Schwann cells expressing nociceptive channel TRPA1 orchestrate ethanol-evoked neuropathic pain in mice
Francesco De Logu, … , Pierangelo Geppetti, Romina Nassini
Francesco De Logu, … , Pierangelo Geppetti, Romina Nassini
Published September 5, 2019
Citation Information: J Clin Invest. 2019;129(12):5424-5441. https://doi.org/10.1172/JCI128022.
View: Text | PDF
Research Article Neuroscience

Schwann cells expressing nociceptive channel TRPA1 orchestrate ethanol-evoked neuropathic pain in mice

Abstract

Excessive alcohol consumption is associated with spontaneous burning pain, hyperalgesia, and allodynia. Although acetaldehyde has been implicated in the painful alcoholic neuropathy, the mechanism by which the ethanol metabolite causes pain symptoms is unknown. Acute ethanol ingestion caused delayed mechanical allodynia in mice. Inhibition of alcohol dehydrogenase (ADH) or deletion of transient receptor potential ankyrin 1 (TRPA1), a sensor for oxidative and carbonyl stress, prevented allodynia. Acetaldehyde generated by ADH in both liver and Schwann cells surrounding nociceptors was required for TRPA1-induced mechanical allodynia. Plp1-Cre Trpa1fl/fl mice with a tamoxifen-inducible specific deletion of TRPA1 in Schwann cells revealed that channel activation by acetaldehyde in these cells initiates a NADPH oxidase-1–dependent (NOX1-dependent) production of hydrogen peroxide (H2O2) and 4-hydroxynonenal (4-HNE), which sustains allodynia by paracrine targeting of nociceptor TRPA1. Chronic ethanol ingestion caused prolonged mechanical allodynia and loss of intraepidermal small nerve fibers in WT mice. While Trpa1–/– or Plp1-Cre Trpa1fl/fl mice did not develop mechanical allodynia, they did not show any protection from the small-fiber neuropathy. Human Schwann cells express ADH/TRPA1/NOX1 and recapitulate the proalgesic functions of mouse Schwann cells. TRPA1 antagonists might attenuate some symptoms of alcohol-related pain.

Authors

Francesco De Logu, Simone Li Puma, Lorenzo Landini, Francesca Portelli, Alessandro Innocenti, Daniel Souza Monteiro de Araujo, Malvin N. Janal, Riccardo Patacchini, Nigel W. Bunnett, Pierangelo Geppetti, Romina Nassini

×

Figure 7

Schwann cell TRPA1 mediates mechanical allodynia evoked by chronic ethanol treatment.

Options: View larger image (or click on image) Download as PowerPoint
Schwann cell TRPA1 mediates mechanical allodynia evoked by chronic ethan...
(A) Overview of the experimental design of the chronic ethanol (EtOH) feeding model. (B) Time-dependent mechanical allodynia evoked by EtOH diet (5% [vol/vol] for 28 days) or control diet (Pair-fed) in Trpa1+/+ and Trpa1–/– mice and Plp-CreERT Trpa1fl/fl and control mice. (C) Mechanical allodynia evoked by EtOH or control diet at day 28 after A967079 (A96, 100 mg/kg, i.p.) and PBN (100 mg/kg, i.p.) or their vehicle (Veh) in C57BL/6J mice. (D) Representative photomicrographs and cumulative data of 4-HNE staining (plantar nerve) and levels (hind paw) and H2O2 levels (hind paw) in Trpa1+/+ and Trpa1–/– mice and Plp-CreERT Trpa1fl/fl and control mice at day 28 after EtOH or control diet. Original magnification ×20. (E) Representative photomicrograph of PGP9.5 staining and cumulative data of intraepidermal nerve fiber (IENF) density in the paw of Trpa1+/+ and Trpa1–/– mice and Plp-CreERT Trpa1fl/fl and control mice at day 28 after EtOH or control diet. BL, baseline. (D, 4-HNE-His, and E) Box plots with horizontal lines at the 25th percentile, the median, and the 75th percentile and vertical lines that extend to the minimum and maximum values; all other data are mean ± SEM with individual data points overlaid; n = 8 mice for each experimental condition. *P < 0.05, ***P < 0.001 vs. pair-fed Trpa1+/+, pair-fed control, or EtOH-fed Veh A96/A96 day 0; §P < 0.05, §§P < 0.01, §§§P < 0.001 vs. EtOH-fed Trpa1+/+, EtOH-fed control, or EtOH-fed Veh A96; unpaired 2-tailed Student’s t test (D, mean gray value), 1-way (D, 4-HNE-His adducts and H2O2, and E) or 2-way (B and C) ANOVA with Bonferroni post hoc correction.