The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4

Abstract

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 paclitaxelinduced behavioral hypersensitivity is prevented and reversed by spinal administration of a TRPV1 antagonist. The number of TRPV1 ϩ 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 ϩ 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.

DNA damage mediates changes in neuronal sensitivity induced by the inflammatory mediators, MCP-1 and LPS, and can be reversed by enhancing the DNA repair function of APE1

“…LPS is expressed on the outer membrane of gram negative bacteria, including the inactivated Mycobacterium tuberculosis present in complete Freund’s adjuvant used in our in vivo inflammation studies. LPS is an exogenous ligand for the TLR4 receptor, which is expressed in sensory neurons (Diogenes et al, 2011, Li et al, 2014, Li et al, 2015) and exposure to LPS enhances the expression of TNFα, IL-1β, COX-2 and MCP-1 in sensory neurons (Tse et al, 2014, Miller et al, 2015), thus recapitulating the activation of multiple pathways elicited by inflammation. Furthermore, LPS acutely enhances the sensitivity of sensory neurons as demonstrated by nociceptive behaviors following injection into the hindpaw of rodents (Ferreira et al, 1993, Calil et al, 2014) and by in vitro experiments, where LPS enhances the excitability and exocytotic activity of sensory neurons (Hou and Wang, 2001, Diogenes et al, 2011, Meseguer et al, 2014).…”

Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain

“…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).…”

“…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)(2)(3)(4)(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).…”

“…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).…”

Pain and infection

“…This nociceptor activation requires Lipid A, the membrane anchored moiety of LPS [3]. LPS may also signal through a Toll-like receptor (TLR4) mediated sensitization of the capsaicin receptor TRPV1 [4,8,11]. …”