Nav1.8, TRPV1 and TRPA1 as possible targets of ambroxol when used for topical treatment of neuropathic pain
Abstract
Sodium channels and the capsaicin receptor TRPV1 in epidermal sensory nerve endings are established targets for topical treatment of neuropathic pain. The secretolytic ambroxol induces effective topically analgesia, a property that may involve a preferential block of Nav1.8. We here examined to what extent ambroxol inhibits human and rat (r) Nav1.8, but also the human (h) orthologues of the irritant receptors TRPV1 and TRPA1 by performing whole-cell patch clamp recordings. Ambroxol-induced tonic inhibition was stronger on rNav1.8 (IC 50 18 µM) than on hNav1.8 (IC 50 279 µM) and TTX-sensitive Na + channels (IC 50 76 µM). Non-inactivating currents of both hNav1.8 and rNav1.8 displayed a higher sensitivity to ambroxol than transient currents. A weak but concentration-dependent activation of hTRPV1 and hTRPA1 exceeded an unspecific increase in intracellular calcium by high concentrations of ambroxol. While the activation mechanism for hTRPV1 involves the vanilloid-binding domain, residues required for menthol-sensitivity of hTRPA1 seems to dictate ambroxol-sensitivity. Ambroxol also inhibited capsaicin-induced currents on hTRPV1 in a concentration-dependent and partly reversible manner. This inhibition was independent of intracellular calcium and preserved on the non-desensitizing mutant hTRPV1-Y672K. Currents induced by mustard oil or carvacrol on hTRPA1 exhibited a concentration-dependent reduction by ambroxol that was stronger on outward as compared to inward currents. We…
Read the paper
Related studies
- Noninvasive and Point-of-Care Surface-Enhanced Raman Scattering (SERS)-Based Breathalyzer for Mass Screening of Coronavirus Disease 2019 (COVID-19) under 5 min
- De Novo Transcriptome Analysis and Detection of Antimicrobial Peptides of the American Cockroach Periplaneta americana (Linnaeus)
- Molecular Characterization and Expression Profiling of Tomato GRF Transcription Factor Family Genes in Response to Abiotic Stresses and Phytohormones
- Assembly of Tight Junction Strands: Claudin-10b and Claudin-3 Form Homo Tetrameric Building Blocks that Polymerise in a Channel-Independent Manner
- Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease‐associated variants, common sequence variants, and results from newborn screening
- Machine Learning-Based SERS Chemical Space for Two-Way Prediction of Structures and Spectra of Untrained Molecules
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.