TY - JOUR
T1 - Schwann cells expressing nociceptive channel TRPA1 orchestrate ethanol-evoked neuropathic pain in mice
AU - De Logu, Francesco
AU - Puma, Simone Li
AU - Landini, Lorenzo
AU - Portelli, Francesca
AU - Innocenti, Alessandro
AU - De Araujo, Daniel Souza Monteiro
AU - Janal, Malvin N.
AU - Patacchini, Riccardo
AU - Bunnett, Nigel W.
AU - Geppetti, Pierangelo
AU - Nassini, Romina
N1 - Funding Information:
We thank A.H. Morice (University of Hull, Hull, UK) for hTR-PA1-HEK293 cells and D. Preti (University of Ferrara, Ferrara, Italy) for providing A967079. We also thank Mary K. Lokken for her expert English revision. This study was funded by Minis-tery of Education, University and Research, MIUR (Rome, Italy) grant PRIN 201532AHAE_003 (to PG), and by grants from the NIH (NS102722, DE026806, DK118971) and the Department of Defense (W81XWH1810431) (to NWB).
Funding Information:
We thank A.H. Morice (University of Hull, Hull, UK) for hTRPA1-HEK293 cells and D. Preti (University of Ferrara, Ferrara, Italy) for providing A967079. We also thank Mary K. Lokken for her expert English revision. This study was funded by Ministery of Education, University and Research, MIUR (Rome, Italy) grant PRIN 201532AHAE_003 (to PG), and by grants from the NIH (NS102722, DE026806, DK118971) and the Department of Defense (W81XWH1810431) (to NWB).
Publisher Copyright:
Copyright: © 2019, American Society for Clinical Investigation.
PY - 2019/12/2
Y1 - 2019/12/2
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI128022
DO - 10.1172/JCI128022
M3 - Article
C2 - 31487269
AN - SCOPUS:85075956975
VL - 129
SP - 5424
EP - 5441
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 12
ER -