Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain.
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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.
Published Version (Please cite this version)10.1073/pnas.1613246113
Publication InfoSisignano, M; Angioni, C; Park, C-K; Meyer Dos Santos, S; Jordan, H; Kuzikov, M; ... Geisslinger, G (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.
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Distinguished Professor of Anesthesiology, in the School of Medicine
Chronic pain is a major health problem in the US, affecting 100 million Americans. The long-term goal of the lab is to identify molecular and cellular mechanisms that underlie the genesis of chronic pain and, furthermore, to develop novel pain therapeutics that can target these mechanisms. We are interested in the following questions. (1) How do neuroinflammation and activation of glial cells (microglia and astrocytes) regulate pain and spinal cord synaptic plasticity via neuro-glia