Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain.
Abstract
Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose- and therapy-limiting
side effect of widely used cytostatics that is particularly difficult to treat. Here,
we report increased expression of the cytochrome-P450-epoxygenase CYP2J6 and increased
concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic
acid) in dorsal root ganglia (DRGs) of paclitaxel-treated mice as a model of CIPNP.
The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased
frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive
neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical
and thermal pain hypersensitivity. In a drug repurposing screen targeting CYP2J2,
the human ortholog of murine CYP2J6, we identified telmisartan, a widely used angiotensin
II receptor antagonist, as a potent inhibitor. In a translational approach, administration
of telmisartan reduces EpOME concentrations in DRGs and in plasma and reverses mechanical
hypersensitivity in paclitaxel-treated mice. We therefore suggest inhibition of CYP2J
isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic
pain.
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https://hdl.handle.net/10161/13681Published Version (Please cite this version)
10.1073/pnas.1613246113Publication Info
Sisignano, Marco; Angioni, Carlo; Park, Chul-Kyu; Meyer Dos Santos, Sascha; Jordan,
Holger; Kuzikov, Maria; ... Geisslinger, Gerd (2016). Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain. Proc Natl Acad Sci U S A, 113(44). pp. 12544-12549. 10.1073/pnas.1613246113. Retrieved from https://hdl.handle.net/10161/13681.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Ru-Rong Ji
Distinguished Professor of Anesthesiology, in the School of Medicine
I have been doing neuroscience and pain research for over 25 years in multiple academic
institutes, including Duke University (2012-current), Harvard Medical School (1998-2012),
Johns Hopkins Medical School, Karolinska Institute, and Peking University. The long-term
goal of my lab is to identify molecular and cellular mechanisms that underlie the
induction and resolution of pathological pain and develop novel pain therapeutics
that can target these mechanisms, with specific focus on

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