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.
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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

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Figure 8

TRPA1 and ADH are present in human Schwann cells.

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TRPA1 and ADH are present in human Schwann cells. (A, B, E, F, J, and K)...
(A, B, E, F, J, and K) Representative images of S100 and ADH expression (A and B), TRPA1 (E and F), and NOX1 immunofluorescence (J and K) in cultured human Schwann cells (HSCs) and human skin. (C) ADH1A, ADH1B, ADH1C, ADH4, ADH5, and ADH7 mRNA relative expression in HSCs. (D) Dose-dependent acetaldehyde (ACD) levels in HSCs exposed to ethanol (EtOH; 1–100 mM) and treated with 4-Mp (100 μM). (G) TRPA1 mRNA expression in HSCs relative to human TRPA1-HEK293 cells. (H) Intracellular calcium ([Ca2+]i) response to allyl isothiocyanate (AITC; 100 μM), H2O2 (10 mM), and ACD (10 mM) in HSCs in the presence of A967079 (A96, 30 μM) or its vehicle (Veh). (I) [Ca2+]i response to EtOH (10 mM) in HSCs in the presence of A96 (30 μM), 4-Mp (100 μM), or their Veh. (L) NOX1 mRNA expression in HSCs relative to A549 cells. (M) H2O2 release evoked by AITC (100 μM), H2O2 (200 nM), and ACD (10 mM) in HSCs in the presence of A96 (30 μM) or Veh or in Ca2+-free medium. Veh is the vehicle of EtOH, AITC, H2O2, and ACD. (C, D, G, L, and M) 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; n = 3 replicates from 2 independent experiments in C, G, and L, and n = 8 replicates from 3 independent experiments in D and M; (H and I) data are mean ± SEM with individual data points overlaid, 41 to 327 cells; n = 3–5 experiments. *P < 0.05, ***P < 0.001 vs. Veh; §P < 0.05, §§§P < 0.001 vs. EtOH (10 mM), AITC (100 μM), H2O2 (200 nM), and ACD (10 mM); (D, H, I, and M) 1-way ANOVA with Bonferroni post hoc correction.