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

Background: A 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 Findings: Electrical 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 mu M) 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 GABA(A) receptors, being mimicked by bath application of the GABA(A) agonist muscimol (0.1-30 mu M) while the GABA(B) agonist baclofen (10-30 mu M) was without effect. Increases in excitability produced by GABA (10-30 mu M) were blocked by the GABA(A) antagonists gabazine (10-20 mu M), bicuculline (10-20 mu M) and picrotoxin (10-20 mu M). Conclusions/Significance: Functional GABA(A) 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. GABA(A) receptor modulation may therefore regulate segmental and peripheral components of nociception.