Neuropathic pain in a Fabry disease rat model
James J. Miller, … , Cheryl L. Stucky, Nancy M. Dahms
James J. Miller, … , Cheryl L. Stucky, Nancy M. Dahms
Published March 22, 2018
Citation Information: JCI Insight. 2018;3(6):e99171. https://doi.org/10.1172/jci.insight.99171.
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Research Article Neuroscience

Neuropathic pain in a Fabry disease rat model

Abstract

Fabry disease, the most common lysosomal storage disease, affects multiple organs and results in a shortened life span. This disease is caused by a deficiency of the lysosomal enzyme α-galactosidase A, which leads to glycosphingolipid accumulation in many cell types. Neuropathic pain is an early and severely debilitating symptom in patients with Fabry disease, but the cellular and molecular mechanisms that cause the pain are unknown. We generated a rat model of Fabry disease, the first nonmouse model to our knowledge. Fabry rats had substantial serum and tissue accumulation of α-galactosyl glycosphingolipids and had pronounced mechanical pain behavior. Additionally, Fabry rat dorsal root ganglia displayed global N-glycan alterations, sensory neurons were laden with inclusions, and sensory neuron somata exhibited prominent sensitization to mechanical force. We found that the cation channel transient receptor potential ankyrin 1 (TRPA1) is sensitized in Fabry rat sensory neurons and that TRPA1 antagonism reversed the behavioral mechanical sensitization. This study points toward TRPA1 as a potentially novel target to treat the pain experienced by patients with Fabry disease.

Authors

James J. Miller, Kazuhiro Aoki, Francie Moehring, Carly A. Murphy, Crystal L. O’Hara, Michael Tiemeyer, Cheryl L. Stucky, Nancy M. Dahms

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Figure 10

Transient receptor potential ankryin 1 (TRPA1) is a therapeutic target for treating Fabry disease neuropathic pain.

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Transient receptor potential ankryin 1 (TRPA1) is a therapeutic target f...
(A) Example traces from calcium imaging experiments showing fluorescence ratios (340/380 nm) with time. Solutions containing allyl isothiocyanate (mustard oil, MO) or K+ were applied as indicated by the arrows. Traces had a greater than 20% increase in response to MO are shown in blue. (B) The number of small diameter (≤32 μm) and large diameter (>32 μm) neurons responding to 30 μM MO. Numbers of responding neurons and total neurons are shown inside each bar. Neurons are from 3 WT and 3 KO male rats at 19–21 weeks. Fisher’s exact test was used to compare WT and KO neuron response percentages. (C) Same as in B, but with 300 nM capsaicin applied. TRPV1, transient receptor potential vanilloid 1. (D) WT and KO male rats at 35–36 weeks were intraplantarly injected with TRPA1 antagonist, HC-030031, or vehicle (n = 4 each group, 16 total rats). An 8.8 g von Frey filament was applied repeatedly to the hind paw, and the response frequency was determined. Significance was determined using 2-way ANOVA and Bonferroni’s post-hoc test. (E) Same as in D, but a needle was applied repeated to the hind paw, and the response frequency was determined. Mean ± SEM are represented in D and E. *P < 0.05, **P < 0.01, ****P < 0.0001.