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-P 450 -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 paclitaxeltreated 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 paclitaxeltreated mice. We therefore suggest inhibition of CYP2J isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic pain.chemotherapy-induced neuropathy | neuropathic pain | TRPV1 | telmisartan | oxidized lipids R ecent studies identified members of the transient receptor potential-family of ion channels (TRPV1, TRPA1, and TRPV4) as contributors to both mechanical and cold allodynia during oxaliplatin and paclitaxel-induced neuropathy (1-5). Activation or sensitization of TRPV1 and TRPA1 can lead to enhanced release of CGRP and substance P, both of which can cause neurogenic inflammation and recruitment of T cells (6, 7).However, it remains unclear which endogenous mediators are involved in paclitaxel-dependent activation or sensitization of TRP channels, as paclitaxel cannot directly activate TRP channels (4,5,8). Interestingly, paclitaxel is an inducer of some Cytochrome-P 450 epoxygenases (e.g., CYP2C8, CYP2C9) (9). CYP epoxygenases can metabolize ω-6 fatty acids, such as arachidonic acid (AA) and linoleic acid (LA), generating either lipid epoxides such as EETs (epoxyeicosatrienoid acids) or ω-hydroxides such as 20-hydroxyeicosatetraenoic acid (20-HETE) (10, 11).Although therapeutic alternatives exist, paclitaxel is still the preferred first line of therapy for metastatic breast cancer (12), causing severe CIPNP in many treated patients. Here, we performed liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipid profiling of sciatic nerve, dorsal root ganglion (DRG), and dorsal horn tissue from paclitaxel-treated mice.We identified 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid), a CYP metabolite of LA, to be strongly synthesized in DRGs 24 h and 8 d after paclitaxel injection in mice. 9,10-EpOME is capable of sensitizing TRPV1 at submicromolar concentrations via a cAMP-PKA-dependent mechanism, causing enhanced frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina II neurons of the spin...

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We present high resolution laboratory spectra of K-shell X-ray lines from inner-shell excited and ionized ions of oxygen, obtained with a reflection grating spectrometer on the electron beam ion trap (EBIT-I) at the Lawrence Livermore National Laboratory. Only with a multi-ion model including all major atomic collisional and radiative processes, are we able to identify the observed K-shell transitions of oxygen ions from O III to O VI. The wavelengths and associated errors for some of the strongest transitions are given, taking into account both the experimental and modeling uncertainties. The present data should be useful in identifying the absorption features present in astrophysical sources, such as active galactic nuclei and X-ray binaries. They are also useful in providing benchmarks for the testing of theoretical atomic structure calculations.