{
  "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 Na V1.8/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 (100 µM) 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 V1.8/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=10 µM).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": [
    {
      "affiliations": [
        "IZKF Neuroscience Research Group, Uniklinik RWTH Aachen, Aachen, Germany",
        "Institute of Neurophysiology, Uniklinik RWTH Aachen, Aachen, Germany"
      ],
      "name": "Sven Christian Engler"
    },
    {
      "affiliations": [
        "IZKF Neuroscience Research Group, Uniklinik RWTH Aachen, Aachen, Germany",
        "Institute of Neurophysiology, Uniklinik RWTH Aachen, Aachen, Germany"
      ],
      "name": "Stanislav Koulchitsky"
    },
    {
      "affiliations": [
        "Institute of Neurophysiology, Uniklinik RWTH Aachen, Aachen, Germany"
      ],
      "name": "Andelain Erickson"
    },
    {
      "affiliations": [
        "Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany"
      ],
      "name": "Tali Hoffmann"
    },
    {
      "affiliations": [
        "Institute of Neurophysiology, Uniklinik RWTH Aachen, Aachen, Germany",
        "Department of Neurology, Uniklinik RWTH Aachen, Aachen, Germany"
      ],
      "name": "Idil Toklucu"
    },
    {
      "affiliations": [
        "Institute of Neurophysiology, Uniklinik RWTH Aachen, Aachen, Germany"
      ],
      "name": "Raya Bott"
    },
    {
      "affiliations": [
        "Institute of Neurophysiology, Uniklinik RWTH Aachen, Aachen, Germany",
        "Department of Anesthesiology, Uniklinik RWTH Aachen, Aachen, Germany"
      ],
      "name": "Jannis Körner"
    },
    {
      "affiliations": [
        "Institute of Clinical Pharmacology, Uniklinik RWTH Aachen, Aachen, Germany",
        "Scientific Center for Neuropathic Pain Aachen, Uniklinik RWTH Aachen, Aachen, Germany"
      ],
      "name": "Ralf Hausmann"
    },
    {
      "affiliations": [
        "Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany"
      ],
      "name": "Karl Messlinger"
    },
    {
      "affiliations": [
        "Institute of Neurophysiology, Uniklinik RWTH Aachen, Aachen, Germany",
        "Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen, Aachen, Germany"
      ],
      "name": "Natja Haag"
    },
    {
      "affiliations": [
        "Department of Plastic Surgery, Hand and Burns Surgery, Uniklinik RWTH Aachen, Aachen, Germany"
      ],
      "name": "Justus P Beier"
    },
    {
      "affiliations": [
        "Department of Neurology, Uniklinik RWTH Aachen, Aachen, Germany"
      ],
      "name": "Robert Brunkhorst"
    },
    {
      "affiliations": [
        "Department of Neurology, Uniklinik RWTH Aachen, Aachen, Germany",
        "Scientific Center for Neuropathic Pain Aachen, Uniklinik RWTH Aachen, Aachen, Germany"
      ],
      "name": "Maike F Dohrn"
    },
    {
      "affiliations": [
        "Institute of Neurophysiology, Uniklinik RWTH Aachen, Aachen, Germany",
        "Scientific Center for Neuropathic Pain Aachen, Uniklinik RWTH Aachen, Aachen, Germany"
      ],
      "name": "Angelika Lampert"
    },
    {
      "affiliations": [
        "Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany"
      ],
      "name": "Roberto DeCol"
    },
    {
      "affiliations": [
        "IZKF Neuroscience Research Group, Uniklinik RWTH Aachen, Aachen, Germany",
        "Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, Centre for Interdisciplinary Medicine, Universitätsklinikum Würzburg, Würzburg, Germany"
      ],
      "name": "Barbara Namer"
    }
  ],
  "title": "Phentolamine selectively blocks C-fiber conduction in different species, including humans",
  "uid": "9268738e-763a-52a5-8f5f-5c9397f7d4fc"
}