Phentolamine selectively blocks C-fiber conduction in different species, including humans
Engler SC, Koulchitsky S, Erickson A, Hoffmann T, Toklucu I, Bott R, Körner J, Hausmann R, Meßlinger K, Haag N, Beier JP, Brunkhorst R, Dohrn MF, Lampert A, De Col R, Namer B (2025)
Publication Type: Journal article
Publication year: 2025
Journal
Abstract
Background Phentolamine is a non-selective competitive α-adrenergic antagonist clinically used to treat different vascular-related diseases. Since recent data suggest an antagonistic effect of phentolamine on voltage-gated sodium channels (VGSCs), further electrophysiological analysis is essential to understand its effects on peripheral sensory nerves. Methods We examined the effects of phentolamine on the amplitude of the stimulus-evoked compound action potential (CAP) of A- and C-type nerve fibers derived from mice, pigs, and humans compared with the effects of lidocaine. To explore potential mechanisms of phentolamine action, we performed single nerve fiber recordings using skin-nerve preparations from wild-type and NaV1.8/NaV1.9 double knockout mice, along with manual and automated whole-cell patch-clamp electrophysiology on ND7/23 or HEK293 cells with heterologously expressed VGSCs. Results Phentolamine decreased CAP amplitudes in a concentration-dependent manner, with significantly lower concentrations needed to affect C-fibers compared with A-fibers. Co-application of the α-adrenergic agonist (R)-(-)-phenylephrine did not alter this effect, suggesting that α-adrenergic receptors do not mediate phentolamine’s action in this case. Phentolamine (100µM) inhibited the electrically evoked action potentials (AP) in the majority of single-unit cutaneous C-fibers, while the same concentration did not provoke AP extinction in A-fibers. C-fibers from NaV1.8/NaV1.9 double knockout mice were significantly less sensitive to phentolamine than those from wild types. In patch-clamp experiments, phentolamine concentration-dependently blocked VGSCs, whereas NaV1.8 showed the highest sensitivity (IC50=10µM). Conclusions Suppressing AP conduction and inhibiting VGSCs, phentolamine exhibits features reminiscent of local anesthetics, but with a stronger effect on C-fibers, which may be attributed to its stronger action on tetrodotoxin-resistant VGSCs. However, due to its markedly higher affinity for α-adrenergic receptors compared with VGSCs, systemic administration of phentolamine is limited by its adrenergic side effects. These findings suggest that phentolamine could be useful for exploring C-fiber function and provide a basis for the development of more selective and potent antinociceptive agents.
Authors with CRIS profile
Tal Hoffmann
Lehrstuhl für Physiologie
Karl Meßlinger
Professur für Zelluläre und Molekulare Neurophysiologie
Roberto De Col
Lehrstuhl für Physiologie
Involved external institutions
Germany (DE)How to cite
APA:
Engler, S.C., Koulchitsky, S., Erickson, A., Hoffmann, T., Toklucu, I., Bott, R.,... Namer, B. (2025). Phentolamine selectively blocks C-fiber conduction in different species, including humans. Regional Anesthesia and Pain Medicine. https://doi.org/10.1136/rapm-2025-106791
MLA:
Engler, Sven Christian, et al. "Phentolamine selectively blocks C-fiber conduction in different species, including humans." Regional Anesthesia and Pain Medicine (2025).
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