Dorsal root ganglion neurons become hyperexcitable and increase expression of voltage-gated T-type calcium channels (Cav3.2) in paclitaxel-induced peripheral neuropathy

Abstract

Here it is shown that paclitaxel induced neuropathy is associated with the development of spontaneous activity (SA) and hyperexcitability in DRG neurons that is paralleled by increased expression of low-voltage-activated calcium channels (T-type; Ca v 3.2). The percentage of DRG neurons showing SA and the overall mean rate of SA were significantly higher at day 7 of paclitaxel treatment than in rats receiving vehicle. Ca v 3.2 expression was increased in L4-6 DRG and spinal cord segments in paclitaxel-treated rats, localized to small calcitonin gene-related peptide expressing and isolectin B4 expressing DRG neurons and to glial fibrillary acidic proteinpositive spinal cord cells. Ca v 3.2 expression was also co-localized with toll-like receptor 4 (TLR4) in both the DRG and dorsal horn. T-type current amplitudes and density were increased at day 7 after paclitaxel treatment. Perfusion of the TLR4 agonist lipopolysaccharide (LPS) directly activated DRG neurons, whereas this was prevented by pretreatment with the specific T-type calcium channel inhibitor ML218 hydrochloride. Paclitaxel-induced behavioral hypersensitivity to mechanical stimuli in rats was prevented but not reversed by spinal administration of ML218 hydrochloride or intravenous (i.v.) injection of the TLR4 antagonist TAK242. Paclitaxel induced inward current and action potential discharges in cultured human DRGs neurons and this was blocked by ML218 hydrochloride pretreatment. Furthermore, ML218 hydrochloride decreased

Possible involvement of transient receptor potential ankyrin 1 in Ca2+ signaling via T‐type Ca2+ channel in mouse sensory neurons

“…Hydrogen sulfide, an endogenous gasotransmitter, activates Cav3.2 resulting in visceral and neuropathic pain (Tsubota-Matsunami, Noguchi, Okawa, Sekiguchi, & Kawabata, 2012). A recent report shows that an increase of Cav3.2 expression contributes to paclitaxel-induced neuropathy (Li et al, 2017). Intraplantar injection of a T-type Ca 21 channel blocker alleviates the mechanical and thermal allodynia (Todorovic, Meyenburg, & Jevtovic-Todorovic, 2002).…”

DNMT3a‐triggered downregulation of K2p1.1 gene in primary sensory neurons contributes to paclitaxel‐induced neuropathic pain

“…Chemotherapy drugs poorly penetrate into the central nervous system, but they have unrestricted access to dorsal root ganglion (DRG) due to the lack of an effective vascular permeability barrier . Chemotherapeutic paclitaxel produced ectopic spontaneous activity in DRG neuronal somata . This abnormal activity, which has been identified as a CIPNP contributor, may be related to the changes in the gene expression at the transcriptional and translational levels in the DRG after chemotherapy drug treatments .…”

“…8,9 Chemotherapeutic paclitaxel produced ectopic spontaneous activity in DRG neuronal somata. [10][11][12][13] This abnormal activity, which has been identified as a CIPNP contributor, [10][11][12][13] may be related to the changes in the gene expression at the transcriptional and translational levels in the DRG after chemotherapy drug treatments. [10][11][12][13][14][15][16][17][18][19] Understanding how chemotherapy drugs drive these changes is essential for improving patient care.…”

Peripheral Sensitization

“…Several studies validated the potential utility of blocking Ca v 3.2 T-type calcium channels to reduce nociception. For example, in a rat model of paclitaxel-induced peripheral neuropathy, T-type current amplitudes and density in DRG neurons were increased at day 7 after paclitaxel treatment and this was prevented by pretreatment of the specific Ca v 3.2 T-type calcium channel inhibitor ML218 hydrochloride [93]. Selective inhibition of Ca v 3.2 channels reversed hyperexcitability of peripheral nociceptors and alleviated thermal and mechanical hypersensitivity in rodent model of postsurgical pain [94].…”