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 1

TRPV1 mediates acute nociception and TRPA1 mediates allodynia evoked by local ethanol.

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TRPV1 mediates acute nociception and TRPA1 mediates allodynia evoked by ...
(A and B) Dose-dependent acute nociception (A) and dose- and time-dependent mechanical allodynia (B) evoked by intraplantar (i.pl., 20 μL) ethanol (EtOH) or vehicle (Veh) in C57BL/6J mice. (C) Acute nociceptive response evoked by EtOH (30%, i.pl.) or Veh in Trpv1+/+ and Trpv1–/– mice. (D) Time-dependent mechanical allodynia evoked by EtOH (30%, i.pl.) or Veh in Trpv1+/+ and Trpv1–/– mice. (E and F) Time-dependent mechanical allodynia evoked by EtOH (30%, i.pl.) or Veh in C57BL/6J mice pretreated with 4-methylpyrazole (4-Mp; 50 mg/kg, intragastric [i.g.], or 100 μg, i.pl.) or Veh 4-Mp. (G and H) Acute nociceptive response (G) and time-dependent mechanical allodynia (H) evoked by EtOH (30%, i.pl.) or Veh in Trpa1+/+ and Trpa1–/– mice. (I and J) Dose-dependent acute nociceptive response (I) and dose- and time-dependent mechanical allodynia (J) evoked by acetaldehyde (ACD; 1–20 nmol, i.pl.) or Veh in C57BL/6J mice. (K and L) Acute nociceptive response and time-dependent mechanical allodynia evoked by ACD (20 nmol, i.pl.) or Veh in Trpa1+/+ and Trpa1–/– mice. BL, baseline. Veh is the vehicle of EtOH or ACD. (A, C, G, I, and K) 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; (B, D–F, H, J, and L) mean ± SEM with individual data points overlaid; n = 8 mice for each experiment. *P < 0.05, **P < 0.01, ***P < 0.001 vs. Veh, Veh-Trpv1+/+, and Veh-Trpa1+/+; §§§P < 0.001 vs. EtOH, EtOH-Trpv1+/+, EtOH-Trpa1+/+, ACD, and ACD-Trpa1+/+; 1-way (A, C, G, I, and K) or 2-way (B, D–F, H, J, and L) ANOVA with Bonferroni post hoc correction.