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 December 2, 2019; First published September 5, 2019
Citation Information: J Clin Invest. 2019;129(12):5424-5441. https://doi.org/10.1172/JCI128022.
View: Text | PDF
Categories: 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 3

Acetaldehyde is generated by both hepatic and Schwann cell ADH.

Options: View larger image (or click on image) Download as PowerPoint
Acetaldehyde is generated by both hepatic and Schwann cell ADH. (A) ADH1...
(A) ADH1, ADH5, and ADH7 mRNA relative expression in hind-paw tissue in C57BL/6J mice. (B and C) Representative images of ADH, S100, and PGP9.5 expression in hind-paw tissue in C57BL/6J mice. (D) Dose-dependent acetaldehyde (ACD) levels in cultured Schwann cells isolated from C57BL/6J mice and exposed to ethanol (EtOH; 1–100 mM) in the presence of 4-Mp (100 μM) or vehicle (Veh 4-Mp). (E) Time-dependent ACD levels (hind-paw tissue) after i.pl. (20 μL) EtOH (30%) in C57BL/6J mice. (F) ACD levels (hind-paw tissue) of C57BL/6J mice receiving EtOH (30%, i.pl.) or Veh and pretreated with 4-Mp (100 μg, i.pl.) or Veh 4-Mp. (G and H) Time-dependent mechanical allodynia and ACD levels (hind-paw tissue) in C57BL/6J mice receiving EtOH (15%, 4 mL/kg, i.g.) or Veh and pretreated with 4-Mp (100 μg, i.pl., or 50 mg/kg, i.g.) or Veh 4-Mp. BL, baseline. Veh is the vehicle of EtOH. “In” and “Out” indicate inside and outside, respectively, the perineurium, delimited by dashed lines. (D, F, and H) 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; (A, E, and G) mean ± SEM with individual data points overlaid; n = 6–8 mice for each experimental condition. *P < 0.05, **P < 0.01, ***P < 0.001 vs. Veh and ACD BL; §P < 0.05, §§P < 0.01, §§§P < 0.001 vs. EtOH and EtOH–4-Mp; 1-way (D–F and H) or 2-way (G) ANOVA with Bonferroni post hoc correction.