title: Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model.
abstract: Fabry disease is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3) in the endothelium and vascular smooth muscles. A hallmark symptom of Fabry disease patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. The α-GalA gene null mouse model (α-GalA(-/0)) has provided molecular evidence for the molecular alterations in small type-C nociceptors in Fabry disease that may underlie their hyperexcitability, although the specific mechanism remains elusive. Here, we have addressed this question and report that small type-C nociceptors from α-GalA(-/0) mice exhibit a significant increase in the expression and function of the TRPV1 channel, a thermoTRP channel implicated in painful heat sensation. Notably, male α-GalA(-/0) mice displayed a ≈2-fold higher heat sensitivity than wild-type animals, consistent with the augmented expression levels and activity of TRPV1 in α-GalA(-/0) nociceptors. Intriguingly, blockade of neuronal exocytosis with peptide DD04107, a process that inhibits among others the algesic membrane recruitment of TRPV1 channels in peptidergic nociceptors, virtually eliminated the enhanced heat nociception of α-GalA(-/0) mice. Together, these findings suggest that the augmented expression of TRPV1 in α-GalA(-/0) nociceptors may underly at least in part their increased heat sensitivity, and imply that blockade of peripheral neuronal exocytosis may be a valuable pharmacological strategy to reduce pain in Fabry disease patients, increasing their quality of life.
authors.affiliation: Department of Pharmacy and Biotechnology (FaBiT), Laboratory of Human and General Physiology, University of Bologna, Italy Institute of Molecular and Cellular Biology, University of Miguel Hernandez, Spain.
authors.forename: Jarmila
authors.initials: J
authors.lastname: Lakomá
authors.affiliation: IRCCS Institute of Neurological Sciences, AUSL Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Rimondini
authors.affiliation: Department of Medical and Clinical Sciences (DIMEC), University of Bologna, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer Montiel
authors.affiliation: Institute of Molecular and Cellular Biology, University of Miguel Hernandez, Spain.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Donadio
authors.affiliation: Institute of Molecular and Cellular Biology, University of Miguel Hernandez, Spain Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.affiliation: Department of Pharmacy and Biotechnology (FaBiT), Laboratory of Human and General Physiology, University of Bologna, Italy m.caprini@unibo.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Caprini
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005089:Exocytosis / Q000502:physiology; D000795:Fabry Disease / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D059225:Nociception / Q000502:physiology; D010146:Pain / Q000235:genetics*; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D000519:alpha-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D000519:alpha-Galactosidase
keywords: Fabry disease; ion channels; pain; small fiber neuropathy; α-GalA null mice