1. Depolarization of mouse DRG neurons by GABA does not translate into acute pain or hyperalgesia in healthy human volunteers.
- Author
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Sohns K, Kostenko A, Behrendt M, Schmelz M, Rukwied R, and Carr R
- Subjects
- Humans, Animals, Mice, Male, Adult, Female, Neurons metabolism, Neurons drug effects, Acute Pain metabolism, Acute Pain physiopathology, Calcium metabolism, Receptors, GABA-A metabolism, Pruritus chemically induced, Pruritus metabolism, Pruritus physiopathology, Young Adult, gamma-Aminobutyric Acid metabolism, Furosemide pharmacology, Solute Carrier Family 12, Member 2 metabolism, Ganglia, Spinal metabolism, Ganglia, Spinal drug effects, Healthy Volunteers, Hyperalgesia metabolism, Hyperalgesia chemically induced, Hyperalgesia physiopathology
- Abstract
The majority of somatosensory DRG neurons express GABAA receptors (GABAAR) and depolarise in response to its activation based on the high intracellular chloride concentration maintained by the Na-K-Cl cotransporter type 1 (NKCC1). The translation of this response to peripheral nerve terminals in people is so far unclear. We show here that GABA (EC50 = 16.67μM) acting via GABAAR produces an influx of extracellular calcium in approximately 20% (336/1720) of isolated mouse DRG neurons. In contrast, upon injection into forearm skin of healthy volunteers GABA (1mM, 100μl) did not induce any overt sensations nor a specific flare response and did not sensitize C-nociceptors to slow depolarizing electrical sinusoidal stimuli. Block of the inward chloride transporter NKCC1 by furosemide (1mg/100μl) did not reduce electrically evoked pain ratings nor did repetitive GABA stimulation in combination with an inhibited NKCC1 driven chloride replenishment by furosemide. Finally, we generated a sustained period of C-fiber firing by iontophoretically delivering codeine or histamine to induce tonic itch. Neither the intensity nor the duration of histamine or codeine itch was affected by prior injection of furosemide. We conclude that although GABA can evoke calcium transients in a proportion of isolated mouse DRG neurons, it does not induce or modify pain or itch ratings in healthy human skin even when chloride gradients are altered by inhibition of the sodium coupled NKCC1 transporter., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sohns et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2024
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