title: Activity-dependent targeting of TRPV1 with a pore-permeating capsaicin analog.
abstract: The capsaicin receptor TRPV1 is the principal transduction channel for nociception. Excessive TRPV1 activation causes pathological pain. Ideal pain mangement requires selective inhibition of hyperactive pain-sensing neurons, but sparing normal nociception. We sought to determine whether it is possible to use activity-dependent TRPV1 agonists to identify nerves with excessive TRPV1 activity, as well as exploit the TRPV1 pore to deliver charged anesthetics for neuronal silencing. We synthesized a series of permanently charged capsaicinoids and found that one, cap-ET, efficaciously evoked TRPV1-dependent entry of Ca(2+) or the large cationic dye YO-PRO-1 comparably to capsaicin, but far smaller electrical currents. Cap-ET-induced YO-PRO-1 transport required permeation of both the agonist and the dye through the TRPV1 pore and could be enhanced by kinase activation or oxidative covalent modification. Moreover, cap-ET reduced capsaicin-induced currents by a voltage-dependent block of the pore. A low dose of cap-ET elicited entry of permanently charged Na(+) channel blockers to effectively suppress Na(+) currents in sensory neurons presensitized with oxidative chemicals. These results implicate therapeutic potential of these unique TRPV1 agonists exhibiting activity-dependent ion transport but of minimal pain-producing risks.
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Chuang
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Cohen
authors.forename: Huai-Hu
authors.initials: HH
authors.lastname: Chuang
mesh_terms: D000818:Animals; D001692:Biological Transport; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D006801:Humans; D051381:Rats; D050916:TRPV Cation Channels / Q000819:agonists*
chemical_list: D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D002211:Capsaicin