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 6

Schwann cell TRPA1 contributes to oxidative stress generation.

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Schwann cell TRPA1 contributes to oxidative stress generation. (A and B)...
(A and B) Representative images of NADPH oxidase-1 (NOX1), S100, and TRPA1 expression in plantar nerve of C57BL/6J mice. (C) Mechanical allodynia evoked by ethanol (EtOH; 15%, 4 mL/kg, i.g.) and acetaldehyde (ACD; 0.1 mg/kg, i.p.) or their vehicle (Veh) after ML171 (100 mg/kg, i.p.) or Veh ML171 in C57BL/6J mice. (D) Time-dependent mechanical allodynia evoked by EtOH (30%, i.pl., and 15%, 4 mL/kg, i.g.) or Veh in Plp-CreERT Trpa1fl/fl and control mice. (E) H2O2 levels (hind paw) after EtOH (30%, i.pl., and 15%, 4 mL/kg, i.g.) or Veh in Plp-CreERT Trpa1fl/fl and control mice. (F) Time-dependent mechanical allodynia evoked by EtOH (30%, i.pl., and 15%, 4 mL/kg, i.g.) or Veh in Adv-Cre Trpa1fl/fl and control mice. (G) H2O2 levels (hind-paw tissue) after EtOH (30%, i.pl., and 15%, 4 mL/kg, i.g.) or Veh in Adv-Cre Trpa1fl/fl and control mice. BL, baseline. Veh is the vehicle of EtOH and ACD. Dashed lines indicate perineurium. Data are mean ± SEM with individual data points overlaid; n = 6–8 mice for each experimental condition. **P < 0.01, ***P < 0.001 vs. Veh; §§P < 0.01, §§§P < 0.001 vs. EtOH i.g. or EtOH i.pl. control; 1-way (E and G) or 2-way (C, D, and F) ANOVA with Bonferroni post hoc correction.