PT  - JOURNAL ARTICLE
AU  - Yan Li
AU  - Pavel Adamek
AU  - Haijun Zhang
AU  - Claudio Esteves Tatsui
AU  - Laurence D. Rhines
AU  - Petra Mrozkova
AU  - Qin Li
AU  - Alyssa K. Kosturakis
AU  - Ryan M. Cassidy
AU  - Daniel S. Harrison
AU  - Juan P. Cata
AU  - Kenneth Sapire
AU  - Hongmei Zhang
AU  - Ross M. Kennamer-Chapman
AU  - Abdul Basit Jawad
AU  - Andre Ghetti
AU  - Jiusheng Yan
AU  - Jiri Palecek
AU  - Patrick M. Dougherty
TI  - The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4
AID  - 10.1523/JNEUROSCI.1956-15.2015
DP  - 2015 Sep 30
TA  - The Journal of Neuroscience
PG  - 13487--13500
VI  - 35
IP  - 39
4099  - http://www.jneurosci.org/content/35/39/13487.short
4100  - http://www.jneurosci.org/content/35/39/13487.full
SO  - J. Neurosci.2015 Sep 30; 35
AB  - Peripheral neuropathy is dose limiting in paclitaxel cancer chemotherapy and can result in both acute pain during treatment and chronic persistent pain in cancer survivors. The hypothesis tested was that paclitaxel produces these adverse effects at least in part by sensitizing transient receptor potential vanilloid subtype 1 (TRPV1) through Toll-like receptor 4 (TLR4) signaling. The data show that paclitaxel-induced behavioral hypersensitivity is prevented and reversed by spinal administration of a TRPV1 antagonist. The number of TRPV1+ neurons is increased in the dorsal root ganglia (DRG) in paclitaxel-treated rats and is colocalized with TLR4 in rat and human DRG neurons. Cotreatment of rats with lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides (LPS-RS), a TLR4 inhibitor, prevents the increase in numbers of TRPV1+ neurons by paclitaxel treatment. Perfusion of paclitaxel or the archetypal TLR4 agonist LPS activated both rat DRG and spinal neurons directly and produced acute sensitization of TRPV1 in both groups of cells via a TLR4-mediated mechanism. Paclitaxel and LPS sensitize TRPV1 in HEK293 cells stably expressing human TLR4 and transiently expressing human TRPV1. These physiological effects also are prevented by LPS-RS. Finally, paclitaxel activates and sensitizes TRPV1 responses directly in dissociated human DRG neurons. In summary, TLR4 was activated by paclitaxel and led to sensitization of TRPV1. This mechanism could contribute to paclitaxel-induced acute pain and chronic painful neuropathy.SIGNIFICANCE STATEMENT In this original work, it is shown for the first time that paclitaxel activates peripheral sensory and spinal neurons directly and sensitizes these cells to transient receptor potential vanilloid subtype 1 (TRPV1)-mediated capsaicin responses via Toll-like receptor 4 (TLR4) in multiple species. A direct functional interaction between TLR4 and TRPV1 is shown in rat and human dorsal root ganglion neurons, TLR4/TRPV1-coexpressing HEK293 cells, and in both rat and mouse spinal cord slices. Moreover, this is the first study to show that this interaction plays an important role in the generation of behavioral hypersensitivity in paclitaxel-related neuropathy. The key translational implications are that TLR4 and TRPV1 antagonists may be useful in the prevention and treatment of chemotherapy-induced peripheral neuropathy in humans.