Journal
MOLECULAR PAIN
Volume 12, Issue -, Pages -Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/1744806916663729
Keywords
Fabry disease; pain; small fiber neuropathy; alpha-GalA null mice; ion channels
Categories
Funding
- Ministero della Salute, Bando Progetti di Ricerca Finalizzata IRCCS-Istituto delle Scienze Neurologiche di Bologna, Italy [2010 RF-2010-2313899]
- MINECO/FEDER
- Generalitat Valenciana, Spain [PROMETEO/2014/011]
- EU [SAF2015-66275-C2-1-R]
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Fabry disease is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (a-GalA) enzyme. alpha-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 alpha-GalA gene null mouse model (alpha-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 alpha-GalA(-/0) mice exhibit a significant increase in the expression and function of the TRPV1 channel, a thermo TRP channel implicated in painful heat sensation. Notably, male alpha-GalA( -/0) mice displayed a approximate to 2-fold higher heat sensitivity than wild-type animals, consistent with the augmented expression levels and activity of TRPV1 in alpha-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 alpha-GalA(-/0) mice. Together, these findings suggest that the augmented expression of TRPV1 in alpha-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.
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