nerves. Notably, the same study only reported an increased electrical excitability and not an activation of C-fibers by GABA.…”

Beyond faithful conduction: Short-term dynamics, neuromodulation, and long-term regulation of spike propagation in the axon

“…Slight depolarization can increase excitability, depending on the stimulus paradigm used. This is for example true for GABA A -mediated responses in a subset of unmyelinated peripheral axons in humans (Carr et al , 2010). Some hippocampal pyramidal cells fire ectopic axonal spikes during some forms of oscillatory network activity during the phase when proximal compartments are inhibited (Papatheodoropoulos, 2008).…”