Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Sisignano, M; Angioni, C; Park, C-K; Meyer Dos Santos, S; Jordan, H; Kuzikov, M; Liu, D; Zinn, S; Hohman, SW; Schreiber, Y; Zimmer, B; Schmidt, M; Lu, R; Suo, J; Zhang, D-D; Schäfer, SMG; Hofmann, M; Yekkirala, AS; de Bruin, N; Parnham, MJ; Woolf, CJ; Ji, R-R; Scholich, K; Geisslinger, G

Published Date

  • November 1, 2016

Published In

Volume / Issue

  • 113 / 44

Start / End Page

  • 12544 - 12549

PubMed ID

  • 27791151

Pubmed Central ID

  • 27791151

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1613246113

Language

  • eng

Conference Location

  • United States