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.
Highlights
Gamma-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the mammalian central nervous system
The cell bodies of dorsal root ganglion (DRG) neurones, which are devoid of synaptic contact, express functional GABAA receptors
The GABAA mediated depolarization is attributed to an elevated intracellular concentration of chloride in dorsal root ganglion neurones [14], a condition established by the predominance of NKCC1-mediated chloride uptake [15] over KCC2-mediated extrusion [16]
Summary
Gamma-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the mammalian central nervous system. The cell bodies of dorsal root ganglion (DRG) neurones, which are devoid of synaptic contact, express functional GABAA receptors (human: [4,5], rat: [6,7], cat: [8], rabbit: [9], chick: [10]). For neurones in the central nervous system, extra-synaptic axonal GABAA receptors are often composed of sub-units with a high sensitivity to GABA allowing ambient concentrations of GABA to modulate neuronal excitability [2]. The effect of GABA on peripheral axons is dependent upon the intracellular chloride concentration which is reported to change following peripheral nerve injury in dorsal spinal horn neurones [22] as well as DRG neurones [23]. The chemosensitivity of unmyelinated axons can be examined by tracking the electrical threshold of the compound C-fibre action potential generated in short isolated segments of isolated sural nerve [25] and in the present study this method has been used to characterize the effect of GABA on unmyelinated axons from humans
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