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Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine
Copyright policy )Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine
International audience; Orphenadrine is a drug acting on multiple targets, including muscarinic, histaminic, and NMDA receptors. It is used in the treatment of Parkinson's disease and in musculoskeletal disorders. It is also used as an analgesic, although its mechanism of action is still unknown. Both physiological and pharmacological results have demonstrated a critical role for voltage-gated sodium channels in many types of chronic pain syndromes. We tested the hypothesis that orphenadrine may block voltage-gated sodium channels. By using patch-clamp experiments, we evaluated the effects of the drug on whole-cell sodium currents in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels, as well as on whole-cell tetrodotoxin (TTX)-resistant sodium currents likely conducted by Nav1.8 and Nav1.9 channel subtypes in primary culture of rat DRG sensory neurons. The results indicate that orphenadrine inhibits sodium channels in a concentration-, voltage- and frequency-dependent manner. By using site-directed mutagenesis, we further show that orphenadrine binds to the same receptor as the local anesthetics. Orphenadrine affinities for resting and inactivated sodium channels were higher compared to those of known sodium channels blockers, such as mexiletine and flecainide. Low, clinically relevant orphenadrine concentration produces a significant block of Nav1.7, Nav1.8, and Nav1.9 channels, which are critical for experiencing pain sensations, indicating a role for sodium channel blockade in the clinical efficacy of orphenadrine as analgesic compound. On the other hand, block of Nav1.1 and Nav1.5 may contribute to the proconvulsive and proarrhythmic adverse reactions, especially observed during overdose.
- Aix-Marseille University France
- French National Centre for Scientific Research France
- University of Bari Aldo Moro Italy
- Université Paris Diderot France
- Vanderbilt University United States
Microsoft Academic Graph classification: chemistry.chemical_compound Orphenadrine Chemistry Tetrodotoxin medicine.drug medicine.medical_specialty Sodium Analgesic chemistry.chemical_element Mexiletine Internal medicine medicine Flecainide Acetylcholine receptor Sodium channel Endocrinology
MESH: Signal Transduction, Male, MESH: Analgesics, MESH: Radiotherapy, MESH: Neurons, MESH: Rats, Sprague-Dawley, Sodium Channels, MESH: Dose-Response Relationship, Drug, Membrane Potentials, Rats, Sprague-Dawley, Ganglia, Spinal, MESH: Animals, MESH: Radiotherapy Dosage, Cells, Cultured, Neurons, Analgesics, MESH: Radiation Tolerance, Neurology, MESH: Ganglia, Spinal, Ion Channel Gating, MESH: Cells, Cultured, MESH: Salivary Glands, MESH: Rats, MESH: Radiation Injuries, MESH: Orphenadrine, MESH: Sodium Channels, MESH: Salivary Gland Diseases, MESH: Radiation-Protective Agents, Orphenadrine, MESH: Membrane Potentials, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Humans, Dose-Response Relationship, Drug, MESH: Apoptosis, MESH: Ion Channel Gating, MESH: Male, Rats, MESH: Head and Neck Neoplasms, Anesthesiology and Pain Medicine, Neurology (clinical), MESH: Disease Models, Animal
MESH: Signal Transduction, Male, MESH: Analgesics, MESH: Radiotherapy, MESH: Neurons, MESH: Rats, Sprague-Dawley, Sodium Channels, MESH: Dose-Response Relationship, Drug, Membrane Potentials, Rats, Sprague-Dawley, Ganglia, Spinal, MESH: Animals, MESH: Radiotherapy Dosage, Cells, Cultured, Neurons, Analgesics, MESH: Radiation Tolerance, Neurology, MESH: Ganglia, Spinal, Ion Channel Gating, MESH: Cells, Cultured, MESH: Salivary Glands, MESH: Rats, MESH: Radiation Injuries, MESH: Orphenadrine, MESH: Sodium Channels, MESH: Salivary Gland Diseases, MESH: Radiation-Protective Agents, Orphenadrine, MESH: Membrane Potentials, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Humans, Dose-Response Relationship, Drug, MESH: Apoptosis, MESH: Ion Channel Gating, MESH: Male, Rats, MESH: Head and Neck Neoplasms, Anesthesiology and Pain Medicine, Neurology (clinical), MESH: Disease Models, Animal
Microsoft Academic Graph classification: chemistry.chemical_compound Orphenadrine Chemistry Tetrodotoxin medicine.drug medicine.medical_specialty Sodium Analgesic chemistry.chemical_element Mexiletine Internal medicine medicine Flecainide Acetylcholine receptor Sodium channel Endocrinology
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).43 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10% citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).43 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
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- Aix-Marseille University France
- French National Centre for Scientific Research France
- University of Bari Aldo Moro Italy
- Université Paris Diderot France
- Vanderbilt University United States
International audience; Orphenadrine is a drug acting on multiple targets, including muscarinic, histaminic, and NMDA receptors. It is used in the treatment of Parkinson's disease and in musculoskeletal disorders. It is also used as an analgesic, although its mechanism of action is still unknown. Both physiological and pharmacological results have demonstrated a critical role for voltage-gated sodium channels in many types of chronic pain syndromes. We tested the hypothesis that orphenadrine may block voltage-gated sodium channels. By using patch-clamp experiments, we evaluated the effects of the drug on whole-cell sodium currents in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels, as well as on whole-cell tetrodotoxin (TTX)-resistant sodium currents likely conducted by Nav1.8 and Nav1.9 channel subtypes in primary culture of rat DRG sensory neurons. The results indicate that orphenadrine inhibits sodium channels in a concentration-, voltage- and frequency-dependent manner. By using site-directed mutagenesis, we further show that orphenadrine binds to the same receptor as the local anesthetics. Orphenadrine affinities for resting and inactivated sodium channels were higher compared to those of known sodium channels blockers, such as mexiletine and flecainide. Low, clinically relevant orphenadrine concentration produces a significant block of Nav1.7, Nav1.8, and Nav1.9 channels, which are critical for experiencing pain sensations, indicating a role for sodium channel blockade in the clinical efficacy of orphenadrine as analgesic compound. On the other hand, block of Nav1.1 and Nav1.5 may contribute to the proconvulsive and proarrhythmic adverse reactions, especially observed during overdose.