{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T00:31:55Z","timestamp":1793665915808,"version":"4.5.1"},"reference-count":98,"publisher":"BMJ","funder":[{"name":"Interdisciplinary Centre for Clinical Research, RWTH Aachen University","award":["TN1-1\/IA 532001"],"award-info":[{"award-number":["TN1-1\/IA 532001"]}]},{"name":"Interdisciplinary Centre for Clinical Research, RWTH Aachen University","award":["TN1-2\/IA 532002"],"award-info":[{"award-number":["TN1-2\/IA 532002"]}]},{"name":"Interdisciplinary Centre for Clinical Research, RWTH Aachen University","award":["TN1-5\/IA 532005"],"award-info":[{"award-number":["TN1-5\/IA 532005"]}]},{"name":"Interdisciplinary Centre for Clinical Research, RWTH Aachen University","award":["TN1-9\/IA 532009"],"award-info":[{"award-number":["TN1-9\/IA 532009"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Reg Anesth Pain Med"],"accepted":{"date-parts":[[2025,9,4]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Phentolamine is a non-selective competitive \u03b1-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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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 Na<jats:sub>V<\/jats:sub>1.8\/Na<jats:sub>V<\/jats:sub>1.9 double knockout mice, along with manual and automated whole-cell patch-clamp electrophysiology on ND7\/23 or HEK293 cells with heterologously expressed VGSCs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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 \u03b1-adrenergic agonist (R)-(-)-phenylephrine did not alter this effect, suggesting that \u03b1-adrenergic receptors do not mediate phentolamine\u2019s action in this case. Phentolamine (100\u2009\u00b5M) 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 Na<jats:sub>V<\/jats:sub>1.8\/Na<jats:sub>V<\/jats:sub>1.9 double knockout mice were significantly less sensitive to phentolamine than those from wild types. In patch-clamp experiments, phentolamine concentration-dependently blocked VGSCs, whereas Na<jats:sub>V<\/jats:sub>1.8 showed the highest sensitivity (IC<jats:sub>50<\/jats:sub>=10\u2009\u00b5M).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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 \u03b1-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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/rapm-2025-106791","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T04:30:23Z","timestamp":1758515423000},"page":"rapm-2025-106791","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Phentolamine selectively blocks C-fiber conduction in different species, including humans"],"prefix":"10.1136","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2788-0145","authenticated-orcid":false,"given":"Sven Christian","family":"Engler","sequence":"first","affiliation":[{"name":"IZKF Neuroscience Research Group, Uniklinik RWTH Aachen, Aachen, Germany"},{"name":"Institute of Neurophysiology, Uniklinik RWTH Aachen, Aachen, 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